research paper outline on cocaine

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Cocaine: An Updated Overview on Chemistry, Detection, Biokinetics, and Pharmacotoxicological Aspects including Abuse Pattern

Rita roque bravo.

1 UCIBIO—Applied Molecular Biosciences Unit, Laboratory of Toxicology, Department of Biological Sciences, Faculty of Pharmacy, University of Porto, 4050-313 Porto, Portugal; tp.pu@020901102pu (R.R.B.); tp.opas@airafmanilorac (A.C.F.); moc.liamg@3042odahcam.aierdna (A.M.B.-d.-C.); tp.pu.ff@omracaneleh (H.C.)

2 Associate Laboratory i4HB—Institute for Health and Bioeconomy, Faculty of Pharmacy, University of Porto, 4050-313 Porto, Portugal

Ana Carolina Faria

Andreia machado brito-da-costa.

3 TOXRUN—Toxicology Research Unit, University Institute of Health Sciences, IUCS-CESPU, Rua Central de Gandra, 1317, 4585-116 Gandra PRD, Portugal

Helena Carmo

Přemysl mladěnka.

4 Department of Pharmacology and Toxicology, Faculty of Pharmacy, Charles University, 500 05 Hradec Králové, Czech Republic; zc.inuc.faf@paknedalm

Diana Dias da Silva

Fernando remião, associated data.

Not applicable.

Cocaine is one of the most consumed stimulants throughout the world, as official sources report. It is a naturally occurring sympathomimetic tropane alkaloid derived from the leaves of Erythroxylon coca , which has been used by South American locals for millennia. Cocaine can usually be found in two forms, cocaine hydrochloride, a white powder, or ‘crack’ cocaine, the free base. While the first is commonly administered by insufflation (‘snorting’) or intravenously, the second is adapted for inhalation (smoking). Cocaine can exert local anaesthetic action by inhibiting voltage-gated sodium channels, thus halting electrical impulse propagation; cocaine also impacts neurotransmission by hindering monoamine reuptake, particularly dopamine, from the synaptic cleft. The excess of available dopamine for postsynaptic activation mediates the pleasurable effects reported by users and contributes to the addictive potential and toxic effects of the drug. Cocaine is metabolised (mostly hepatically) into two main metabolites, ecgonine methyl ester and benzoylecgonine. Other metabolites include, for example, norcocaine and cocaethylene, both displaying pharmacological action, and the last one constituting a biomarker for co-consumption of cocaine with alcohol. This review provides a brief overview of cocaine’s prevalence and patterns of use, its physical-chemical properties and methods for analysis, pharmacokinetics, pharmacodynamics, and multi-level toxicity.

1. Introduction

Cocaine is a naturally occurring sympathomimetic alkaloid from the plant Erythroxylon coca that has been used as a stimulant, by chewing the leaves or brewing teas, in South America for over 5000 years. Cocaine was firstly isolated from the leaves in the mid-1800s and was at that time considered safe and used in toothache drops, nausea pills, energy tonics, and the original ‘Coca-Cola’ beverage [ 1 , 2 ]. Currently, it is found in one of two forms for (ab)use: Cocaine hydrochloride (also known as ‘coke’, ‘blow’ or ‘snow’), a fine white crystalline powder, which is soluble in water and consumed mainly through the intranasal route (‘sniffing’/‘snorting’), orally or intravenously; or as a free base (resulting from reaction of cocaine hydrochloride with ammonium or baking soda), commonly known as ‘crack cocaine’ or simply ’crack’, and typically consumed via inhalation (the solid mass is cracked into ‘rocks’ that are smoked, using glass or makeshift pipes) [ 2 , 3 ].

Cocaine abuse remains a significant public health problem with serious socio-economic consequences worldwide [ 4 ]. According to the most recent World Drug Report, 0.4% of the global population aged 15–64 reported cocaine use in 2019—this corresponds to approximately 20 million people [ 5 ]. The latest edition of the European Monitoring Centre for Drug and Drug Addiction (EMCDDA) Drug Report states that it remains the second most abused substance in the European Union, second only to cannabis [ 6 ]. Furthermore, despite the global COVID-19 pandemic, European authorities have intercepted at seaports growing amounts of cocaine in 2020 [ 5 ]. All the while, case reports detailing the harmful consequences of cocaine use abound [ 7 , 8 , 9 , 10 , 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 , 20 ].

The present review aims to provide an informative overview of the available data on cocaine physicochemical properties and detection methods, pharmacodynamics, pharmacokinetics, effects and toxicity, patterns of abuse as well as its prevalence.

2. Results and Discussion

2.1. natural occurrence and chemical characterisation of erythroxylum coca.

The coca shrub, from which cocaine is extracted, is a plant of the genus Erythroxylum that grows in Central and South America, and it has over 250 identified species, of which the two most important are E. coca and Erythroxylum novogranatense ; however it is from E. coca Lam. var. coca (also referred to as ‘Bolivian’ or ‘Huanuco’ coca) that the majority of cocaine supply is extracted [ 21 , 22 ]. The coca plant presents large, thick, dark green leaves with an elliptical shape and a somewhat sharp apex, and has small red fruits [ 23 ]. Circa 18 different alkaloids can be found in the leaves of the coca plant, such as cinnamoylcocaine, tropacocaine, methylecgonine, benzoylecgonine (BE) and pseudotropine—all of these are significantly less euphoric and less toxic than cocaine ( Figure 1 ) [ 21 , 22 ].

Examples of different alkaloids that can be found in the leaves of the coca plant.

Coca leaves have been traditionally used by the indigenous Andean populations and were/are consumed mostly by chewing; coca leaves as a part of religious occasions and other celebrations by the Inca, as well as employed for medicinal purposes [ 22 ]. It was from the coca leaves that Albert Niemann first isolated cocaine in 1859–1860 [ 21 , 24 ]. A study from one hundred years later found that dry leaves of E. coca var. coca have around 6.3 mg of cocaine per gram of plant material [ 25 ].

2.2. Physicochemical Properties of Cocaine and Analytical Methods for Identification

Cocaine is a tropane alkaloid with weak basic properties. In the free base form, cocaine is unionised and insoluble in aqueous medium, displaying a boiling point of 187 °C; while its ionised hydrochloride salt is readily dissolved in water and presents high stability at very high temperatures, as such, it does not volatilise in the smoke. Table 1 summarises a few of the physical and chemical properties of cocaine [ 26 , 27 ].

Physical and chemical properties of cocaine.

One of the most employed methods of detection for cocaine are immunoassays, a fast method that allows a qualitative presumptive assessment of the drug in the biological matrix tested (e.g., blood, urine). However, as this type of test is subjected to a certain degree of false positive and false negative results, a confirmatory quantitative method should be employed afterwards [ 28 , 29 , 30 ]. Cocaine can be detected in both biological and non-biological matrices through chromatographic methods. A number of reports in the literature describe the detection of cocaine, and its metabolites, in human urine samples [ 31 , 32 , 33 , 34 , 35 ] but also in blood/plasma or hair [ 36 , 37 , 38 ]. A comparison of methodologies between gas chromatography coupled with mass spectrometry (GC-MS) and high-performance liquid chromatography (HPLC) for the analysis of human urine reported similar outcomes [ 39 ]. This allowed laboratories to resort to HPLC for sample examination without such a demanding pre-treatment. Kintz et al. first described a GC-MS method suitable for the simultaneous identification of the ‘crack’-specific metabolite, anhydroecgonine methyl ester (AEME), as well as the parent drug cocaine and additional metabolites (BE, ecgonine methyl ester (EME) and cocaethylene (CE)) in plasma, saliva, urine, sweat and hair samples [ 37 ]. This method was successfully applied to 1 mL samples of urine, saliva and plasma, 50 mg of hair, and sweat extracted from a sweat patch, yielding limits of detection for AEME of 1 ng/mL for the first three matrices (with a linearity range of 5–1500 ng/mL), 0.1 ng/mg for the hair (with a linearity range of 0.2–25 ng/mg) and 0.5 ng/patch (with a linearity range of 2–100 ng/patch). Recently, published research by Fernandez et al. described a validated method for the detection of cocaine and several of its metabolites in 0.5 mL of urine samples, resorting to a simple derivatization step following a solid phase extraction (SPE)—the method achieved low limits of quantification from 2.5 to 10 ng/mL by using GC-MS with electron ionization [ 40 ]. Liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS) was also successfully employed to detect cocaine and BE both in urine and oral fluid [ 41 ], as it was ultra-performance liquid chromatography coupled with tandem mass spectrometry (UPLC-MS/MS) in dried blood samples [ 42 ]. Of note, cocaine in blood/plasma samples may undergo spontaneous and enzymatic hydrolysis to its metabolite BE, if the samples are not treated with a pseudocholinesterase (PChE) inhibitor, such as sodium fluoride [ 24 ]. As such, samples suspected to contain cocaine should be adjusted to pH 5 with acetic acid and refrigerated at 4 °C or frozen to increase stability of the drug, although some degradation occurs along the time, even at −20 °C.

2.3. Legal Status

Since 1961, the International Single Convention on Narcotic Drugs has internationally ruled the recreational use of cocaine as a crime [ 43 ]. In the United States, in 1970, the Comprehensive Drug Abuse Prevention and Control Act established cocaine as a Schedule II drug (a substance that has high abuse potential but has medical use in specific instances), a definition the Drug Enforcement Administration (DEA) has been kept to this day [ 1 , 44 ]. The state of Oregon is the only state where, currently, the possession of cocaine (and other drugs) for personal use is decriminalised for amounts under 2 g [ 45 ]. In the United Kingdom, the Misuse of Drugs Act, enacted in 1971, made it illegal to possess a Class A drug, such as cocaine [ 46 ]. In Europe, cocaine is also generally illegal to possess, sell and transport, as is cultivating coca plant. However, the use of cocaine has a few legal exceptions, such as in Portugal, which has decriminalised the use of major illegal drugs such as cannabis, cocaine and heroin, within the respective threshold amount (also 2 g for cocaine) [ 47 ]. The Netherlands has also implemented a decriminalisation model in 1976, where no legal or administrative sanctions apply in the case of possession of any drug (within the threshold amounts of 0.5 g) [ 48 ]. Concerning the South American countries, Bolivia has a decriminalisation regime for possession and cultivation of coca leaf; while Chile, Colombia, Peru, Uruguay, Paraguay and Argentina have decriminalised the possession of cocaine when it is proved to be for personal use and meets a set threshold amount [ 45 ].

2.4. Prevalence, Patterns of (Ab) Use and Public Health Concerns

The most recent data regarding prevalence of cocaine use shows that, in the European Union, 1.2% of adults between the ages of 15 and 64 years have used cocaine in the past year [ 6 ]. In South America, the percentage of users in 2019 was almost identical (1%) to that observed in Europe for the same age range, while in North America the prevalence increased to 2.1% [ 5 ]. Cocaine is produced mainly in Bolivia, Colombia, and Peru, and from there it is trafficked to intermediate or final destinations. The 2021 edition of the United Nations Office on Drugs and Crime (UNODC) World Drug Report details that 1436 tonnes of cocaine were seized globally in 2019, representing a 9.6% increase when compared to the previous year, and 83% of the seizures took place in the Americas (North, Central and South) [ 5 ]. Likewise, the European Drug Report of 2021 informs of a record 213 tonnes seized in the European Union in 2019, accompanied by an increase in product purity and in the number of individuals seeking specialised treatment for cocaine abuse [ 6 ].

In Europe, the majority of cocaine users seeking treatment are males of a mean age of 35, whose age of first use averages at 23; have a use frequency of 2–6 days per week; and choose sniffing as their form of intake [ 6 ]. Differences in the level of social integration of powder cocaine and ‘crack’ cocaine users are also detailed in the UNODC’s World Drug Report of 2021, albeit these disparities have been fading out in recent years. Users with stable living and work conditions have more sporadic use patterns, consuming cocaine in recreational/nightlife contexts, tending to prefer powdered cocaine, and selecting the intranasal route more often than other ways. On the other hand, users with unstable living and employment conditions tend to select ‘crack’, consume it by inhalation, and have a more frequent use pattern than the first user group [ 49 ]. In fact, ‘crack’ use is more likely to result in chronic and heavy use, as it is often associated with specific social groups (e.g., homeless individuals, sex workers) and systemic violence. Polydrug abuse is a frequent practice by both subsets of cocaine users; however, it is more common in the latter group rather than the former, particularly in conjunction with alcohol and heroin (see section ‘Polydrug Use’) [ 5 , 50 ], but also with nicotine and cannabinoids.

In the United States, according to data gathered since the year 2011, reported by the Substance Abuse and Mental Health Services Administration, cocaine was the most common drug of abuse that resulted in hospital treatment, with 505,224 Emergency Department visits (40.3% of all reported drug-related visits), which translates to a rate of 162 visits per 100,000 individuals [ 51 ]. A specialised 2021 report by the EMCDDA concerning drug-related deaths in Europe stated that there has been a rise in intravenous cocaine hydrochloride use, as well as the (intravenous) use of ‘crack’, which translates to an increase in cocaine-related emergency department visits and deaths, with the number of fatalities increasing year after year [ 52 ].

2.5. Pharmacokinetics

2.5.1. absorption.

As previously mentioned, the form of cocaine the user choses (cocaine salt or the free base), the route of administration and patterns of use vary. By virtue of its hydrophilicity, cocaine hydrochloride is generally consumed by ‘snorting’ [ 53 , 54 ]. ‘Crack’ cocaine is generally the only form of cocaine that is smoked—this is due to the fact that cocaine hydrochloride has an elevated boiling point and does not vaporise at the temperatures of combustion [ 24 ]. These routes that involve the respiratory system tend to be favoured for both forms of cocaine, as they allow for the stimulant to reach the brain circulation in around 6 to 8 s; the inhalation route presents higher peak plasma concentrations that are reached faster when compared to intranasal administration [ 53 , 54 ]. It should be noted that, for the intranasal route, the vasoconstrictive properties of cocaine slow down the drug’s own absorption, causing a 60-min delay of peak plasmatic concentrations [ 54 ]. In terms of bioavailability, the inhalation route has the greatest bioavailability, which surpasses 90%, while the intranasal route has roughly 80% [ 24 ]. Regarding time to peak effects and duration of action, inhalation yields peak stimulation within 1 to 3 min after dosing, the stimulus lasting between 5 and 15 min [ 24 ]. The intranasal route determines a longer effect, ranging between 15 and 30 min [ 53 ].

Intravenous administration of cocaine hydrochloride, by dissolving the powder in an aqueous medium, is also used by consumers [ 53 , 54 ]. Compared with the inhalation and intranasal routes, when cocaine is administered intravenously it takes twice as much time to reach the brain circulation and the peak plasma concentrations are higher and reached faster [ 53 , 54 ]. The bioavailability is closer to the inhalation route [ 24 ]. In 1995, Edward Cone published a study directly comparing the pharmacokinetics of cocaine by inhalation, intranasal and intravenous administration (at 42 mg ‘crack’ cocaine, 32 mg cocaine HCl, and 25 mg cocaine HCl, respectively) using the same test subjects for the different routes (cross-over design), and concluded that the peak plasma concentrations were reached within 5 min through intravenous injection and inhalation, whereas the intranasal route took approximately 50 min [ 55 ].

Cocaine hydrochloride can also be administered orally, or applied to mucous membranes of the mouth, vagina or rectum [ 53 , 54 ]. Oral administration is associated with the lowest bioavailability, presenting a slower and more erratic absorption. The low degree of bioavailability in this case is explained by gastric breakdown and intestinal metabolism [ 4 , 24 ]. This administration route is often associated with a delayed onset of effects, having the longest effect duration (between 1 and 2 h) [ 53 ].

Coca chewing, as an alternative method to consume cocaine, greatly favours sublingual absorption. However, this amounts to smaller doses of the drug when compared to the use of cocaine powder; while the maximum total 24-hour dose of cocaine attained by chewing coca leaves is situated around 200–300 mg (and given that absorption of cocaine will not be 100%, the actual value will certainly be much lower), the average ‘line’ of cocaine hydrochloride has between 20 and 50 mg of the drug, and users will frequently ‘snort’ multiple ‘lines’ in one session. As such, the dose of cocaine administered by users in a recreational session can be significantly greater and the drug whole blood concentration nearly 50 times greater [ 21 ]. Holmstedt et al. reported that chewing powdered coca leaves (7–20 g) containing 17–48 mg of cocaine, originated peak plasma concentrations of 11–139 ng/mL cocaine within 0.4–2 h [ 56 ]. In addition, in two reported cases of sublingual cocaine HCl use (following neutralization with bicarbonate to increase its absorption and to reduce acidity), a slower onset of action, a later peak effect and a longer duration of action were described when compared with an intravenous route [ 57 ]. One other way of consuming coca leaves is through the brewing of teas. Jenkins et al. reported that tea bags containing an average of 4.86 mg (leaves from Bolivia) and 5.11 mg (leaves from Peru) of cocaine per bag, when brewed, produced teas with 4.29 mg and 4.14 mg of cocaine, respectively [ 58 ].

2.5.2. Distribution

Cocaine has a fast disposal to the tissues, with a distribution volume ranging between 1 and 3 L/Kg [ 53 , 59 ]. Cocaine binds to albumin and α1-acid glycoprotein at a rate of around 90% and can be found at the highest concentrations in the brain, spleen, kidney, and lungs, followed by blood, the heart and muscle tissue [ 60 ]. The average half-life of cocaine is between 40 and 90 min, which may vary depending on the route of administration (shorter for intravenous route, longer for insufflation).

2.5.3. Metabolism

Cocaine yields two main metabolites: EME and BE, which may both undergo further hydrolysis into ecgonine (EC). EME is a pharmacologically inactive metabolite formed in plasma and in the liver through the action of PChE and carboxylesterase type 2 (hCE 2 ), respectively. The other major inactive metabolite of cocaine for all routes of administration, BE, can be formed spontaneously at physiological pH [ 53 ] or in the liver by hCE 1 [ 61 , 62 ]. Cocaine may also undergo N -demethylation by cytochrome P450 (CYP) enzyme CYP3A4, generating norcocaine (NCOC), a highly hepatotoxic metabolite capable of crossing the blood–brain barrier (BBB). NCOC accounts for approximately 5% of the absorbed cocaine and was described as a more potent local anaesthetic and more effective at inhibiting noradrenaline uptake by brain synaptosomes than the parent drug [ 24 , 63 ]. BE and EME may undergo further N -demethylation by CYP, producing norbenzoylecgonine (NBE) and norecgonine methyl ester (NEME), respectively [ 62 ]. Additional minor metabolites are meta-hydroxybenzoylecgonine ( m -OH-BE), para-hydroxybenzoylecgonine ( p -OH-BE), meta-hydroxycocaine ( m -OH-COC), ecgonidine (ED) and norecgonidine methyl ester (NEDME) [ 32 , 64 ]. Figure 2 summarises the metabolic pathways of cocaine.

Metabolic pathways of cocaine. Cocaine is mainly metabolized through hydrolysis into benzoylecgonine ( BE ) and ecgonine methyl ester ( EME ), both of which can be further hydrolysed to ecgonine ( EC ). Cocaine may also undergo hydroxylation to yield para-/meta-hydroxycocaine ( p-/m-OH-COC ). Another minor metabolic reaction is the N -demethylation of cocaine to norcocaine ( NCOC ). In the presence of ethanol ( EtOH ), cocaine will undergo transesterification and form cocaethylene ( CE ). AEME , anhydroecgonine methyl ester; CYP450 , cytochrome P450; ED , ecgonidine; EDEE , ecgonidine ethyl ester; EEE , ecgonine ethyl ester; FADM, flavin adenine dinucleotide-containing monooxygenase; hCE 1 , human carboxylesterase type 1; hCE 2 , human carboxylesterase type 2; NBE , norbenzoylecgonine; NCE , norcocaethylene; NCOC-NO • , norcocaine nitroxide; NCOC-NO + , norcocaine nitrosonium; NEDME , norecgonidine methyl ester; NEME , norecgonine methyl ester; N-OH-NCOC , N-hydroxy-norcocaine; (p-/m-)OH-BE , (para-/meta-)hydroxybenzoylecgonine; PChE , pseudocholinesterase.

Of particular relevance, the co-consumption of cocaine and alcohol leads to the formation of CE, a transesterification product of both drugs. Interestingly, it is only produced in vivo via catalysis by hCE 1 [ 65 ]. Harris et al. carried out a study where 10 human subjects received intravenous administrations of cocaine (at 0.3, 0.6 and 1.2 mg/Kg) and a single oral dose of ethanol (at 1 g/Kg), 1 h prior to cocaine intake [ 66 ]. They demonstrated that 17% of the intravenous cocaine dose was converted into CE and that ethanol ingestion decreased urinary levels of BE. Another study, resorting to 10 experienced cocaine users, demonstrated that the percentage of CE originated through oral administration of cocaine was larger than that produced by intravenous administration and inhalation (34 ± 20% vs. 24 ± 11% and 18 ± 11%, respectively) [ 67 ]. CE is an active metabolite that displays pharmacological activity, with a longer average half-life (148 ± 15 min) than cocaine [ 24 ]. Some studies report that it may be more lethal and induce graver acute toxic reactions, also producing a greater increase in heart rate, compared to cocaine [ 67 , 68 ]. CE is used as a biomarker for concomitant use of alcohol and cocaine, which can be detected either in urine to determine recent use, or in hair for chronic exposure [ 69 , 70 ].

Smoking ‘crack’ leads to the formation of another biomarker of exposure, AEME, which is the main product of cocaine’s thermal degradation [ 71 ]. In vitro and in vivo studies show that AEME appears to have effects on the cardiovascular system, by acting as a muscarinic agonist [ 72 ]. Furthermore, neurotoxic effects were also reported for this metabolite [ 71 , 73 ]. AEME can be further hydrolysed by hCE 1 into ED, or into ecgonidine ethyl ester (EDEE) when alcohol is present [ 62 ]. The determination of AEME and ED in different biological fluids has been proposed as a biomarker for ‘crack’ use [ 32 , 60 ]. The application of the analytical method of Kintz et al. [ 37 ] to genuine ‘crack’ users’ samples, allowed identification of AEME in urine (90 samples; concentration range 5–1477 ng/mL), sweat (1 case of overdose; 53 ng/patch), saliva (1 case of overdose; 5–18 ng/mL), hair (32 samples, including foetal hair; concentration range 0.20–21.56 ng/mg), but not in blood. EDEE was further suggested as a possible additional forensic marker for the particular situation of ‘crack’ and ethanol co-consumption [ 34 ].

2.5.4. Excretion

Following metabolism, cocaine and its main metabolites are excreted in urine. EME and BE constitute the major excretion products, irrespective of the route of administration (intravenous, inhalation and intranasal) [ 74 ]. Moreover, approximately 1–3% of cocaine metabolic products excreted in urine are those resulting from N -demethylation to a norecgonine base, such as NBE, in addition to EC [ 24 ]. A subject who drank a cup of the Peruvian (4.14 mg cocaine) or Bolivian teas (4.29 mg cocaine) had, in their urine, a BE concentration of 3940 ng/mL and 4979 ng/mL, 10 and 3.5 h after ingestion, respectively [ 58 ].

Huestis et al. carried out a study resorting to 6 human subjects, where they investigated the urinary excretion pattern of cocaine and of some metabolites (BE, EME, m -OH-BE, p -OH-BE, NBE and EC), following smoking [ 33 ]. This study demonstrated a dose-dependent increase of the Maximum Concentration (C max ) of all analytes, while the parameter Time-to-Maximum (T max ) failed to show direct proportionality. Among the metabolites, EME presented the longest detection time (up to 164 h after a 40 mg dose). Another work by the same group assessed the urinary excretion of ecgonine and five other metabolites (BE, EME, m -OH-BE, p -OH-BE, NBE) following controlled inhalation, oral, intravenous, and intranasal administrations of cocaine, demonstrating that the route of administration does not significantly impact on C max or T max [ 35 ]. On the contrary, Cone et al. performed a study in 6 healthy male volunteers who were administered nearly equipotent doses of cocaine intravenously, through smoking and intranasally, and demonstrated that the elimination half-lives for cocaine and metabolites (BE, EME, NCOC, NBE, m -OH-BE, p -OH-BE, m -OH-COC and para-hydroxycocaine) were typically quicker for inhalation, intermediate for intravenous administration, and were the longest after intranasal administration [ 31 ].

2.6. Pharmacodynamics

Cocaine has different pharmacodynamic properties that make possible its use as a local anaesthetic and as a sympathomimetic stimulant at the central nervous system (CNS).

The anaesthetic action of cocaine is related to its capacity to block voltage-gated sodium channels by stabilizing these channels in an inactive state ( Figure 3 ). The binding of cocaine to the channel’s pore prevents sodium from flowing through it into the cells and thus blocking the depolarization process and the propagation of the electrical impulses [ 1 , 24 , 75 ]. The current medical use is very limited as most countries consider it obsolete. It can still be used as a topical anaesthetic, which might be particularly useful for endoscopic sinus surgery, given its vasoconstrictive effects. There are, however, controversies related to the development of mild morbidities, such as hypertension and tachycardia [ 76 ].

Schematic representation of cocaine’s interaction with voltage-gated sodium channels. Cocaine enters the channels and binds to them by two pathways (hydrophilic and hydrophobic). In the hydrophobic pathway cocaine interacts with the sodium channel at the membrane level, alternatively in hydrophilic pathway, the cocaine is ionized in cytoplasm before the interaction. In both cases, the flow of sodium is blocked, which diminishes the propagation of electrical impulses and causes a local anaesthetic effect.

On the other hand, the psychoactive and sympathomimetic effects of cocaine derive from the blockade of presynaptic transporters responsible for the reuptake of serotonin, noradrenaline, and dopamine. In the case of the latter, the blockade of the presynaptic dopamine transporter (DAT) in the synaptic cleft causes an extracellular increase in dopamine with an overstimulation of the dopaminergic postsynaptic receptors, inducing the euphoric ‘rush’ [ 3 , 53 ]. Further mechanisms of tolerance at this level are responsible by the subsequent drop in the dopamine levels experienced as a dysphoric ‘crash’. A recent meta-analysis showed that chronic cocaine users display a significant reduction in dopamine receptors D 2 and D 3 in the striatum, the caudate and putamen brain regions, as well as a significantly increased availability of DAT all over the striatum [ 77 ].

When cocaine is consumed, an exacerbated dopaminergic activity along the mesocorticolimbic pathways occurs. Neurons from these pathways are located in the ventral tegmental area and project to other brain locations, including the nucleus accumbens [ 78 ]. This could explain why the drug has such an addictive potential, since it is well acknowledged that the nucleus accumbens may have an important role in the rewarding and addictive properties of cocaine and other drugs [ 79 ]. However, it should be mentioned that cocaine’s capacity to increase serotoninergic activity (which may induce seizures) could also contribute to the drug’s addictive potential [ 80 , 81 ]. Figure 4 schematically represents cocaine’s pharmacodynamic action over the monoaminergic system.

Schematic representation of cocaine’s pharmacodynamics at the noradrenergic, serotonergic or dopaminergic synapse. Cocaine acts by blocking the presynaptic transporters of dopamine, serotonin and noradrenaline, preventing the reuptake of the neurotransmitters into the presynaptic terminal, which will cause intense and prolonged stimulation of the postsynaptic receptors. DAT, dopamine transporter; NAT, noradrenaline transporter; SERT , serotonin transporter.

The sympathomimetic properties of cocaine are related to the above-mentioned inhibition of noradrenaline reuptake via noradrenaline transporter (NAT). Because cocaine impedes this reuptake of noradrenaline, and thus increases its availability, there will be an increase in the stimulation of the α- and β-adrenergic receptors, and an augmented adrenergic response—which relates to the marked vasoconstrictive properties of the drug (responsible for a few of the cardiotoxic effects) [ 2 , 82 , 83 ].

Additionally, cocaine also has the capacity to directly target adrenergic, N -methyl- D -aspartate (NMDA), and sigma and kappa opioid receptors. Cocaine affects NMDA receptors, as exposure to the drug modulates (for greater or lesser) receptor subunit expression, alters receptor distribution in the synapse, and influences the crosstalk of the NMDA receptor with the dopaminergic receptor D 1 , in different brain areas, for example, the nucleus accumbens, the ventral tegmental area and the prefrontal cortex [ 84 ]. Lastly, cocaine acts directly over the sigma opioid receptors, binding with greater affinity to the σ 1 receptor than to the σ 2 receptor; agonism at the σ 1 by cocaine partially mediates the hyperlocomotion and seizures, and these receptors are paramount in the establishment of cocaine-induced conditioned place preference in mice [ 53 , 82 , 85 ].

Recently, it has been suggested that the pharmacological action of cocaine over DAT may not be as simple as the sole inhibition of the transporter’s reuptake function, as its behaviour is distinct from other DAT inhibitors of equal or greater potency (with matched capacity for crossing the BBB) and resembles methylphenidate (a norepinephrine-dopamine reuptake inhibitor that also induces the release of synaptic dopamine). As such, it was hypothesised that, similar to amphetamines, cocaine functions as a negative allosteric modulator of DAT (i.e., a DAT ‘inverse agonist’), altering transporter function and reversing transport direction [ 86 ]. However, more research is necessary in this area to further clarify cocaine pharmacodynamics.

2.7. Effects and Toxicity of Cocaine

Cocaine’s LD 50 has been previously determined in a few studies using different animal models: in mice, using an intraperitoneal administration, it was valued at 95.1 mg/Kg [ 1 ]; in rats and dogs using an intravenous route, the values were 17.5 and 21 mg/Kg, respectively [ 53 ].

As previously stated, cocaine targets the CNS, inducing a myriad of physical, psychological, and behavioural effects, which are inherently dependent on the user’s profile, route of administration and dose. While many of the severe pathological effects induced by cocaine could be attributed to a chronic consumption pattern (e.g., neurodegeneration, premature brain aging, depression, blood vessels damage), certain effects, such as tachycardia, hypertension, hyperthermia, diaphoresis, tremors, seizures, mydriasis, headaches, abdominal pain, muscle hyperactivity, haemorrhagic stroke, and multiorgan failure, arise with acute abuse patterns (all too often, even after a single dose). It is important to keep in mind that some cocaine metabolites maintain the ability to cross the BBB, thus contributing to both desirable effects and adverse/toxic reactions reported by users [ 54 ].

2.7.1. Subjective and Physiological Effects

Moderate doses of cocaine induce euphoria, improve alertness and concentration, increase libido, promote a general sensation of well-being, and reduce fatigue and appetite. This is, however, accompanied by insomnia, anxiety, irritability, dysphoria, and impulsive behaviour—the less desirable effects may not be noticed immediately and might increase in frequency with continued drug use. Hallmark physiological effects of cocaine include those of the cardiovascular nature, such as vasoconstriction, tachycardia, and hypertension. Moreover, hyperthermia, diaphoresis, tremors and seizures, mydriasis, headaches, abdominal pain, and muscle hyperactivity may also arise, compromising furthermore the health of the user, and potentially leading to convulsions and/or cardiovascular and respiratory failure [ 83 , 87 , 88 ].

2.7.2. Hyperthermia

The use of cocaine is associated with hyperthermia, which represents one of the most clinically relevant aspects in the drugs’ toxicity as the high body temperature can cause disseminated intravascular coagulation, rhabdomyolysis, and other multi-organ toxic events (‘heat infarct’) [ 89 ]. In fact, cocaine-induced hyperthermia potentiates the risk of user’s death at plasmatic concentrations 10–20 times lower than the average fatal level (~6 mg/L) [ 90 ]. Hyperactivity induced by cocaine leads to a further increase in body temperature; in addition to this, the vasoconstrictive effect of the drug also contributes to a generalised rise in the user’s body temperature, by limiting dermal blood flow and impairing heat dissipation [ 89 , 91 , 92 ]. Activation of dopaminergic and serotoninergic receptors is postulated to contribute towards the hyperthermic effects of cocaine: in a recently published work, the dopaminergic-serotoninergic antipsychotic risperidone, the serotonin 2A receptor antagonists ritanserine and ketanserine, as well as selective dopaminergic antagonist haloperidol and selective D 1 -antagonist SCH23390 were capable of reverting cocaine-induced hyperthermia in Wistar rats intraperitoneally administered with a 30 mg/Kg dose [ 93 ]. The same work additionally demonstrated that the cocaine bolus increased the levels of dopamine, noradrenaline, and serotonin in the hypothalamic thermoregulatory centre of the body, resulting in an impairment of the body temperature set point and an imbalance of heat production and dissipation mechanisms. Furthermore, the frequent co-consumption of alcohol alongside cocaine contributes to dehydration and to a decrease in sweat production, adding to the difficulty in keeping the body’s temperature regulated [ 92 ], which is further aggravated by the consumptions settings (e.g., the drug is often consumed in crowded and hot places associated with the continuous dancing without sufficient rest or rehydration) [ 94 ].

2.7.3. Cardiovascular System

The cardiovascular system is particularly susceptible when it comes to cocaine toxicity. Typical cardiovascular manifestations related to cocaine use are hypertension, tachycardia, and ischemia, but more severe consequences are also frequent. They include acute myocardial infarction, dysrhythmias, aneurysm, accelerated atherosclerosis, cardiomyopathy, decreased left ventricular function and heart failure [ 95 , 96 ].

The literature reports on numerous mechanisms to explain the toxicity of cocaine at the cardiovascular level. Firstly, by interfering with the reuptake of catecholamines and indirectly acting over α- and β-adrenergic receptors, cocaine can induce vasoconstriction of the coronary arteries and markedly increases oxygen demands by speeding up the heart rate and stimulating contractility of the heart. Moreover, the induced increase of endothelin-1 (a vasoconstrictor) and reduction in the production of nitric oxide (a vasodilator) creates an imbalance that favours vasoconstriction [ 96 ]. Consequently, oxygen supply to tissues decreases, with myocardial ischemia and acute myocardial infarction as possible outcome ( Figure 5 ) [ 97 , 98 ].

Influence of cocaine over the cardiovascular system. Cocaine promotes vasoconstriction, through indirect agonism of α-/β-adrenergic receptors, blockade of voltage-gated sodium channels, and increases in endothelin-1 and decrease of nitric oxide. These factors will increase the heart rate and blood pressure, decrease the supply of oxygen to tissues, and ultimately induce dysrhythmias.

As previously mentioned, the drug has the capacity to block the nerve’s voltage-gated sodium channels, thus preventing the conduction of the nervous impulse. This blockage compromises intracardial signal conduction, which results in a prolonged QRS interval, leading to dysrhythmia [ 95 , 96 ]. Additionally, a delay in ventricular depolarization ensues, ultimately causing a decrease of the left ventricular function [ 99 ]. Furthermore, the inhibition of the sodium currents could lead to a distortion of sodium-calcium extra-intracellular exchange with a subsequent decrease in the contractility of cardiomyocytes, due to low calcium cardiomyocyte cytosolic concentrations ( Figure 3 ) [ 75 ].

Generation of reactive oxygen species (ROS) and oxidation products such as aminochromes and free radicals due to catecholamine oxidative metabolism, may also contribute towards cardiotoxicity, as increases in oxidative stress have been linked to apoptosis and cellular malfunction in the heart [ 83 , 100 ].

2.7.4. Respiratory System

The respiratory system is also vulnerable to cocaine’s effects. The existing literature details that inhalation of ‘crack’ induces acute alterations in the respiratory tract, which does not occur when the same dose of the drug is administered intravenously [ 101 ]. Respiratory complications associated to cocaine use are, for example, bronchoconstriction, pneumothorax, pneumomediastinum, pulmonary hemorrhage, non-cardiogenic pulmonary edema, asthma exacerbation, among others [ 82 , 102 , 103 ]. These effects are not only due to a local irritant effect that induces bronchospasm, but also arise from the lungs exposure to cocaine vapor with toxic products deriving from cocaine pyrolysis (e.g., AEME), impurities, adulterants of ‘crack’ (such as caffeine, lidocaine and prilocaine) and combustion products [ 54 , 83 ].

The vasoconstrictive properties of cocaine also affect the respiratory system, particularly at the nasal level for intranasal administration. The cocaine-induced midline destructive lesion occurs because of the continuous vasoconstriction, which the vessels in the nasal lining mucosa are subjected to when users ‘snort’ cocaine [ 3 ]. Prolonged vasoconstriction of the tissue leads to the development of ischemia and, in conjunction with the inflammatory process, ultimately results in the perforation of the nasal septa [ 3 ].

‘Crack lung’ is an acute pulmonary syndrome characteristic of individuals who select smoking as their preferred route of cocaine administration. A typical ‘crack lung’ case will manifest as chest pain, fever, hemoptysis, and hypoxemia associated with acute pulmonary infiltrates [ 54 , 83 ]. Additionally, the lung may have an anthracotic appearance due to the accumulation of carbon in macrophages and coughed-up secretions may be black [ 3 ].

All mechanisms involved in pulmonary alterations are not fully known. However, the pulmonary vasculature presents adrenergic receptors that can be activated by excessive catecholamine activity. While the stimulation of α1-adrenergic receptors is related to contraction of bronchial capillaries, the activation of β2-adrenergic receptors induces bronchial muscle dilation. Of note, non-cardiogenic pulmonary oedema may occur due to damage of the endothelium of pulmonary vessels, which will also increase their permeability [ 83 ].

2.7.5. Renal System

Cocaine can induce acute kidney failure, in particular with a chronic abuse pattern. There are many factors that can instigate cocaine-related kidney injury, involving oxidative stress, renal atherogenesis, changes in glomerular matrix synthesis and local hemodynamic changes [ 83 ]. In addition, rhabdomyolysis, renal infarction, vasculitis, acute interstitial nephritis, thrombotic microangiopathy and malignant hypertension are also often associated causes [ 104 , 105 ]. Each of these events has underlying causes. The development of rhabdomyolysis may occur: (1) in response to hyperthermia with subsequent release of myoglobin that may cause cytotoxicity in the kidney cells causing acute tubular necrosis; (2) as a consequence of the vasoconstrictive effects of the drug—causing muscle ischemia and necrosis; (3) by direct toxicity resulting in skeletal myofibrillar degeneration; the formation of free radicals can also contribute towards this [ 105 ]. Renal infarction is related to increased thromboxane production, platelet aggregation, vasoconstriction, and matrix accumulation [ 83 , 104 ].

A few studies have explored the mechanisms of nephrotoxicity of cocaine at the cellular level. In primary cultured human proximal tubular epithelial cells, cocaine at 5 mM (arguably an extremely high dose not likely to be found in users’ bodies) caused a decrease in cellular viability after 48-h exposure and impacted intracellular adenosine triphosphate (ATP), while 0.5 mM were enough to diminish reduced glutathione (GSH) levels [ 106 ]. Furthermore, this same study demonstrated that cocaine concentrations between 0.1 and 2.5 mM induced an increase in apoptotic cells, and necrotic cells appeared following 5 mM cocaine exposure. An in vivo study, where mice were administered with 60 mg/Kg cocaine via IP per day, reported increases in oxidative stress demonstrated through several findings such as enhanced lipid peroxidation and protein oxidation, decrease in the ratio of reduced/oxidized glutathione, reduced activity of glutathione reductase and peroxidase and increased superoxide dismutase (SOD) activity, as well as changes in the expression of anti- and pro-apoptotic proteins. Histopathological changes such as focal tubular necrosis, hemorrhage and congestion, tubular epithelial vacuolization, and interstitial mononuclear cell infiltration and greater tubulointerstitial injury were observed [ 107 ]. A recent study exploring cysteine metabolism in cocaine self-administering rats found that 185 mg/Kg of cocaine (intravenous) led to an increase in reactive sulfur species in kidneys, which remained significantly high following 10-day abstinence, indicating that cocaine shifted cysteine metabolism to an anaerobic pathway [ 108 ]. The same research group published a previous work in which rats administered 10 mg/Kg of cocaine also shifted cysteine metabolism—a single dose of cocaine led to increased sulfane sulfur whole pool, decreased bound sulfane sulfur and levels of ROS and glutathione-S-transferase, while a repeated dose regime (5 days) induced a decrease in hydrogen sulfide and caused an increase in sulfane sulfur whole pool and lipid peroxidation [ 109 ].

2.7.6. Brain

Cocaine and crack use also have a myriad of repercussions for the brain. The use of these drugs is associated with the occurrence of ischemic and hemorrhagic stroke, the increase in arterial blood pressure being the main culprit, although interferences with normal hematological parameters induced by cocaine may also play a role [ 54 , 89 ]. The occurrence of intracranial and subarachnoid hemorrhages is equally related to the dysregulated increase in blood pressure [ 83 , 110 ]. Due to the increase in blood pressure, as well as the effect of cocaine over serotoninergic and dopaminergic systems, headaches are also common [ 110 ]. Seizures also occur frequently. They arise not only in chronic users but also after a single dose, as cocaine has the capacity to lower seizure threshold, through a chronic low intensity stimulation of the limbic system (kindling) [ 83 , 89 ]. The blockade of noradrenaline by cocaine is also a contributing factor for this increased seizure occurrence. Of note, a recent work determined that cocaine’s kindling effect, which is related to a significant increase in p53 expression in the brain, can be attenuated by p53 genetic depletion [ 111 ].

In vivo and in vitro studies have also shown that cocaine has a neurotoxic potential. Cunha-Oliveira et al. saw that 1 mM of cocaine led to an increase in calcium concentrations and caspase-3 activity, as well as a decrease in mitochondrial membrane potential and ATP in rat cortical neurons exposed for 24 h [ 112 ]. Furthermore, cocaine exposure in models of rat primary hippocampal neurons (1 mM) and mouse primary cortical neurons (1, 10, 100 and 200 μM) increased the expression of autophagy markers LC-3 I and II [ 113 , 114 ]. Nifedipine, a selective blocker of L-type calcium channels, reverted the reduction of cerebral blood flow and tissue oxygenation induced by increases in neuronal calcium currents, in the prefrontal cortex of rats exposed to 1 mg/Kg cocaine [ 115 ]. Increased oxidative stress is another mechanism contributing to cocaine’s neurotoxic effects [ 83 ]; for example, one study investigating cocaine’s effects in rat cerebellum proved that, after 18 days of a 15 mg/Kg administration, the drug increases oxidative stress, by decreasing the activity of glutathione peroxidase (GPx) as well as reducing the reduced to oxidized glutathione ratio, and by increasing the concentration of glutamate, nuclear factor kappa B and CD68, indicating microglial-macrophage activation [ 116 ].

Morphological differences between users and non-users of cocaine have also been investigated. One research delving into the grey matter abnormalities of crack users discovered diminished cortical thickness in the left temporal, orbitofrontal and rostro frontal cortexes and reduced grey matter volume in the right hippocampus and ventral diencephalon [ 117 ]. The left and right nucleus accumbens, a brain area crucial in reward, pleasure, and reinforcement learning processes, has also been proven to have a reduced volume in crack users compared to healthy controls (with no differences in intracranial volume) [ 118 ].

2.7.7. Liver

Cocaine is a well-known hepatotoxic substance. This was first demonstrated in humans in 1987, when the presence of inflammation and periportal necrosis with moderate infiltration of lipids was verified—prior to this, hepatotoxicity was reported solely in animal models. This first case was consistent with earlier and later studies [ 119 , 120 , 121 ]. The hallmark hepatic lesion following cocaine use is hepatocellular necrosis, which was also demonstrated in animal studies [ 83 , 122 ]. Other pathological characteristics of cocaine-induced hepatic injury include increased infiltration with fatty acids, increased blood aspartate aminotransferase levels and pernicious conjugates of reactive cocaine metabolites with cellular macromolecules [ 83 ].

Research has shown a connection between cytochrome P450-mediated cocaine bioactivation and the inhibition of hepatic metabolism, with the drug’s hepatotoxic properties. After the formation of NCOC (also catalyzed by flavin adenine dinucleotide-containing monooxygenases), it is oxidized in the liver, leading to the generation of oxidative metabolites (such as N -hydroxynorcocaine (N-OH-NCOC) and norcocaine nitroxide (NCOC-NO • )). The subsequent oxidation of NCOC-NO • forms a highly reactive cation, norcocaine nitrosonium, which binds in an irreversible manner to cellular proteins and causes cell death. Additionally, NCOC-NO • can also be reduced toN-OH-NCOC, contributing to the formation of free radicals, which will induce oxidative stress and ultimately result in cell death [ 62 , 122 , 123 ].

Cocaine’s ability to interfere with the hepatocytes’ antioxidant system (e.g., SOD, GPx, catalase) and to depress mitochondrial respiration is well-known. A recent work by Mai et al., investigating the protective potential of GPx, exemplifies the cellular damage of cocaine (at 60 and 90 mg/Kg BW) in an in vivo study using mice. There were significant increases in SOD activity, ROS, protein carbonylation and lipid peroxidation, cleaved caspase-3 expression and intramitochondrial calcium, accompanied by a significant decrease in GPx. Examples of histological changes include hemorrhage, congestion, periventricular necrosis and hydropic degeneration [ 124 ]. Notably, enhanced expression of GPx protected the animals from having such severe outcomes, as did the depletion of p53 [ 125 ]. Another study investigating the influence of cocaine and its N-oxidative metabolites over mitochondrial respiration, determined that while cocaine had no influence over respiration states 3 and 4 or respiratory control ratio, the metabolites NCOC, N -hydroxycocaine and NCOC-NO • did impact mitochondrial respiration. It was therefore suggested that these metabolites are in fact responsible for the depletion of intracellular stores of ATP and ensuing cell death [ 126 ]. Furthermore, cocaine can stimulate a cascade of reactions, including caspase-3 activation and cytochrome c release, leading to hepatocellular apoptosis [ 62 ]. The study by Kowalczyk-Pachel et al., where rats self-administered cocaine (to the maximum of 185 mg/Kg), found that, compared to control animals, cocaine decreased the levels of reactive sulfur species, and sulfate levels were also impacted; similar to effects in kidneys, these alterations remained even during the abstinence period, and reflected the impact of cocaine over cysteine metabolism [ 108 ].

One recent study used a metabolomics approach to study the effects of cocaine in the HepG2 hepatoma cell line, after exposure to 200 mM of the drug. Significant alterations to amino acid metabolic pathways (e.g., glycine, serine, threonine, arginine, proline, taurine) were observed, which were most marked in the cases of glutamate, aspartate and alanine [ 127 ]. A previous study, using a more metabolically competent model (Sprague-Dawley rats), analyzed plasma of cocaine-addicted animals (which were given a dose of 10 mg/Kg) and found significant changes to the levels of L-threonine, spermidine, cysteine and n-Propylamine [ 128 ].

2.8. Abuse Potential, Dependence, and Tolerance

The abuse and dependence of cocaine is strongly related to the drug’s capacity to induce the release of dopamine within the mesocorticolimbic circuit (also known as the reward system). As the user continues to consume cocaine, desensitization occurs and so larger doses are necessary to induce stimuli of the same magnitude as before, as well as to minimize withdrawal symptoms [ 129 ]. Cocaine dependence/addiction specifically is not included in the Diagnostics and Statistics Manual of Mental Disorders 5th edition (DSM-5); however, the criteria for stimulant use disorder can be applied. The criteria set for this are: hazardous use, neglected major life roles (e.g., work, parenting) to use, social/interpersonal problems related to use, craving, withdrawal, tolerance, activities given up to use, much time spent using, used larger amounts/longer, physical/psychological problems related to use, and repeated attempts to quit/control use [ 130 ].

Cocaine has been demonstrated to possess an elevated abuse potential, with experimental studies reporting it induces place preference conditioning and readily acts as reinforcer for drug self-administration [ 131 , 132 , 133 , 134 ]. Di Chiara and Imperato tested the effect of cocaine on extracellular dopamine content in two terminal dopaminergic brain areas of rats (the dorsal caudate nucleus and the nucleus accumbens septi), and found that the drug has the capacity to increase dopamine concentrations in both the areas, but especially in the nucleus accumbens, postulating that this ability could be a key element of drugs of abuse [ 135 ]. The dorsal striatum also seems to be involved in cocaine dependence, given that in dependent individuals, the exposure to cocaine cues (a video of subjects consuming ‘crack’) reduced the binding of a radioligand to D2 receptor in this brain region, and greater displacement of the radioligand corresponded with craving. Subjects with the highest degrees of withdrawal and addiction also had the greatest degree of displacement [ 136 ]. Furthermore, Volkow et al. determined that, when compared to non-dependent individuals, cocaine-dependent subjects demonstrate impaired dopamine increases in the dorsal and ventral striatum in response to methylphenidate, which did not differ from that elicited by the placebo. This same study found that the baseline levels of dopaminergic D2 and D3 receptors of the ventral striatum were markedly lower for cocaine abusers, [ 137 ]. Recent advances in the field revealed that the heteromerization of receptors D2-NMDA induced by a cocaine regimen in mice was sustained after an abstinence period, and was associated with behavioral sensitization by the drug [ 138 ]. Furthermore, D2-NDMA heteromeric complexes were demonstrated to be necessary for the development and reinstatement of conditioned place preference induced by cocaine, and inhibiting their formation did not interfere with natural reward processes [ 138 ].

‘Crack’ dependence has been proven to affect working memory: ‘crack’-dependent young women performed similarly to healthy older women, in an inferior manner to younger healthy women (for both groups) [ 139 ]. It seems clear that, while a fuller and more complete picture of the mechanisms that underlie cocaine abuse and dependence is beginning to form, more research is still necessary to better help those struggling with cocaine addiction.

The continued use of cocaine at high doses can lead to the development of tolerance to the cardiovascular and subjective effects reported by users, with cocaine-dependent volunteers who underwent continuous infusions describing a subdued ‘rush’ as time passed, but still feeling the ‘high’ [ 140 ]. In fact, one study approaching long-term cocaine users in Philadelphia and applying the ‘Cocaine History Questionnaire’ found that there was a negative correlation between the amount of cocaine consumed and the sensation of euphoria achieved from the use, while some negative effects (mood swings, paranoia and agitation) associated with the use increased [ 141 ]. Animal studies have also helped to shed some light regarding cocaine tolerance. At the pharmacodynamic level, cocaine self-administration at 1.5 mg/Kg (40 injections per day for five consecutive days) reduced the amount of dopamine and the velocity at which the neurotransmitter is released, as observed in rat brain slices [ 142 ]; this same treatment led to a reduction in effect of several dopamine-noradrenaline uptake blockers (bupropion and nomifensine), but did not affect response to dopaminergic releasers (e.g., methamphetamine and phentermine). Furthermore, the same regimen of cocaine intake led Sprague Dawley rats to increase the number of self-administrations within the first hour of the session over five consecutive sessions, and a tolerance for the locomotor-activating effects of cocaine [ 143 ]. In addition, the self-administration of cocaine caused a reduction in the amount of presynaptic dopamine and its uptake in the nucleus accumbens, and DAT showed a reduced sensitivity to cocaine’s capacity to inhibit dopamine uptake [ 143 ]. The development of tolerance—where the pleasurable effects of the drug are diminished—could lead the individual to feel the need to administer a new bolus (increase the dose and/or intake frequency) while plasma concentrations are still elevated, and thus increasing the likelihood of severe and even possibly fatal toxicity [ 2 , 96 , 144 ].

2.9. Polydrug Use

Adulterants and contaminants are often present in cocaine samples, as indicated by analysis of a pool of samples acquired in the street that averaged 40%. Many of these additives are often included to increase the perceived volume (e.g., talc, sugar or corn starch) or purity of cocaine (e.g., lidocaine, benzocaine, and procaine; caffeine, ephedrine) and may modulate cocaine’s biological effects, including toxicity [ 24 ]. In addition to these substances, polydrug use with both licit and illicit drugs is a common practice among cocaine users [ 2 , 145 , 146 , 147 , 148 ]. Polydrug use constitutes a risk for users for a myriad of reasons, including the potentiation of noxious effects of one drug by the other(s) due to the formation of new (and perhaps more toxic) metabolites and/or the competitive inhibition of metabolizing systems. The choice of the drug to combine with cocaine is often based on the desire to counteract the stimulant (‘upper’) effects of cocaine, so another drug to ‘mellow down’ (a ‘downer’) is frequently selected. Examples of these drugs are alcohol, benzodiazepines (e.g., lorazepam and diazepam), cannabis and opioids (e.g., heroin) [ 149 ]. Two of the most common combinations are cocaine in conjunction with alcohol and opioids/heroin (also known as ‘speedball’) [ 1 , 24 ], and therefore will be given special standout.

2.9.1. Alcohol

A vast majority of cocaine users co-consume it with alcohol, and report that this combination extends the duration of the stimulation and counterbalances the dysphoria subsequent to cocaine use [ 24 ]. Generally, ethanol potentiates both the morbidity and mortality of cocaine [ 150 , 151 ]. The use of cocaine in combination with alcohol is cardiotoxic [ 100 ] and leads to the formation of CE, a pharmacologically active metabolite, as previously mentioned. CE appears to be more selective for DAT than cocaine itself; CE is also capable of inducing an increase in blood pressure and heart rate, and it seems to enhance the effects cocaine has at the level of the CNS [ 152 ]; CE also possesses a longer half-life compared to cocaine and is capable of inhibiting the conversion of cocaine into BE. All these factors contribute to a more durable and thus simultaneously more dangerous stimulation [ 24 , 123 , 152 ]. One recent study attempted to establish a relationship between blood concentrations of cocaine and CE and the severity of clinical manifestations among individuals hospitalised due to cocaine intoxication [ 153 ]. The mean blood concentrations of cocaine and CE were 0.34 ± 0.45 μg/mL and 0.38 ± 0.34 μg/mL, respectively, and while it was not possible to establish a pattern between patient prognosis or their treatment course with the blood concentrations of these substances, the evaluation could be helpful to indicate the severity of the intoxication.

2.9.2. Heroin/Opioids

The co-use of cocaine and heroin is commonly known as ‘speedball’. In this combination, the heroin and cocaine can be administered in a mixture, or the cocaine may be administered immediately before or after heroin [ 146 ]. Both drugs compete for the same enzymes, such as hCE, in the metabolic process, which can prolong their biological effects. The social and health-related consequences of the use of cocaine by opioid-dependents seem to be particularly negative, due to the high frequency of use through the intravenous route and the short half-life of cocaine, which drives up the number of times the user injects. Furthermore, the practice of sharing syringes contributes to the spread of infectious diseases [ 146 ]. The EMCDDA 2021 report on drug-associated deaths in Europe discloses that opioids are the most commonly found drug in cocaine-related deaths [ 52 ]. Despite its capacity to moderately increase cerebral oxygen levels, cocaine does not impact brain hypoxia induced by high doses of heroin [ 154 ]. The motives for this co-use differ in accordance with the user’s goals: to experience the unique effects of the combination of heroin and cocaine (this stimulation is different from either drug alone), to attain greater euphoric effects, or even to be able to reduce heroin use and the withdrawal symptoms [ 146 ].

2.10. Management of Acute Intoxications and Cocaine Use Disorder

2.10.1. treatment of acute intoxication.

Determining the ‘lethal dose’ of cocaine is difficult, due to the high degree of variability associated with the manner in which users react to cocaine intake and metabolize it, due to the variations in the metabolic rate of individuals, potential drug interactions and genetic polymorphisms of metabolizing enzymes [ 96 ]. Furthermore, there seems to be no relation between blood concentrations and toxicity, with plasma cocaine concentrations of 0.029 mg/L found in a patient who died, and few symptoms occurring in an individual with 3.9 mg/L (a concentration previously considered nearly fatal) [ 155 ]. Comparatively, in Swiss-Webster mice, cocaine’s LD50 was estimated at 93 mg/Kg [ 156 ].

A severe cocaine intoxication can result in a fatal outcome if not given the necessary medical treatment [ 157 ]. Given the ever-present risk of cardiorespiratory arrest, monitoring vital signs is extremely important, and cardiorespiratory resuscitation should be performed as soon as necessary. If this fails, the administration of vasopressin is recommended (this therapeutic option has demonstrated greater effectiveness than epinephrine, the first-line drug for cardiac resuscitation) [ 158 , 159 ].

Benzodiazepines are useful in the treatment of subjects who, in addition to showing signs of myocardial ischemia, are anxious, tachycardic or hypertensive. Not only do benzodiazepines exert anxiolytic action, but they also attenuate toxic effects at the cardiovascular and cerebral level, by reducing both blood pressure and cardiac output, which makes them a key first approach in treating cocaine acute intoxications [ 96 , 160 ]. Of note, when the subject rejects benzodiazepines’ oral administration, the intramuscular or intravenous routes are recommended [ 89 , 160 ].

In some cases, even after receiving the administration of oxygen, aspirin, benzodiazepines, and nitroglycerin, the subjects still have chest pain. In these instances, administration of the non-selective α-adrenoceptor antagonist phentolamine is recommended to induce vasodilation, as β-adrenergic blockers are not useful in treating this clinical manifestation [ 2 , 96 ]. While the usefulness of calcium channel antagonists in the treatment of cocaine-related chest pain is not fully known, verapamil is considered effective in reversing the vasoconstriction, and should therefore be administered after the benzodiazepines to ensure some protection for the CNS [ 2 , 161 ].

The use of antipsychotics to manage cocaine intoxications is questionable and potentially dangerous, as they may intensify the risk of cardiac dysrhythmias. Furthermore, in the case of subjects medicated with other drugs, such as tricyclic antidepressants, there is a high risk of potentiation of these drugs’ effects [ 162 ]. For these reasons, the administration of antipsychotics should be considered with caution [ 163 ].

2.10.2. Treatment of Cocaine Addiction/Dependence

Currently, no pharmacological therapies are approved in Europe or the United States for the management of cocaine use disorder (CUD). The most promising pharmacological strategies for treatment of CUD include the use of dopaminergic agonists, such as long-acting amphetamine or drugs capable of influencing glutamatergic and GABAergic systems such as topiramate [ 164 ]. The effectiveness of these treatments was evaluated in preliminary clinical trials. In the Netherlands, 73 patients with treatment-refractory heroin and cocaine dependence reported fewer days of cocaine use (45 days) after 12 weeks of oral administration of sustained-release dexamphetamine (60 mg/day) compared with placebo-treated patients (61 days) [ 165 ]. Regarding the use of glutamatergic/GABAergic medications, 170 cocaine- and alcohol-dependent individuals treated with topiramate (300 mg/day for 13 weeks) were significantly more likely to achieve abstinence from cocaine during the last 3 weeks of treatment [ 166 ]. Modafinil has also shown promising results in treating moderate CUD, as it can weaken cocaine-induced euphoria in humans; however, it is not effective in reducing cocaine intake if the subjects have an alcohol dependence in conjunction with CUD [ 167 ].

Psychosocial approaches remain limited but linger nonetheless as the treatment of choice for CUD, with standard approaches including contingency management and cognitive behavioural therapy. Although no figures on the rates of success of such approaches are available, a recent meta-analysis comparing treatment options for CUD in adults concluded that contingency management therapies were the only treatment positively associated with a reduction in the use of cocaine [ 168 ].

3. Conclusions

Cocaine remains to this day a matter of concern for public health, as it holds strong as the second most used illicit substance in most countries. Whether it is in the form of cocaine powder or ‘crack’ cocaine, its prevalence and use by individuals from all walks of life should be taken seriously as it will not spare users from the inherent toxicity of the drug’s use. This review will hopefully assist the reader in obtaining a global, clear, and more complete picture of what is known about cocaine toxicity, be this in terms of the analytical methods to detect it, the (non-)biological matrices where it can be detected, its pharmacokinetics and pharmacodynamics, the possible pathophysiological repercussions for users, and the existing courses of treatment for cocaine intoxication and CUD.

Acknowledgments

Open Access Educational Materials on Naturally Occurring Molecules ( https://portal.faf.cuni.cz/OEMONOM/EN/ ).

Abbreviations

Key contribution.

Cocaine is a naturally occurring alkaloid that can be extracted from its botanical source and formulated into cocaine hydrochloride or ‘crack cocaine’. Cocaine induces its main psychoactive effects by impeding monoamine reuptake. The drug impacts several organs, such as the heart; brain; liver; kidneys; lungs; and has complex underlying mechanisms of toxicity that are herein described.

Author Contributions

Conceptualization, D.D.d.S. and F.R.; writing—original draft preparation, R.R.B., A.C.F. and A.M.B.-d.-C.; writing—review and editing, H.C., P.M., D.D.d.S. and F.R.; supervision, D.D.d.S. and F.R.; project administration, P.M. and F.R.; funding acquisition, P.M. and F.R. All authors have read and agreed to the published version of the manuscript.

This open-access review paper was supported by the Erasmus+ Programme of the European Union, Key Action 2: Strategic Partnerships, Project no. 2020-1-CZ01-KA203-078218. The authors also acknowledge the support of FCT—Fundação para a Ciência e a Tecnologia, I.P., in the scope of the projects UIDP/04378/2021 and UIDB/04378/2021 of the Research Unit on Applied Molecular Biosciences—UCIBIO; the project LA/P/0140/2021 of the Associate Laboratory Institute for Health and Bioeconomy—i4HBM; and the PhD grants 2020.04493.BD and 2021.04999.BD. This publication is also based upon work from COST Action EUVEN CA19144, supported by COST (European Cooperation in Science and Technology).

Institutional Review Board Statement

Informed consent statement, data availability statement, conflicts of interest.

The authors declare no conflict of interest.

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• Review Article
• Published: 05 February 2018

Environmental, genetic and epigenetic contributions to cocaine addiction

• R. Christopher Pierce 1 ,
• Bruno Fant 1 ,
• Sarah E. Swinford-Jackson 1 ,
• Elizabeth A. Heller 2 ,
• Wade H. Berrettini 1 &
• Mathieu E. Wimmer 3  

Neuropsychopharmacology volume  43 ,  pages 1471–1480 ( 2018 ) Cite this article

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DNA methylation

• Genetic markers

Decades of research on cocaine has produced volumes of data that have answered many important questions about the nature of this highly addictive drug. Sadly, none of this information has translated into the development of effective therapies for the treatment of cocaine addiction. This review endeavors to assess the current state of cocaine research in an attempt to identify novel pathways for therapeutic development. For example, risk of cocaine addiction is highly heritable but genome-wide analyses comparing cocaine-dependent individuals to controls have not resulted in promising targets for drug development. Is this because the genetics of addiction is too complex or because the existing research methodologies are inadequate? Likewise, animal studies have revealed dozens of enduring changes in gene expression following prolonged exposure to cocaine, none of which have translated into therapeutics either because the resulting compounds were ineffective or produced intolerable side-effects. Recently, attention has focused on epigenetic modifications resulting from repeated cocaine intake, some of which appear to be heritable through changes in the germline. While epigenetic changes represent new vistas for therapeutic development, selective manipulation of epigenetic marks is currently challenging even in animals such that translational potential is a distant prospect. This review will reveal that despite the enormous progress made in understanding the molecular and physiological bases of cocaine addiction, there is much that remains a mystery. Continued advances in genetics and molecular biology hold potential for revealing multiple pathways toward the development of treatments for the continuing scourge of cocaine addiction.

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Introduction

The estimated percentage of US residents who are current users of cocaine has remained more or less constant since 2007, which unfortunately translates to a steady state of nearly 2 million Americans who use cocaine at least monthly, or around 0.7% of the population aged 12 or older. It is estimated that over 850,000 Americans meet the DSM-IV criteria for cocaine dependence [ 1 ]. The cocaine abuse epidemic continues to plague each generation of US citizens. Indeed, young adults have the highest percentage of current users and an estimated 29,000 US adolescents are cocaine dependent [ 1 ]. Clearly cocaine addiction is and remains a serious public health issue in the US and worldwide.

Despite decades of intense research effort, there remain no effective treatments for cocaine addiction. This is particularly frustrating since there are at least somewhat effective therapeutic options for opioid, alcohol, and nicotine addiction. A broad array of agents acting in the central nervous system (CNS), some with stronger rationales than others, have been assessed as potential cocaine addiction therapeutics [ 2 , 3 ]. All have failed. Even substitution therapy, that is using an orally administered psychostimulant such as amphetamine or methylphenidate to minimize cocaine withdrawal and craving, has had mixed success [ 4 , 5 , 6 , 7 ]. Moreover, the doses of psychostimulants tested to treat cocaine dependence produce relatively high rates of adverse events including sleeping problems, agitation, irritability and increased heart rate [ 4 ].

It has long been appreciated that environmental and genetic factors influence the propensity to become addicted to drugs of abuse, including cocaine. More recently, changes in epigenetic modulation of gene expression have emerged as another factor contributing to the development of addiction. Some of these epigenetic modifications are heritable, leading to changes in descendent physiology and behavior. This review focuses on environmental, genetic and epigenetic factors (including trans-generational effects) that contribute to risk of cocaine addiction. The emphasis is on the identification of physiological targets based on this research that may serve as platforms for the development of cocaine addiction therapeutics.

Environment

An intuitive prediction would be that easy access to cocaine is more likely to lead to cocaine use escalating to addiction relative to an environment in which cocaine is not present. This common-sense assumption is supported by human twin studies indicating the importance of shared environmental experiences on addiction risk [ 8 , 9 ], which is a factor for addiction to all classes of abused substances rather than being drug specific [ 8 , 9 ]. As an example, exposure to parental cocaine use increases the risk of substance abuse generally but not necessarily cocaine addiction specifically. Known environmental risk factors for addiction include drug availability, childhood abuse, parental attitude regarding drug use, household drug use, peer drug use and lack of participation in social activities; somewhat surprisingly parental supervision/monitoring does not appear to be a risk factor for the initiation of cocaine use [ 10 ].

The two major twin studies of addictions [ 8 , 9 ] reported broadly similar results with one major exception. The earlier study indicated that, unlike other illicit drugs of abuse, most of the genetic effects on heroin addiction were unique to this substance [ 8 ]. Interestingly, this article focused exclusively on twins who served in the military during the Vietnam war era [ 8 ]; those soldiers serving in southeast Asia were exposed to an environment in which heroin was readily available. Subjects in the subsequent study in which heroin-specific heritability was not observed, in contrast, were derived from the Virginia Twin Registry [ 9 ]. Rates of heroin exposure were lower in the Virginia sample and heroin-specific heritability was not observed [ 9 ]. Although this work did not focus on cocaine, it is an excellent example of the general influence of drug availability on drug use and dependence, which skewed the results of the report from Tsuang and colleagues.

Numerous animal studies also have documented the effect of environment on subsequent drug self-administration. These studies primarily focus on environmental enrichment, which consists of group housing in larger enclosures with running wheels, toys, and other features that rodents find appealing. Although this is the accepted nomenclature, there is general acknowledgement in the field that these “enriched” environments are actually closer to a natural environment, whereas the comparison standard environment could be characterized as impoverished [ 11 ]. Numerous studies have examined the effects of rodent enriched environment on stimulant-associated behaviors. An early study showed that environmental enrichment enhanced cocaine self-administration in rats using a two-bottle choice paradigm [ 12 ]. Consistent with this finding, environmental enrichment increased amphetamine-induced conditioned reward in rats [ 13 ]. However, the same group that published this amphetamine finding subsequently reported that environmental enrichment decreased i.v. amphetamine self-administration in male and female rats [ 14 , 15 ]. It also has been shown that environmental enrichment makes rats less sensitive to the discriminative stimulus effects of cocaine and amphetamine [ 16 ] and, in mice, environmental enrichment decreased cocaine conditioned reward [ 17 , 18 ]. On balance, these results indicate that environmental enrichment blunts the reinforcing effects of stimulants. This conclusion fits well within the framework established by the clinical literature, whereby participation in social activities are highly predictive of reduced susceptibility to develop substance use disorder [ 19 ]. These findings were also the basis of the long-held idea that the etiology of addiction emanates from complex interactions between environmental and genetic factors.

Drug dependence is highly familial. Thus, rates of cocaine, opioids, alcohol, marijuana, and nicotine dependence are increased in siblings and relatives of drug dependent individuals [ 20 , 21 ]. Two major population based twin studies examined the major classes of addictive drugs, revealing that genetics is a substantial risk factor in every instance [ 8 , 9 ]. Moreover, as noted above, abuse of drugs in one class is highly correlated with drug dependence in other categories, suggesting a common vulnerability [ 8 ]. In terms of the stimulants, relatively little genetic variance is stimulant specific [ 8 ]. These results indicate that genetic factors predisposing individuals to drug abuse are common across classes of addictive substances [ 9 , 22 ]. Importantly, these conclusions apply to both males and females [ 23 ]. Interestingly, as a side note, the genetic risk factors for abuse of illicit drugs appear to differ from alcohol and nicotine [ 23 ]. The finding that the genetics of addiction are similar across illicit substances indicates that genetic variation in the primary site of action of various drugs of abuse is not likely to contribute substantially to increased risk of substance use disorder [ 22 ].

Drug addiction is among the most heritable of psychiatric disorders, with the heritability of cocaine estimated at 65% for females [ 24 ] and 79% in males [ 25 ]. Although other cocaine heritability estimates are somewhat lower than these values [ 23 , 26 ], genetic influences consistently explain the majority of risk for cocaine addiction [ 27 ]. There is not a clear pattern of Mendelian transmission, suggesting that addiction heritability is likely polygenic [ 28 ]. The monozygotic:dizygotic twin concordance ratios for the inheritance of addiction are low for all drugs of abuse with the exception of cocaine. A ratio of 4:1 for cocaine suggests that multiple alleles functioning in combination may underlie the heritability of cocaine addiction [ 27 ]. Candidate gene-driven approaches have revealed a number of single nucleotide polymorphisms (SNPs) associated with aspects of cocaine addiction [ 29 ] in proximity to genes including dopamine beta hydroxylase [ 30 ], neuron-specific vesicular protein (as known as calcyon) [ 31 ], catechol-O-methyltransferase [ 32 , 33 ], neuronal calcium sensor 1 [ 34 ], l -type calcium channel CACNA1D [ 35 ], cannabinoid receptor 1 [ 36 , 37 ], delta opioid receptor [ 38 , 39 ] tryptophan hydroxylase-2 [ 40 ], and Homer 1 [ 41 ]. Although these findings are compelling, several of these results have not yet been replicated and it is not clear that any of these genes, with the possible exception of delta opioid receptors and l -type calcium channels, represent clearly viable targets for novel drug development.

As noted above, the available evidence indicates that common genetic factors underlie the addiction liability of all illicit drugs of abuse [ 8 , 9 , 22 ]. The missense polymorphism rs16969968:G > A in CHRNA5 , which encodes an amino acid change (D398N) that leads to hypofunctionality of (α4β2) 2 α5 nicotinic acetylcholine receptors (nAChRs) [ 42 ], is associated with risk for nicotine addiction [ 43 , 44 , 45 , 46 ]. This association is likely the most replicated finding in the human psychiatric genetics literature [ 47 ]. It was reasonable, therefore, to posit that rs16969968:G > A might also play a role in cocaine addiction. This hypothesis was tested through a genetic association analysis, which revealed a significant association between the CHRNA5 variant rs16969968 and cocaine addiction, but the direction was opposite that of nicotine addiction [ 48 ]. That is, expression of the A relative to the G allele of rs16969968 in CHRNA5 is a risk factor for nicotine addiction but is protective for cocaine addiction [ 48 , 49 , 50 ]. The physiological basis of this distinction is not completely clear but animal studies show that nAChR antagonists decrease the reinforcing effect of cocaine [ 51 , 52 ], whereas mice with a null mutation of Chrna5 increase their intake of higher doses of nicotine [ 53 ].

To date, only one genome wide association study (GWAS) specifically focused on cocaine dependence has been published [ 54 ]. Using a symptom count-based analytic approach, one genome-wide significant association with cocaine dependence at rs2629540 was identified. This SNP maps to an intron of the FAM53B (family with sequence similarity 53, member B) gene on chromosome 10 [ 55 ]. FAM53B has not been studied extensively, such that its function is not clear. A gene homolog in fish is associated with cell proliferation [ 56 ] and axonal extension during development [ 57 ]. Changes in several other SNPs were identified with near genome-wide significance, which were associated with genes encoding voltage-gated sodium and potassium channels as well as cyclin-dependent kinase 1 [ 55 ]. A systems genetics study that assessed cocaine self-administration in 39 strains of recombinant inbred BDX mice revealed that Fam53b was one of six genes that exhibited midbrain expression levels that mapped to the cocaine self-administration behavioral quantitative trait loci [ 58 ].

It has been difficult to identify common germline alleles that explain even a small amount of the risk (e.g., odds ratios >1.3) for cocaine addiction [ 55 ]. Part of the reason for this is the fact that human GWASs require subject pools numbering in the tens of thousands to achieve appropriate statistical power [ 59 ]. This is a situation where animal studies represent an alternative, cost-effective means to identify alleles associated with relative levels of cocaine use. Unfortunately, few insights have emerged from the preclinical literature, which may be partially due to the fact that self-administration experiments in mice, the non-human species of choice for genetic studies, are methodologically difficult. However, a few studies in mice have addressed this issue. For example, B x D mice strains with poor reversal learning (a measure of inhibitory control over impulsive responding) acquired cocaine self-administration more readily and maintained higher rates of cocaine intake relative to strains with good reversal learning [ 60 ]. These results suggest that heritable differences in inhibitory control affect cocaine self-administration [ 60 ]. Consistent with these findings in rodents, fMRI studies of cocaine-addicted individuals show impaired functional connectivity within and between frontostriatal circuits that is associated with compulsive drug use and trait impulsivity [ 61 ]. Although experiments designed to assess the genetic underpinnings of this phenomena have not been undertaken, there is evidence that B x D strains that display poor reversal learning have decreased D2 dopamine receptor expression in the brain [ 62 ] similar to the observation in human cocaine addicts [ 63 ].

Some rodent studies, although not all [ 64 ], indicate that the initial behavioral response induced by psychostimulants is predictive of subsequent higher levels of self-administration [ 65 ]. Cocaine-induced locomotor activity differed significantly across 45 inbred mouse strains, suggesting a likely genetic basis for these phenotypic differences [ 66 ]. A number of studies in rats have assessed various psychostimulant self-administration behaviors and have reported differences among (primarily inbred) strains [ 67 , 68 , 69 , 70 , 71 ]. Although the individual studies reveal interesting information, they are collectively problematic in that no one study has systematically examined a broad range of rat strains using consistent methodology and focusing on a specific psychostimulant. Thus, the extant literature suggests that there are differences in psychostimulant self-administration among rat strains but it is impossible to state with certainty the extent and magnitude of these disparities.

In a successful example of the use of animal models to investigate the genetic factors underlying cocaine addiction, a missense mutation in the Cyfip2 gene was shown to be the basis for differential acute cocaine locomotor response as well as behavioral sensitization in two substrains of the C57BL/6 model mouse [ 72 ]. C57BL/6 N mice maintained by the NIH for the International Knockout Mouse Consortium (IKMC) project show lower acute response and sensitization to cocaine at several doses than their C57BL/6 J counterparts, which are maintained at the Jackson Laboratory. An intercross quantitative trait loci (QTL) analysis between these two strains for cocaine response yielded a single QTL on chromosome 11. Further sequencing of this QTL revealed a single nonsynonymous SNP leading to a missense S968F mutation in the Cyfip2 gene, causing rapid degradation of the CYFIP2 proteins. Animals exhibiting the mutant allele have lower numbers of striatal medium spiny neuron spines and fewer mESPCs, which could account for their decreased cocaine sensitivity. Knockout of the Cyfip2 mutant allele partially restores cocaine sensitivity, thus strongly implicating Cyfip2 as being at least partially responsible for the differential cocaine behavioral phenotypes [ 72 ]. Thus, exploiting the vast amount of information regarding mouse genetics is a viable path to identifying novel targets for the development of therapeutics for cocaine addiction.

Epigenetics

Even though the identity of the specific genes underlying the heritability of cocaine addiction remains elusive, there is abundant evidence that repeated exposure to cocaine results in pronounced changes in gene expression in various nuclei, particularly in the limbic system. Candidate gene, gene array, and genome-wide approaches have delineated changes in gene expression in the nucleus accumbens, the hub of the limbic system that modulates numerous cocaine-mediated behaviors [ 73 , 74 , 75 , 76 ]. Changes in gene expression are regulated by complex interactions between transcription factors, chromatin, and epigenetic processes. Here, we will focus on epigenetics since the role of transcription factors in addiction have been reviewed in depth elsewhere [ 77 , 78 ]. The identification of epigenetic mechanisms underlying cocaine-induced alterations in gene expression has accelerated in recent years and represents a promising new avenue for therapeutic development.

Although the definition of epigenetics is somewhat contentious (as reviewed in more detail in the next section focusing on cross-generation effects), in the most general sense epigenetics is the study of molecular mechanisms that influence gene transcription without changing the DNA sequence. Examples include DNA methylation and post-translational modifications (PTMs) of histone N-terminal tails, including acetylation and methylation. Epigenetic processes regulate the accessibility of the nearly two meters of DNA packaged into the nucleus of the vast majority of eukaryotic cells. In the nucleus, DNA is so tightly wrapped around octamers of histone proteins (two each of H2A, H2B, H3, and H4) that gene transcription cannot take place unless the DNA is first unwound. Each histone octamer is encircled with around 147 base pairs of DNA, a unit known as the nucleosome, which is somewhat analogous to thread (DNA) wrapped around a spool (histone). All nucleosomes together make up chromatin, which is further organized into chromosomes. The transition between open and closed chromatin regulates access by the transcriptional machinery to neighboring genes, thereby promoting or repressing gene transcription, respectively. Histone PTMs, which are added and removed by writer and eraser proteins, respectively, make up a “histone code”, which is decrypted by reader molecules that recruit activating or repressing complexes and influence the compaction of chromatin.

During development, many genes in a given cell are silenced permanently in the process of cell fate determination. Generally, regions of the genome harboring more highly methylated areas of the genome are less transcriptionally active [ 79 ]. Thus, irrelevant genes in neurons, for example those associated with liver function, can be silenced during development through DNA methylation. Like histone PTMs, DNA methylation can and does change across the lifespan. Indeed, there are numerous examples of environment-mediated changes in DNA methylation and histone epigenetic modifications across the lifespan that alter phenotypes [ 80 , 81 ]. A growing literature focuses on epigenetic changes induced by drugs of abuse, including cocaine. Here, we review particularly salient examples of functionally relevant cocaine-induced histone PTMs or DNA methylation in the nucleus accumbens.

Histone PTMs

Although the list of histone PTMs continues to expand, neuroscience research has focused primarily on acetylation and methylation. Histone acetylation tends to result in open chromatin, which is permissive for gene transcription. The influence of histone methylation is more complex in that transcriptional enhancement or repression depends on the residue modified as well as the number of methyl marks added, which can vary from 1 to 3. An early study examined genome-wide histone acetylation and methylation the day after seven days of experimenter-delivered cocaine in mice. Their results showed that cocaine-induced increases in the expression of genes including Arc, Cart, Cdk5 NFκB , and Period 1 were associated with increased H3 and/or H4 acetylation and either unchanged or decreased H3 methylation [ 82 ]. Increased methylation at H3 following repeated cocaine injections was associated with decreased expression of Kv8.2 , microtubule associated protein 2 and cGMP dependent protein kinase in the nucleus accumbens [ 82 ].

The effect of histone acetylation on cocaine-mediated behaviors has been assessed with histone deacetylase (HDAC) inhibitors, which attenuate the removal of acetyl groups from histone tail lysine residues thereby facilitating gene transcription. Most studies of this sort have focused on environmental conditioning associated with the subjective effects of cocaine in rodents as measured by the conditioned place preference (CPP) paradigm. Systemic administration of a general HDAC inhibitor facilitated the extinction of cocaine-mediated CPP and attenuated the subsequent reinstatement response [ 83 ]. HDACs are subdivided into subclasses. Class II HDACs include HDAC4 and HDAC5, which shuttle between the cytoplasm and nucleus in response to various cell signals. Over-expression of HDAC4 in the nucleus accumbens attenuated cocaine CPP [ 84 ]. Using the cocaine self-administration paradigm, daily HDAC inhibitor treatment into the nucleus accumbens increased the motivation of rats to consume cocaine, an effect that was reversed by virally mediated over-expression of HDAC4 in the accumbens shell [ 85 ]. Cocaine-mediated CPP was enhanced in HDAC5 knockout mice, an effect that was reversed by increasing HDAC5 expression in the nucleus accumbens [ 86 ]. Repeated cocaine dephosphorylates HDAC5 resulting in its accumulation in the nucleus [ 87 ]. Accumbens expression of a mutant form of HDAC5 that cannot be phosphorylated at S279 attenuated the development of cocaine CPP [ 87 ]. There also is evidence that the sirtuins, which are class III HDACs, are involved in cocaine-mediated behavioral plasticity. Thus, repeated cocaine exposure increased H3 acetylation associated with Sirt1 and Sirt2 as well as Sirt1 and Sirt2 catalytic activity in the nucleus accumbens [ 82 ]. Administration of a sirtuin inhibitor directly into the nucleus accumbens attenuated both cocaine CPP and self-administration [ 82 ]. Collectively, these results indicate that cocaine-induced acetylation of histones increases the expression of various genes in the nucleus accumbens [ 88 ], which combine to promote cocaine conditioned reward as well as increase the reinforcing efficacy of cocaine.

In contrast to acetylation, histone methylation can either repress or activate gene transcription depending upon which histone residue is methylated and the number of methyl groups added. Early work on repressive marks modified by repeated cocaine focused on trimethylation of lysine 9 on histone H3 (H3K9me3). Repeated experimenter-delivered cocaine injections persistently reduced H3K9me3 abundance in the nucleus accumbens, which resulted in the unsilencing of LINE-1 retrotransposable elements, among other effects [ 89 ]. These modifications may reflect global changes in genomic stabilization in the nucleus accumbens following repeated cocaine [ 89 ]. A selectively bred rat line that displays persistent cocaine seeking was shown to have increased H3K9me3 association to D2 dopamine receptor (D2DR) promoter and decreased D2DR expression in the nucleus accumbens, with both normalizing following cocaine self-administration [ 90 ]. Repeated cocaine also decreased levels of the repressive mark, H3K9me2, in the nucleus accumbens, which was due to the repression of the lysine dimethyltransferase, G9a [ 91 ]. Viral-mediated reduction in accumbal G9a increased cocaine-mediated CPP and enhanced the expression of a number of genes including several associated with cocaine-mediated dendritic changes in the nucleus accumbens [ 91 ]. Consistent with these results, over-expression of G9a specifically in D1DR-expressing, but not D2DR-containing, accumbens neurons reduced cocaine CPP [ 92 ]. Taken together, these results indicate that changes in both activating and repressing histone methylation in the nucleus accumbens contribute to cocaine-induced neuronal and behavioral plasticity.

A recent genome-wide examination of the effects of repeated cocaine exposure focused on several repressive (H3K9me2, H3K9me3, and H3K27me3) and activating (H3K4me1, H3K4me3, and H3K36me3) marks in the mouse nucleus accumbens. Their results indicated that cocaine produced substantial modifications in each of these marks at numerous genes and non-genic loci [ 74 ]. Somewhat surprisingly, repeated cocaine produced dramatic increases in alternative splicing in the accumbens. Indeed, repeated cocaine only regulated total transcript levels of around 100 genes, whereas over 1000 genes displayed altered splicing [ 74 ]. Further analysis of the neuron-specific splicing factor A2BP1 revealed that repeated cocaine resulted in translocation of A2BP1 to the nucleus where it associated with H3K4me3 and activated several hundred genes (including differential expression and alternative splicing). A functional role of A2BP1 was confirmed in that conditional knockdown of A2BP1 in the nucleus accumbens attenuated cocaine CPP [ 74 ]. Interestingly, H3K4me3 may also play an important role in mediating conditioned reward of other psychostimulants including methamphetamine. For example, viral-mediated knockdown of the H3K4me3 methyltransferase Mll1 in the nucleus accumbens attenuated CPP induced by methamphetamine [ 93 ].

H3K4me3 is in close proximity to H3R2me2a, a repressive mark that counteracts the activating effect of H3K4me3. Protein-R-methyltransferase-6 (PRMT6) is a nuclear enzyme that asymmetrically dimethylates R2 on H3. Recent evidence indicates that H3R2me2a and PRMT6 are decreased in the nucleus accumbens following repeated exposure to cocaine in mice, rats and humans [ 94 ]. Interestingly, these cocaine-induced decreases in accumbens H3R2me2a and PRMT6 occurred selectively in D2DR-containing accumbens output neurons, activation of which suppresses cocaine-mediated behavioral effects. Indeed, over-expression of PRMT6 in D2DR-containing accumbens neurons increased cocaine CPP [ 94 ]. The decrease in accumbens H3R2me2a was associated with increased H3K4me3, which promoted the transcription of a small set of genes including Srcin1 , a Src repressor that dampens the behavioral effects of cocaine [ 94 ].

Given the potentially broad effects of histone PTMs on gene expression, a challenge to the field is to develop methodologies to modulate histone PTMs as selectively as possible. To this end, engineered transcription factors were used to selectively modify chromatin at specific genes. Zinc-finger proteins (ZFPs) or transcription activator-like effectors (TALEs) were designed to recognize and bind to a narrowly defined locus in the genome and deliver specific histone modifications [ 95 ]. A recent study investigating the mechanism linking chromatin dynamics to reward pathology applied ZFP-p65 or ZFP-G9a, targeting histone H3 lysine 9/14 acetylation (H3K9/14ac), a transcriptionally active mark, or H3K9me2, which is associated with transcriptional repression, respectively, to the Fosb gene [ 95 ], the transcriptional regulation of which is strongly implicated in the actions of drugs of abuse [ 91 , 96 ]. These ZFPs were sufficient to modify histones at the targeted region of the Fosb promoter in nucleus accumbens and to control drug-evoked transcriptional and behavioral responses. Intriguingly, Fosb -ZFP-G9a was sufficient to block cocaine-induced Fosb activation via interference with CREB phosphorylation [ 95 ], providing direct evidence of the hierarchy between chromatin modifiers and transcription factors in gene regulation. More recent studies applied cell-type specific epigenetic editing using Fosb -ZFPs expressed in specific neuronal cell types using Cre-dependent HSV expression in mice transgenic for Cre recombinase in one of two types of accumbens principal neurons [ 97 ].

Fosb is just one of thousands of genes under epigenetic control in the context of drug exposure. There is growing evidence that cyclin-dependent kinase 5 (Cdk5) expression in accumbens influences reward-related behaviors [ 98 ]. A recent study found that HSV-mediated expression of ZFP-p65 and ZFP-G9a targeting the Cdk5 locus in NAc were sufficient to bidirectionally regulate Cdk5 gene expression via enrichment of their respective histone modifications at the Cdk5 promoter [ 99 ]. Further, Cdk5 -targeted H3K9/14ac increased cocaine-induced locomotor behavior while Cdk5 -targeted H3K9me2 attenuated cocaine reward. These data are especially compelling given that conventional Cdk5 overexpression or knockdown caused opposite behavioral phenotypes [ 98 , 100 , 101 ], demonstrating the importance of targeted epigenetic remodeling tools to invoke subtler, but physiologically-relevant, changes in gene regulation.

Gene transcription also is profoundly influenced by cytosine modifications including methylation, which occurs mainly at 5′-cytosine-phosphate-guanine-3′ (CpG) sites. Regions of DNA with a high concentration of CpG sites are known as CpG islands, which tend to be concentrated at promoters located near transcription start sites. Methylation of multiple CpGs in an island, via enzymes such as DNA methyltransferases (DNMTs), can result in the stable silencing of gene transcription. In contrast, cytosine methylation within the gene body can promote gene expression [ 102 ]. Interactions with other proteins is necessary to produce DNA conformational changes. For example, methyl CpG binding protein 2 (MeCP2) binds to methylated DNA and recruits additional proteins to form a complex that can result in chromatin compaction, HDAC recruitment and transcription factor repulsion, all of which result in gene silencing. It also has been shown that in certain circumstances MeCP2 recruits the transcription factor CREB and promotes gene expression [ 103 ].

In animal models, cocaine exposure has been shown to induce global hypomethylation in the nucleus accumbens [ 104 ]. Somewhat surprisingly, rodents exposed to cocaine repeatedly also displayed persistently increased expression of methylation-inducing Dnmt3a [ 105 ] and Dnmt3b [ 104 ]. Moreover, the increases in accumbens Dnmt3a following repeated cocaine were selective to D1DR-expressing neurons [ 106 ]. These changes in DNMTs were shown to be functional in that systemic administration of a methyl donor attenuated the development of cocaine-induced behavioral sensitization and cocaine priming-induced reinstatement of cocaine seeking [ 104 ]. Consistent with these results, viral-mediated modulation of accumbens Dnmt3a resulted in opposing effects on cocaine CPP in that upregulation of accumbens Dnmt3a suppressed cocaine CPP, while down-regulation of accumbens Dnmt3a produced the opposite effect [ 105 ]. DNMT3a over-expression also reversed cocaine-induced increases in spine density in the accumbens [ 105 ].

The reinstatement of cue-induced cocaine seeking behavior, an animal model of craving, progressively increases, or “incubates”, over the first several weeks following the cessation of cocaine self-administration [ 107 ]. This is particularly interesting given that 1 day following cocaine self-administration Dnmt3a was decreased but Dnmt3a expression increased after 28 days of forced cocaine abstinence [ 105 ]. Consistent with this observation, the extent of DNA methylation in the nucleus accumbens was enhanced following 30 days of cocaine abstinence relative to the first day. These cocaine-induced increases in accumbens DNA methylation were at least partly negatively correlated with gene expression [ 108 ]. Intra-accumbens administration of a DNMT inhibitor attenuated the incubation of cocaine reinstatement, whereas a methyl donor enhanced cocaine cue-mediated reinstatement of drug seeking [ 108 ]. Administration of the DNMT inhibitor prior to the reinstatement session influenced a number of genes including demethylation of the estrogen receptor 1 ( Esr1 ) promoter and activation of mRNA expression. A subsequent experiment revealed that an ESR1 agonist attenuated the incubation of cocaine reinstatement [ 108 ]. This work demonstrates how examination of patterns of DNA methylation following cocaine self-administration can lead to the identification of novel potential therapeutic targets for cocaine addiction.

The transcriptional silencing effect of MeCP2 is mediated, in part, by its phosphorylation at Ser421, which is enhanced by exposure to amphetamine in a D2DR-dependent manner [ 109 ]. MeCP2 also appears to play a role in the conditioned rewarding effect of amphetamine in that viral-mediated knockdown of MeCP2 in the nucleus accumbens enhanced amphetamine-induced CPP, whereas over-expression of accumbens MeCP2 produced the opposite effect [ 109 ]. Cocaine self-administration increases MeCP2 expression in the dorsal striatum and viral-mediated knockdown of MeCP2 in this brain region reduces cocaine self-administration [ 110 ]. Decreased dorsal striatal MeCP2 also potentiates the ability of cocaine to increase expression of the short non-coding RNA, miR-212 [ 110 ]. Viral-mediated increases in striatal miR-212 decreases the expression of BDNF, a neurotrophin that promotes enhanced cocaine intake [ 110 ]. It is important to note that microRNA-induced RNA silencing is a post-translational process that regulates gene expression and is, therefore, epigenetic [ 111 ]. While we do not include it in the scope of this review, an emerging literature focuses on the role of microRNAs in cocaine-induced neuronal and behavioral plasticity [ 112 , 113 ].

Oxidation of 5-methylcytosine to products including 5-hydroxymethylcytosine (5hmC) has been identified as an intermediate step to DNA demethylation, but recent evidence suggests 5hmC itself may function as an epigenetic mark to regulate gene expression. Repeated administration of cocaine increased 5hmC at gene body and intergenic regions associated with enhancer elements and alternative splicing sites [ 114 ]. Enrichment of 5hmC was associated with upregulation of genes involved in synaptic plasticity and implicated in addiction including Adcy1 and Nrtk2 , a receptor for BDNF. Moreover, increased 5hmC concomitant with higher Adcy1 and Nrtk2 gene expression persisted for one month following cocaine administration [ 114 ]. Interestingly, repeated cocaine delivery also downregulated expression of ten-eleven translocation 1 ( Tet1 ), an enzyme known to catalyze the conversion of 5-methylcytosine to 5hmC [ 114 ]. Virally-mediated knockdown of Tet1 increased cocaine CPP and, counterintuitively, mirrored the effect of cocaine to enrich 5hmC in the same subset of genes [ 114 ]. This study highlights the importance of locus in determining the impact of epigenetic marks like methylation or hydroxymethylation as well as the effect of factors known to regulate their expression. Elucidating the role of novel epigenetic marks like 5hmC in the cellular and behavioral response to cocaine may be critical to fully understanding the epigenetic landscape of addiction.

Cross-generational epigenetics

One of the more interesting aspects of epigenetic regulation is the influence of parental life experiences on subsequent generations through stable epigenetic alterations in the germline. Unfortunately, the terminology in the general area of heritable epigenetics is not always standardized, often confusing and sometimes controversial. The very definition of the term epigenetics has been a source of debate, with each faction of related fields favoring one version over the other. The word was coined by Waddington [ 115 ] and literally means “above” or in “addition to” genetics. The standard definition of an epigenetic trait is a stably heritable phenotype resulting from changes in a chromosome without alterations in the DNA sequence [ 116 ] that are transmitted either to progeny through germline modifications or to daughter cells directly. In contrast, we have used the term epigenetics to describe all functional changes in DNA methylation and histone PTMs in neurons, the vast majority of which are post-mitotic. Semantics aside, this section focuses on influences of exposure to cocaine on the behavior and physiology of descendants, with an emphasis on studies with an epigenetic mechanistic component.

In this context, another important distinction to make is the one between intergenerational and transgenerational effects of drug exposure. When the effects of environmental perturbations such as drug exposure are transmitted across generations and direct effects on fetuses or gametes cannot be ruled out, this is known as intergenerational heritability. Fetal alcohol syndrome is an example of intergenerational inheritance. A pregnant woman who drinks alcohol heavily puts her baby at risk of CNS damage among other signs and symptoms. Thus, maternal behavior can influence the phenotype of the offspring, which may or may not result from changes in the baby’s DNA sequence or epigenetic marks. If the fetus is female, three generations are nested one inside of the other: the mother, the fetus and the primary oocytes that will ultimately produce the grandchildren. Paternal environmental insults also can produce intergenerational effects by influencing the sperm epigenome, which can reorient early developmental programming and impact progeny. Therefore, any changes in biology or behavior in the children (maternal and paternal lineage) or grandchildren (maternal lineage) could completely or partly result from direct exposure to the environmental insult making it difficult to tease apart the mechanisms underlying physiological changes in descendants.

In contrast, if transmission of the phenotype remains stable across multiple generations in the absence of fetus or oocyte exposure to the environmental perturbation, that is an example of transgenerational inheritance. Several instances of transgenerational heritability in humans have been reported. For example, around the turn of the twentieth century, the remote community of Överkalix, Sweden routinely experienced periods of food abundance and famine. Retrospective studies indicated that if the paternal grandfather experienced a period of food excess during the slow growth phase of adolescence, his grandsons had increased risk of diabetes-related mortality [ 117 , 118 ]. The mechanism underlying this transgenerational phenomenon may be conserved germline epigenetic marks. This is a controversial concept since, traditionally, it was thought that all epigenetic marks were erased soon after fertilization. Moreover, sperm histones are replaced by protamines, which allows for higher chromatin compaction. Following fertilization, paternal protamines are replaced by histones of maternal origin [ 119 ]. Despite these steps to erase any current epigenetic information early on in development, it is now clear that some parental DNA methylation is conserved [ 120 ] and a limited number of paternal histones and their epigenetic marks are retained and influence development following fertilization [ 121 ]. Findings like these provide mechanistic bases for transgenerational epigenetic inheritance. What follows are several recent examples of heritable effects of exposure to cocaine. This section will focus on paternal manipulations, which circumvent some of the potentially confounding factors associated with studies of maternal cocaine exposure including changes in maternal behaviors. In rodent models, the sole contribution of sires to their progeny comes from the genetic and epigenetic material in their sperm. Hence studies of paternal cocaine exposure provide an opportunity to systematically delineate the possible modes of transmission from fathers to their descendants. This is by no means a comprehensive survey of this literature. Recent reviews provide a broader examination of the cross-generational influences of exposure to drugs of abuse [ 122 , 123 , 124 ].

In order to assess the effects of paternal cocaine exposure on offspring behavior, investigators have used different rodent models of addiction. Generally, male rodents were either allowed to self-administer cocaine or received non-contingent injections of cocaine for over two months, which covers the duration of spermatogenesis in mice and rats. During the latter stages of spermatogenesis, chromatin becomes highly compacted obviating modifications in epigenetic marks. Thus, there is a relatively short window of sensitivity when cocaine can plausibly interact with the epigenetic and transcriptional machineries in the germline to reprogram heritable epigenetic marks that can later influence neurodevelopment. Following the cocaine regimen, sires are mated with drug naïve females and the resulting first generation (F1) progeny were behaviorally assessed as adults. As the number of paternal cocaine exposure studies has grown, so too has the variability in the observed phenotypes on the next generation of animals. The unequivocal conclusions that can be reached from this research is that paternal cocaine exposure affects several behavioral modalities including propensity to consume drugs of abuse, reward processing, measures of mood and anxiety as well as cognitive processes [ 125 , 126 , 127 , 128 , 129 , 130 , 131 ].

Most publications have reported that paternal cocaine exposure has a protective effect on addiction-like behavior using either drug self-administration [ 126 , 131 ] or conditioned place preference [ 132 ]. In two of these examples, the effects were specific to male offspring and cocaine-reward [ 126 , 131 ]. In sharp contrast, a multigenerational mouse model suggested that paternal cocaine affected both non-drug (sucrose) and cocaine-rewards in both male and female offspring [ 132 ]. These discrepancies highlight the need to assess both male and female progeny in these studies and underscore the complexity of how information can be carried across generations. One possibility is that the species used in the studies (mice vs. rat) can lead to divergent results, which is not surprising and consistent with a large body of research on this subject. The mechanisms underlying the sex specificity of many of the transgenerational effects of cocaine remain unclear and represent a major challenge for the field.

The jury is still out regarding changes in anxiety-like behavior, with reports noting an increase in anxiety-like behavior in the progeny of cocaine-exposed sires [ 127 , 132 ] versus two other articles observing no change in baseline anxiety [ 130 , 131 ]. Given the fact that anxiety-like behavior is notoriously difficult to assess in rodents and the added variability in methodologies to generate the F1 generation, these discrepancies are perhaps not surprising. Similarly, about half of the publications reports deficits in cognitive capacities in progeny of cocaine-exposed sires [ 128 , 129 ], while others observed no impact of paternal cocaine on memory in male or female offspring [ 130 , 132 ].

Only a few articles have explored the neuroepigenetic mechanisms underlying the behavioral phenotypes derived from paternal cocaine exposure. The consensus is that BDNF mRNA and protein expression in the PFC of drug naïve, adult cocaine-sired rats are increased [ 126 , 131 ] and that these changes are functionally relevant for reducing the reinforcing efficacy of cocaine in the male F1 cocaine-sired progeny [ 126 ]. Overexpression of BDNF was likely driven by increased acetylation of histone H3 in the PFC. Intriguingly, the association of acetylated histone H3 with Bdnf promoters was also increased in the sperm of sires that self-administered cocaine [ 126 ]. These findings indicated that paternal cocaine self-administration reprograms the germline resulting in enhanced BDNF expression in the mPFC, which blunted the reinforcing efficacy of cocaine only in the male progeny. Another potential mode of transmission between sires and progeny is through methylation of DNA in sperm [ 131 ]. Some of the differences in DNA methylation elicited by paternal cocaine taking were maintained from the sires to the F1 generation, particularly near the transcription start sites of genes. These stable alterations to the germline epigenome could explain the transgenerational reduction in cocaine self-administration reported in both F1 and F2 male offspring [ 131 ].

The mode of drug delivery in sires (non contingent vs. self-administration) may have a profound influence on the behavioral endpoints in the progeny. In fact, a recent study suggests that the motivational state of the sires for earning infusions of cocaine is a critical component for conferring a cocaine-resistance phenotype in the F1 generation and for reprogramming of the germline methylome by cocaine [ 131 ]. These kinds of studies begin to indirectly address the elusive question of how exactly cocaine reprograms the germline. There are cocaine binding sites in the testes, but it remains unclear whether reprogramming occurs as a consequence of direct interactions in the testes and/or through a combination of direct and indirect mechanisms that also involve cocaine’s actions on the brain and/or endocrine systems. To date, no study has directly tackled this fascinating question. It is notable that the number of studies examining the impact of paternal cocaine exposure beyond the first generation offspring is extremely sparse [ 131 ].

Although the study of potential cross-generational effects of addictive drugs remains an emerging field, several intriguing effects have been delineated. It is particularly interesting that most of the influences of ancestral exposure to drugs of abuse are sex specific. As reviewed above, there is evidence that drugs of abuse can modify epigenetic marks in the germline. Sex-specific influences on progeny could result from changes in mitochondrial genes or genes found on the Y chromosome. Genomic imprinting also is a plausible mechanism that thus far remains unexplored. The impact of sex hormones during development also may be suppressed or enhanced due to complex epigenetic effects leading to changes in behavior. There are well-characterized effects of female sex hormones on drug self-administration behavior [ 133 ]. Testosterone also has profound influences during development leading to a number of sexually dimorphic characteristics. For example, the bed nucleus of the stria terminalis, which plays an important role in addiction-related behaviors, is larger in males than females [ 134 ]. A major challenge going forward is to characterize drug-induced epigenetic changes in the germline that might plausibly influence physiology and behavior across generations. This is a significant hurdle for the entire field of transgenerational epigenetics, which will likely require the development of new methods to accurately trace the influence of a specific germline modification through embryogenesis and development.

Conclusions

According to PubMed, over 39,500 scientific papers focusing on cocaine have been published to date. Although we have reviewed only a small fraction of these articles here, the question remains: how can we know so much about the physiological effects of cocaine and still have no therapeutics for cocaine addiction? Fortunately, the situation is not completely bleak. There are some promising developments that could lead to therapeutics based on limiting the access of cocaine to the brain via a cocaine vaccine [ 135 , 136 , 137 ] or cocaine hydrolase [ 138 , 139 ]. Initial studies also suggest that transcranial magnetic stimulation may produce prolonged reduction of cocaine intake in human addicts [ 140 , 141 ]. Preclinical [ 142 , 143 , 144 , 145 , 146 ] as well as clinical case studies [ 147 , 148 ] suggest that deep brain stimulation of the nucleus accumbens may be effective in the treatment of refractory cocaine dependence. We must acknowledge, however, that these advances are based on immunology, pharmacology and systems neuroscience rather than genetics or epigenetics.

The single genome wide analysis of genes associated with cocaine dependence failed to generate promising novel targets for cocaine therapeutic development [ 55 ]. This could be due to the fact that the heritability of cocaine addiction is highly polygenic and/or because the study was under-powered. It is now clear that GWASs focusing on psychiatric disorders require subject pools numbering in the tens of thousands. Human studies assessing specific genes in addiction have produced numerous positive effects, but the targets are derived almost exclusively from the animal literature. Given the staggering cost of human GWASs, animal genetic experiments are a more cost-effective and potentially equally valid alternative [ 72 ]. Cross-generational animal studies are a potential source of targets for cocaine addiction drug development. Multiple studies have shown that cocaine reinforcement is blunted in the male offspring of cocaine-exposed sires (Vassoler et al. 2013; [ 131 , 132 ]). A comprehensive survey of the changes in gene expression and epigenetic marks in these cocaine-resistant rats has yet to be assessed and is critically important.

Therapeutics targeting epigenetic mechanisms are becoming more common, particularly in the treatment of various cancers. Valproate is an anticonvulsant that also used to treat bipolar disorder and migraine. The specific mechanism of action responsible for its therapeutic effects is unclear but valproate acts as an HDAC inhibitor, among other effects [ 149 ]. As reviewed above, animal studies indicate that HDAC inhibitors attenuate cocaine-induced conditioned place preference [ 84 , 86 , 87 ] as well as cocaine self-administration [ 85 ]. Valproate is the subject of ongoing cocaine addiction clinical trials although published work has been mixed in terms of reducing cocaine use [ 150 , 151 ] or craving [ 152 ]. A limitation of drugs such as valproate is a lack of specificity generally including its epigenetic influences. The latest epigenetic editing tools such as ZFPs and TALEs, which target specific genomic locations of epigenetic marks, have effectively modulated cocaine-mediated behaviors in animal studies [ 95 , 99 ] and are likely to produce fewer side-effects than non-specific compounds such as general HDAC inhibitors. Exploiting these new developments in epigenetics in a clinical setting is clearly a distant prospect, but these kinds of advances hold the promise for new therapeutic developments for cocaine addiction, which are desperately needed.

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This work was supported by the following NIH grants: DA39308 (MEW), DA44250 (EAH) DA40972 (WHB), DA33641 and DA40837 (RCP).

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R. Christopher Pierce, Bruno Fant, Sarah E. Swinford-Jackson & Wade H. Berrettini

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Pierce, R.C., Fant, B., Swinford-Jackson, S.E. et al. Environmental, genetic and epigenetic contributions to cocaine addiction. Neuropsychopharmacol 43 , 1471–1480 (2018). https://doi.org/10.1038/s41386-018-0008-x

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DOI : https://doi.org/10.1038/s41386-018-0008-x

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Cocaine DrugFacts

What is cocaine.

Cocaine is a powerfully addictive stimulant drug made from the leaves of the coca plant native to South America. Although healthcare providers can use it for valid medical purposes, such as local anesthesia for some surgeries, recreational cocaine use is illegal. As a street drug, cocaine looks like a fine, white, crystal powder. Street dealers often mix it with things like cornstarch, talcum powder, or flour to increase profits. They may also mix it with other drugs such as the stimulant amphetamine, or synthetic opioids, including fentanyl. Adding synthetic opioids to cocaine is especially risky when people using cocaine don’t realize it contains this dangerous additive. Increasing numbers of overdose deaths among cocaine users might be related to this tampered cocaine.

How do people use cocaine?

People snort cocaine powder through the nose, or they rub it into their gums. Others dissolve the powder and inject it into the bloodstream. Some people inject a combination of cocaine and heroin, called a Speedball.

Another popular method of use is to smoke cocaine that has been processed to make a rock crystal (also called "freebase cocaine"). The crystal is heated to produce vapors that are inhaled into the lungs. This form of cocaine is called Crack, which refers to the crackling sound of the rock as it's heated. Some people also smoke Crack by sprinkling it on marijuana or tobacco, and smoke it like a cigarette.

People who use cocaine often take it in binges—taking the drug repeatedly within a short time, at increasingly higher doses—to maintain their high.

How does cocaine affect the brain?

• Cocaine increases levels of the natural chemical messenger dopamine in brain circuits related to the control of movement and reward.

Normally, dopamine recycles back into the cell that released it, shutting off the signal between nerve cells. However, cocaine prevents dopamine from being recycled, causing large amounts to build up in the space between two nerve cells, stopping their normal communication. This flood of dopamine in the brain’s reward circuit strongly reinforces drug-taking behaviors. With continued drug use, the reward circuit may adapt, becoming less sensitive to the drug. As a result, people take stronger and more frequent doses in an attempt to feel the same high, and to obtain relief from withdrawal.

Short-Term Effects

Short-term health effects of cocaine include:

• extreme happiness and energy
• mental alertness
• hypersensitivity to sight, sound, and touch
• irritability
• paranoia— extreme and unreasonable distrust of others

Some people find that cocaine helps them perform simple physical and mental tasks more quickly, although others experience the opposite effect. Large amounts of cocaine can lead to bizarre, unpredictable, and violent behavior.

Cocaine's effects appear almost immediately and disappear within a few minutes to an hour. How long the effects last and how intense they are depend on the method of use. Injecting or smoking cocaine produces a quicker and stronger but shorter-lasting high than snorting. The high from snorting cocaine may last 15 to 30 minutes. The high from smoking may last 5 to 10 minutes.

What are the other health effects of cocaine use?

Other health effects of cocaine use include:

• constricted blood vessels
• dilated pupils
• raised body temperature and blood pressure
• fast or irregular heartbeat
• tremors and muscle twitches
• restlessness

Long-Term Effects

Some long-term health effects of cocaine depend on the method of use and include the following:

• snorting: loss of smell, nosebleeds, frequent runny nose, and problems with swallowing
• smoking: cough, asthma, respiratory distress, and higher risk of infections like pneumonia
• consuming by mouth: severe bowel decay from reduced blood flow
• needle injection: higher risk for contracting HIV, hepatitis C, and other bloodborne diseases, skin or soft tissue infections, as well as scarring or collapsed veins

However, even people involved with non-needle cocaine use place themselves at a risk for HIV because cocaine impairs judgment, which can lead to risky sexual behavior with infected partners (see "Cocaine, HIV, and Hepatitis" textbox).

Cocaine, HIV, and Hepatitis

Other long-term effects of cocaine use include being malnourished, because cocaine decreases appetite, and movement disorders, including Parkinson’s disease, which may occur after many years of use. In addition, people report irritability and restlessness from cocaine binges, and some also experience severe paranoia, in which they lose touch with reality and have auditory hallucinations —hearing noises that aren't real.

Can a person overdose on cocaine?

Yes, a person can overdose on cocaine. An overdose occurs when a person uses enough of a drug to produce serious adverse effects, life-threatening symptoms, or death. An overdose can be intentional or unintentional.

Death from overdose can occur on the first use of cocaine or unexpectedly thereafter. Many people who use cocaine also drink alcohol at the same time, which is particularly risky and can lead to overdose. Others mix cocaine with heroin, another dangerous—and deadly—combination.

Some of the most frequent and severe health consequences of overdose are irregular heart rhythm, heart attacks, seizures, and strokes. Other symptoms of cocaine overdose include difficulty breathing, high blood pressure, high body temperature, hallucinations, and extreme agitation or anxiety.

How can a cocaine overdose be treated?

There is no specific medication that can reverse a cocaine overdose. Management involves supportive care and depends on the symptoms present. For instance, because cocaine overdose often leads to a heart attack, stroke, or seizure, first responders and emergency room doctors try to treat the overdose by treating these conditions, with the intent of:

• restoring blood flow to the heart (heart attack)
• restoring oxygen-rich blood supply to the affected part of the brain (stroke)
• stopping the seizure

How does cocaine use lead to addiction?

As with other drugs, repeated use of cocaine can cause long-term changes in the brain’s reward circuit and other brain systems, which may lead to addiction. The reward circuit eventually adapts to the extra dopamine caused by the drug, becoming steadily less sensitive to it. As a result, people take stronger and more frequent doses to feel the same high they did initially and to obtain relief from withdrawal.

Withdrawal symptoms include:

• increased appetite
• unpleasant dreams and insomnia
• slowed thinking

How can people get treatment for cocaine addiction?

Behavioral therapy may be used to treat cocaine addiction. Examples include:

• cognitive-behavioral therapy
• contingency management or motivational incentives—providing rewards to patients who remain substance free
• therapeutic communities—drug-free residences in which people in recovery from substance use disorders help each other to understand and change their behaviors
• community based recovery groups
• While there are no FDA-approved medications for the treatment of cocaine use disorder, NIDA supports a robust medication development pipeline in this area.

Points to Remember

• Cocaine is a powerfully addictive stimulant drug made from the leaves of the coca plant native to South America.
• Street dealers often mix it with things like cornstarch, talcum powder, or flour to increase profits.
• They may also mix it with other drugs such as the stimulant amphetamine or the synthetic opioid fentanyl.
• People snort cocaine powder through the nose or rub it into their gums. Others dissolve the powder and inject it into the bloodstream, or inject a combination of cocaine and heroin, called a Speedball. Another popular method of use is to smoke Crack cocaine.
• A person can overdose on cocaine, which can lead to death.
• Behavioral therapy may be used to treat cocaine addiction.

For more information about cocaine, visit our:

• Cocaine webpage
• Commonly Used Drug Charts webpage

For more information about drug use and HIV/AIDS, visit our webpage, Drug Use and Viral Infections (HIV, Hepatitis) .

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Substance Use Disorders

Clinical research on cocaine.

Approximately 1.4 million Americans 12 years or older have a stimulant use disorder, with the majority having a cocaine use disorder. Although cocaine use has gone down in the past decade, cocaine addiction remains a persistent problem that remains recalcitrant to treatment. While there are various psychosocial interventions that have shown some clinical utility, there remains the need for effective pharmacologic and novel psychosocial approaches targeting stimulant use disorders. Our Division has been at the forefront of investigating the neurobiology underlying treatment response, pharmacologic interventions, immunotherapies, and computerized technologies for the treatment of cocaine use disorders in patients with and without additional psychiatric comorbidities. Our Division is particularly focused on a translational approach to treatment development. The effect of novel medications on cocaine self-administration are examined under controlled laboratory conditions and those that look promising are further studied in a treatment setting. Currently, we are evaluating combined pharmacotherapies and a computer assisted behavioral and pharmacologic intervention for cocaine use disorder. Further, we continue to investigate how alterations in dopamine transmission (as determined by neuroimaging techniques) relates to treatment response.

Faculty conducting clinical cocaine research:

• Kenneth Carpenter, PhD
• Elias Dakwar, MD
• Frances Levin, MD
• John Mariani, MD
• Diana Martinez, MD
• Wilfred Raby, MD

Laboratory Research on Cocaine

Research on the behavioral pharmacology of cocaine in human drug users is aimed at better understanding the antecedents and consequences of cocaine use. The current main focus is on how cocaine use affects decision-making. Cocaine users repeatedly make maladaptive decisions to continue using cocaine. These decisions are based on each individual’s past behavioral history of drug use, the physiological and neural effects of long-term drug use, their cognitive abilities, and the perceived short vs. long-term consequences of each decision. A better understanding of decision-making processes will provide information about how to tailor treatments to address specific behavioral and cognitive processes that can be improved to help individuals decide to not use drug.

Faculty conducting laboratory cocaine research:

• Elias Dakwar MD
• Suzette Evans, PhD
• Richard Foltin, PhD
• Margaret Haney, PhD
• Robert Vorel, MD, PhD

UC cocaine research disrupts traditional theory

Study emphasizes pharmacological explanation behind why people use the drug.

For more than 50 years, the conventional wisdom in the field of research in cocaine use has been that people take cocaine based on the theory of the drug providing positive reinforcement to the user.

New research out of the University of Cincinnati shows that a pharmacological equation disproves that concept and could spark a major shift in that field of research.

The study was published in the journal Scientific Reports .

Andrew Norman, PhD, professor in the Department of Pharmacology and Systems Physiology at the UC College of Medicine and corresponding author of the study, says that in 1968, the first paper on cocaine self-administration was published showing that it was an example of operant behavior theory, a method of learning that uses rewards and punishment to modify behavior. It suggests that certain things like food or drugs motivate the behavior according to schedules of reinforcement.

“The theory maintains that the more reinforcing a drug is, the faster users take it,” Norman says. “Interestingly, animals that self-administer cocaine slow down intake as doses get higher, implying that higher doses are less reinforcing, which doesn’t make sense. But at really lower unit doses, the actual number of presses the animal does goes up as you increase the dose.”

Luis Tron Esqueda, student researcher in the UC College of Medicine

It was believed, Norman says, this means that low cocaine doses produce positive reinforcing effects, but high doses produce more rate-limiting effects, so low doses were believed to provide more useful information. He says his research shows that this is not correct.

“We came along in 1998 and formulated this pharmacological-based theory that explained injection intervals, or the time between injections of cocaine” says Norman.

Norman took a different approach by developing an equation with that can be measured quantitatively and it accurately describes the behavior. He says there is none of the elements of “reinforcement” or “wanting” or “liking” that is the basis of the traditional research approach to cocaine self-administration. The study was published in 1999 in Brain Research.

Norman says the recently-published research was led by two students working in his lab, Jhanvi Desai and Luis Tron Esqueda, who suggested they conduct a new experiment building on an explanation of cocaine self-administration that Norman had published in 2001.

Desai and Tron Esqueda revived the research in 2022 after talking with Norman and expressing a desire to design an experiment to test Norman’s original idea.

Jhanvi Desai, student researcher in the Norman lab in the UC College of Medicine

“When Dr. Norman was discussing his background, he was explaining to us his previous idea, it was more of an experimental design, and we asked him if he had tested that,” Tron Esqueda says. When Norman said he had not tested that, Tron Esqueda and Desai saw an opportunity.

“When Dr. Norman had initially explained to us the paradigm it was very clear,” Desai says. “We predicted what the data should look like, and when we did the experiments and analyzed the data, we found exactly what we were expecting. The only surprising thing was that it was so obvious to us, so I can’t understand why other researchers don’t see it the way we do.”

A subsequent study Desai conducted which just got published shows another phenomenon. When access to cocaine is terminated rats continue lever pressing for a while, but after the number of presses to get a dose was increased there was a huge increase in the rate of lever pressing for no cocaine, which had never been recognized before.

“The students were right. It was important to do it,” Norman says. “The surprising finding was the huge increase in lever pressing behavior when the animals go on these high schedules of lever pressing which we’d never used before, so I’d never seen that. I believe that is why the field was misled for more than 50 years. They interpreted this as the reinforcing effects of cocaine. Jhanvi’s paper shows that it’s the schedule, not the cocaine that does the ‘reinforcing.’ It’s been misinterpreted all those decades."

UC is a top research university and there is really good mentorship, good resources and the research we do here is top level.

“As pharmacologists, we know that drug effects are related to concentration,” adds Norman. “The first question a pharmacologist asks is what is the response that is being induced by this drug. In our case, it’s the lever pressing behavior. Our big innovation with this latest research is that we calculated what the concentration of cocaine is in the body every second of the session. What we show is that there is a range of cocaine concentrations that drive the behavior.”

“We are hoping that it will open up everyone else’s eyes to what’s actually been seen for multiple decades now,” Tron Esqueda says. “It will hopefully start shifting the current idea on how to study cocaine addiction into a newer idea.”

“I think it’s going to be a paradigm shift of how to approach preclinical cocaine self-administration studies in animal models,” Desai says. “This will hopefully be an example of how to design experiments and interpret data appropriately so that the knowledge can be applied to cocaine use in humans.”

Desai, who was an undergraduate neuroscience student in the UC College of Arts & Sciences when she joined the Norman lab, says this project has shifted her career goal from being a medical docdtor to enrolling in the combined research-directed MD/PhD program in the UC College of Medicine.

 “This is my first research experience,” she says. “UC is a top research university and there is really good mentorship, good resources and the research we do here is top level.”

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For more than 50 years, the conventional wisdom in the field of cocaine self-administration research has been that people take cocaine based on the theory of the drug providing positive reinforcement to the user. New research out of UC shows that a pharmacological equation disproves that concept and could spark a major shift in that field of research.

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Research challenges traditional theory of mechanisms of cocaine self-administration

by Bill Bangert, University of Cincinnati

More information: Jhanvi N. Desai et al, The ascending limb of the cocaine unit dose–response function in rats as an experimental artifact, Scientific Reports (2023). DOI: 10.1038/s41598-023-43506-y Journal information: Scientific Reports

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The Morning

America’s other drug problem.

The crisis increasingly involves drugs besides opioids.

By German Lopez

When political leaders talk about America’s current drug crisis, they are typically referring to opioids like painkillers, heroin and fentanyl. And when they have passed laws to deal with the problem in the past decade, those policies have centered on opioids. They have, for example, focused on boosting access to medications that treat only opioid addiction or reverse only opioid overdoses.

That narrow focus has neglected the rise of other drugs, as my colleague Jan Hoffman reports today . In the last five years, overdose deaths involving methamphetamine have tripled. Those linked to cocaine have doubled. People addicted to opioids increasingly use other substances, including meth, cocaine and prescription medications like Valium and Xanax.

Meth use, in particular, has also made it difficult to stabilize patients and keep them in treatment for any drug, as one addiction doctor explained to Jan:

The paranoia and hallucinations caused by meth disorient them, he said. One patient threw himself in a river to escape nonexistent people who were chasing him. Others insisted that dumpsters were talking to them, that color-coded cars were sending them messages.

These types of problems are why experts have long urged policymakers to take a comprehensive approach to drug addiction. More support for opioid addiction medications is important, but so is funding underused treatments that address meth and cocaine addiction (such as paying people to stop using drugs ).

Revolving door

The changing nature of the drug crisis was predictable, because drug use is historically faddish. In the 1970s, America struggled with heroin. In the ’80s, it was cocaine. In the ’90s and early 2000s, meth. Since then, opioids have taken off.

One explanation for this is what’s known as generational forgetting : Young people tend to avoid the drug that is currently causing a crisis. But because they don’t have personal experiences with the drugs that caused harm before their time, they are more willing to use those substances.

Different drugs can also complement each other, and so their popularity can rise simultaneously. Opioids, for example, often cause users to doze off, which can leave those who live on the streets vulnerable to theft or rape. So opioid users sometimes use stimulants, like meth and cocaine, to stay awake. And if they receive treatment for opioid addiction, they may continue using stimulants.

All of this leads to a revolving door for different kinds of drug crises. It has happened before, and it is happening again.

Read Jan’s full story , which includes details about the rise of a kind of meth so pure that some are calling it “super meth.”

Related: Arizona rehab centers provided shoddy or nonexistent addiction treatment to Native Americans that cost the state as much as $1 billion, officials say.

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“It’s only going to get worse”: As fighting rages on in Gaza, Israeli military raids and violent protests are on the rise in the West Bank .

More than 100,000 people marched in cities across France to support Jewish citizens and protest antisemitism.

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Here are columns by David French on abortion and Jamelle Bouie on Republican culture wars .

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Less than charming: Meet the people whose job is to find and euthanize invasive pythons in Florida.

Treasure: Billions in gold and jewels sank in 1708. Colombia’s government wants them found .

A morning listen: One Tennessee county arrested and illegally jailed children. Listen to the four-part story, “ The Kids of Rutherford County ,” from “Serial.”

Metropolitan Diary: “ I have a strange request .”

Lives Lived: Karen Davis was a fierce animal-rights activist who led campaigns to recognize the dignity of chickens, turkeys and other farmyard fowl. She died at 79 .

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Around the N.F.L.: The Houston Texans upset the Cincinnati Bengals, 30-27, thanks to the rookie phenom C.J. Stroud. And the Detroit Lions outlasted the Los Angeles Chargers in a 41-38 shootout. Here are takeaways .

Superstar: Caitlin Clark became Iowa’s all-time points leader in women’s basketball during the Hawkeyes’ win over Northern Iowa.

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Recent history: Most of Netflix’s “The Crown” has felt quaint and far away in its dramatization of the reign of Queen Elizabeth II. But the latest season — the first part of which arrives on Thursday — will tackle one of the most analyzed eras in recent British history: the final days of Diana, Princess of Wales , and the fallout from her death.

The show’s depiction of the period has already set off conversations about accuracy and sensitivity . “People who lived through Diana’s death feel a sense of ownership over that history,” Annie Sulzberger, the head of research for the show, said.

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Programs teaching children how to be YouTubers are popping up everywhere, The Washington Post reports.

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Make-ahead recipes are key to a stress-free meal. This year Melissa Clark created a truly delicious make-ahead turkey that travels well, too.

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Skip takeout and cook your own delicious sesame chicken .

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Cocaine Research Paper

Summary of andean cocaine by paul gootenberg.

Introduction Written and published in 2008 by Paul Gootenberg, History professor and Latin American studies at University of New York at Stony Brook, “Andean Cocaine: The Making of a Global drug” retraces the pivotal stages of the illicit cocaine trafficking, starting from the boundless coca fields in Latin America to the chemistry laboratories in Europe up until the streets of U.S. cities. The aim of this book review is to provide the reader with a short but detailed insight of what is the main content of the book, by paying particular attention to its structure, objectivity and style. Scope & Organisation Adopting a meticulous chronological approach, Gootenberg describes the infamous and complex untold history of cocaine, analysing and

Drugs In The 1970's

Illicit drugs are drugs that have been considered illegal, such as, heroin, cocaine, and marijuana, in some locations (Levinthal, 2016). Legislating drugs began around 1900. In essence, the government let society govern the use and opinions of drugs. Most of society looked down upon the nonmedical use of drugs.

Opioid Crisis Essay

The opioid crisis in the United States has been a problem since the late 1970’s. The use of cocaine started increasing by the early 80’s. In this time, many considered cocaine to be the drug for the famous. At one point, it was called “the champagne of drugs,” which made people feel like they were living like the rich and the high-line people. All celebrities and famous athletes would take cocaine, therefore, all their fans followed in their footsteps.

Cocaine In The 1880's

Drug enforcement agencies throughout North America spend over 40 billion tax dollars annually on their government funded war on drugs. The DEA currently classifies cocaine as an addictive and dangerous, schedule-two drug. Around the 1880’s, however, cocaine was celebrated in the United States for its “magical, medicinal purposes” (New Ulm Weekly Review). The miracle medicine of the late 19th century, cocaine, is derived from the coca plant native to South America, more specifically, the Andes Mountains. South Americans chewed the coca leaves for thousands of years to counter the nauseating effects of living in thin mountain-air environments and to stimulate their heart and breathing rates for hunting purposes.

Cocaine Decline

History: Cocaine is the oldest and most dangerous drug. In ancient times they would chew on coca leaves to get their hearts racing and speed up their breathing. In the 1880s it became popularized and used in the medical field. They used it as a cure to depression and sexual impotence.

Drugs In The 1800s

Humans have used drugs of one sort or another for thousands of years. Wine was used at least from the time of the early Egyptians; narcotics from 4000 B.C.; and medicinal use of marijuana has been dated to 2737 B.C. in China. But not until the 19th cent. A.D. were the active substances in drugs extracted. There followed a time when some of these newly discovered substances—morphine, laudanum, cocaine—were completely unregulated and prescribed freely by physicians for a wide variety of ailments.

Cocaine Opposing Viewpoints In Context

To access this database you will need your DC Public Library library card or Onecard PIN number. “Cocaine.” Opposing Viewpoints in Context. N.p.: n.p., n.d. N. pag.

Institutional Affiliation: Cocaine

Cocaine Name: Institutional Affiliation: Cocaine History Cocaine is obtained from the Erythroxylon coca plant. Although the powdered form of cocaine was not used until the twentieth century, coca leaves had been previously used as a stimulant during the 16th century. The use of coca leaves (cocaine) dates back to 3,000 BC by the ancient Incas in the Andreas Mountain (Narconon, 2017).

Cocaine In Texas

Freud, however, would use Cocaine regularly and even recommended it to his patients, without knowing of its addictive nature and the possibility of it being capable of killing anyone through overdosing. In the period ranging between 1850 to 1900, the dangers of Cocaine started to be discovered and in 1903, Coca-Cola removed it from its drink. Moving forward to the late 1970’s, Cocaine was known as the wealthy man’s drug since it was very costly. Onward, from the late 1980’s to the late 2010’s, Cocaine rose to be the second most smuggled drug in the globe and is the source of many crime and

Cocaine Experiment

Purpose: Cocaine seems to be the most addictive drug out of all the abusive drugs. This concept is demonstrated in an extreme experiment on lab animals were willingly consumed the drug after it was purposely given to them. The article argues that abnormalities in human brain, before being exposed to cocaine, could be associated with a higher exposure to addicting drugs. In this experiment the authors decided to study how it is possible that some malfunctioning parts of the brain could encourage the dopamine system to promote cocaine self administration. The researchers used tomography to examine the brains of different participants with different drug use history; some of the participants ranged from being acute users to chronic users.

Methamphetamine Vs Meth Essay

This stimulant drug is derived from the coca plant, and when used as a

Crack Cocaine Informative Speech

Also cocaine is known as a stimulant drug and it is a schedule II narcotic. Cocaine is also known to be called C, coke, white dust and snow. Cocaine has 2 main forms that it can be used in. The forms that cocaine can be used in are, crack cocaine and cocaine hydrochloride (powder cocaine). Crack cocaine can be known as rock or crack on the streets as well.

Why Was Cocaine Invented

Cocaine comes from high mountain ranges in South America. Cocaine is grown from the cocoa plant and was originally not used as a drug to get high on. The coca leaves were used as a stimulant for people who lived there. Later Not until 1859 by German chemist, Albert Niemann, Cocaine was removed from the Coca leaves. At first in the 1880s, Cocaine was used for medical purposes.

Teen Drug Abuse Research Paper

With this large number of overdoses, it is an important consequence of drug use and abuse to

History of Drug Abuse and its Effects on the Body

The reason people love the way cocaine feels is because of its feeling of euphoria the increase of energy levels and elevated mood of self esteem. In accordance to drugabuse.com short term side effects of using cocaine are, Paranoia, Dizziness, Muscle twitches, Dilated pupils, High body temperature, loss of sexual appetite. In addition the long term effects of cocaine include rectal functions from eating cocaine, could end up getting HIV from using the same needle again or with another person, Heart attacks, Constant nose bleeds, Strokes and even Seizures. Alternative names used among the streets are, Coke, Toot, Base, Powder, Candy, White, Flake, Basa, Rail, Snow, Bump, Yeyo and the list goes on.

More about Cocaine Research Paper

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• Psychoactive drug
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Free Research Paper About Cocaine

Type of paper: Research Paper

Topic: Drugs , Abuse , Cocaine , Violence , Bullying , Sexual Abuse , Drug Abuse , Abuser

Words: 1100

Published: 01/26/2021

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Drug abuse is one of the burning issues of the world society in the modern times. The youth of the world is threatened by the jeopardy of drug abuse, and there has to be immediacy in action on the part of the state machineries and governments to curb the abuse of the harmful substances. Cocaine is one of the most dangerous forms of drug that has found its way to impede the future of the younger generations of the society. Cocaine is a very powerful addictive stimulant drug that gets made from the leaves of the plant named coca. This is a native plant of South America. The drug goes on to produce a short-term euphoria, talkativeness, energy. Moreover, it has certain potentially dangerous physical effects that raise the blood pressure and heart rate of the individual who consumes the substance. Cocaine comes in the form of a powder or crystal. This powdered form of the dug gets mixed with various substances like talcum powder, corn starch and some other drugs like procaine or amphetamines. This drug was originally developed before to serve as a painkiller. Cocaine is consumed by sniffing as the powdered form gets absorbed into the bloodstream of the person via the nasal tissues. Apart from this, the drug can be rubbed into the gums or ingested. Apart from this, for the purpose of more rapid consumption into the body, the substance abusers also take injections, although that enhances the chances of being overdosed. Another form of consumption by abusers is by inhalation of cocaine as a vapor or smoke- something that is of lesser risk that injections. There are many ill-effects of using the drug. Firstly, any abuser would show specific symptoms of cocaine abuse that are related to his mood. The person would feel anxious and restless. Such an abuser would have a perspective that he or she is superior to others. Moreover, there would be feelings of euphoria as well as panic. Irritation and fearfulness are other telltale signs of cocaine abuse. The behavioral symptoms of such an abuser would include extreme talkativeness and a show of enhanced energy level. The person might indulge in borrowing or stealing money for sufficing his or her needs to obtain the drug from the peddler. Apart from showing signs of bizarre and erratic behavior, the person can become violent at times. Moreover, abandonment of actions once he or she has enjoyed is another behavioral sign of drug abuse. All of this gets supplemented by the impediment of his or her risky and reckless behavior. While the above-mentioned ones are the mental symptoms of cocaine abuse, there are other physical symptoms that can be the telltale sign of drug abuse in this form. A person who is involved in cocaine consumption would have a diminished need for sleep. However, there would be an enhancement in the need for sleep after consumption of the drug. Moreover, the person would face headaches and muscle twitches. An abuser of cocaine would suffer from malnutrition. Cocaine also works massively to give rise to abnormal rhythms of the heart of the abuser. Constriction of the blood vessels is also caused by the abuse of this drug. The nose of the abuser would run chronically, apart from bleeding from the nose. Nasal perforation and hoarseness are other two common symptoms of cocaine consumption. The body temperature of the person involved would rise considerably. The appetite of the person would be hampered by the drug abuse- something that adds to the problems. The pupils of such a person would remain dilated. Sexual dysfunction is another telltale sign of such abuse. The bowel of the human body gets afflicted by gangrene due to drug abuse of cocaine. Apart from this, the person’s risk of getting affected by hepatitis and various other blood borne pathogens gets enhanced. Cravings and tremors are also very common in such persons. The psychological symptoms of cocaine abuse involve psychosis, intense paranoia, hallucination, break from reality, rationalization of use of drug, inability to exert good judgment, lack of motivation, and so on. On the other hand, if a person is facing withdrawal symptoms of cocaine abuse, the individual would have specific symptoms. Such a person would go into depression. He or she would also show signs of anxiety. There would be chills and body aches, apart from the shakiness and tremors. The person would feel immense pain during the withdrawal, and he or she would not be able to feel pleasure at all. Exhaustion is another symptom that is very common during withdrawals from cocaine. The person would not be able to concentrate, and there would be an intense craving for the drug. Unfortunately, there are no such FDA-approved medicines that can be used to treat the people who are involved in cocaine abuse. However, the various behavioral treatments that have been used to treat the abusers are quite effective for soothing the abusers. Contingency management or motivational incentives are found to be effective for treatment. Cognitive-behavioral therapy is also used to treat the patients. The youngsters are more prone to getting addicted to cocaine. The teenagers or people in their early twenties are more prone to drug abuse of this kind. Drug abuse can be seen as a result of peer pressure or the will to explore in the youngsters. There has to be proper awareness among one and all about the negative effects of drug abuse. While cocaine can be seen to be very euphoric and useful by the abusers, they have to be conditioned to understand the cons of such abuses. Legal steps cannot be the only way to prevent drug abuse. There has to be holistic understanding of the problem that threatens the society and the citizens. Only then the problem can be countered to the utmost degree.

Cocaine Abuse & Addiction Signs, Effects & Symptoms. In Acadania Addication Center. Retrieved from http://www.acadianaaddiction.com/addiction/cocaine/symptoms-signs-effects DrugFacts: Cocaine. In National Institute on Drug Abuse. Retrieved from http://www.drugabuse.gov/publications/drugfacts/cocaine What is Cocaine? In Foundation for a Drug-free World. Retrieved from http://www.drugfreeworld.org/drugfacts/cocaine.html What treatments are effective for cocaine abusers? In National Institute on Drug Abuse. Retrieved from http://www.drugabuse.gov/publications/research-reports/cocaine/what-treatments-are-effective-cocaine-abusers

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Outline For Cocaine Research Paper

Show More Looking for the Fix for the Fix Cocaine also referred to as blow or coke as been a problem in the world for the past half century. The white power has been starting wars and ruining lives faster than any other drug. Before cocaine was used in the form of a powder, it was chewed in its leaf form. The plant cocaine comes from is called coca. It was used by Ancient Incas approximately 3000 BC they would chew it to get their hearts racing during rituals. The actual drug cocaine was first extracted from the plant in 1859 German chemist Albert Niemann. However it did not become popular among the medical community until 1880. The first person to support cocaine as a tonic cure for depressions and sexual impotence was Austrian psychoanalyst Sigmund …show more content… The energizing effects that coca-cola gave people due to the added cocaine lead to its quick growth in popularity. After this cocaine’s dangers became more evident as it became more popular. In 1903 coca-cola was pressured to take the cocaine out of the popular soft drink. Only two years after the drug was cut from Coca-Cola, it became popular to snort the drug in powder form. In 1912 over 5,000 cocaine related deaths were accounted for, and in 1922 the drug was officially banned in America. In the 1970’s cocaine emerged again as a popular drug for businessmen, they raved about how helped them stay up and provided a large amount of energy. Shortly after the reamergance of Cocaine Colombian drug traffickers began setting up an elaborate system to smuggle Cocaine into America. The smuggling of amazing amounts of cocaine leads to the peak of the cocaine business around the 1990’s. However the cocaine industry has peaked, and it is beginning to be overcome by other major drugs in the united states, for example heroin . Heroin is becoming a country wide epidemic. Heroin is cheap, and very addictive, it is almost impossible to be cured of a heroin addiction. We can look at how the world dealt with cocaine to help us fight heroin in a more effective

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Cocaine is one of the oldest and the most dangerous drug that migrate through the United States. Studies have proven to show that coca leaves were used to get the heart racing and to speed up the breathing pattern. Coca was also used for religious purposes during ceremonies. There were also rumors saying coca was the cure for depression. In the eighteen hundreds coca was know as the “magical substance”.…

Theories Of Reinforcement Theory

Often, media fails to display appropriate results of drug usage, other than the expected “high”. The media also glorified not only cocaine, but all narcotic trafficking to a level of prestige. Interestingly enough, as stated above, the media in a symbolic way, showed both positive and negative reinforcement with the involvement of cocaine trafficking. Unfortunately, in American Gangster, the movie failed to show the negative effects of cocaine manufacturing processing, usage, and trafficking. In order for responsible consumption of cocaine, one must conduct research of potency of cocaine, how it is manufactured, the difference between powdered and crack cocaine, and it’s processing speed in the body depending on the type of consumption.…

Related Topics

• Single Convention on Narcotic Drugs

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Everything you need to know about cocaine

Cocaine is a highly addictive and a naturally occurring anesthetic, or pain blocker.

It is extracted from the leaves of Erythroxylon coca (E. coca) , also known as the coca scrub, a plant that grows in the Andean highlands of South America.

It is the most powerful stimulant of natural origin. When Coca-Cola was first produced, it contained 9 milligrams of cocaine per glass. In 1903, this ingredient was removed, but the drink still has coca flavoring.

In 1884 , Karl Koller, an Austrian ophthalmologist, first used cocaine as an anesthetic during eye surgery. It was a popular and widely used anesthetic until the early 20th century.

As the medical profession came to realize that cocaine was addictive, safer anesthetics were developed. Cocaine, in its basic form, is no longer routinely used.

However, cocaine and its derivative, crack cocaine, are widely used as illegal recreational drugs.

Fast facts on cocaine

Here are some key points about cocaine. More detail is in the main article.

• Cocaine can be smoked, injected, or snorted
• Crack is a type of cocaine
• Long-term cocaine use increases the risk of heart disease
• Cocaine can make changes to the structure of the brain

Recreational use

As a recreational drug, cocaine is known as powder, snow, ski, soft, blow, slopes, coca, marching powder, benzoylmethylecgonine, and nose candy.

It is normally found as a white, crystalline powder or as an off-white, chunky substance.

In powder form, it usually consists of cocaine hydrochloride diluted with other substances, such as lidocaine, a local anesthetic, sugars (lactose), inositol, and mannitol.

Diluting the cocaine enables the seller to make more profit by “stretching” the amount of pure cocaine they have to sell.

Cocaine can be taken by:

• Snorting or inhaling through the nose. It enters the bloodstream via the nasal tissues
• Injecting, which releases it directly into the bloodstream
• Smoking or inhaled into the lungs, where it rapidly enters the bloodstream

What is crack?

Crack is the street name for a type of cocaine that has had the hydrochloride removed, making it possible to smoke.

When the mixture is heated, it makes a crackling sound, hence the name. Crack producers make crack with baking soda (sodium bicarbonate) or ammonia and water, and it is heated to remove the hydrochloride.

The crack smoker receives large doses of cocaine. The effect is intense and virtually immediate, as with injected cocaine, but the “high” lasts only around 5 minutes.

Cocaine has a very powerful stimulating effect on the nervous system. It raises levels of dopamine, a neurotransmitter linked to pleasure, movement, and the brain’s reward circuit.

Normally, neurons release dopamine in response to a pleasurable stimulus, such as the smell of good food. Once the dopamine has passed on its message, it returns inside the neuron, and the signal stops.

Cocaine stops the dopamine from getting back into the neuron, so it accumulates and continues to send the pleasurable message to the brain.

The excess dopamine gives the user a feeling of enhanced well-being, euphoria, alertness, motor activity, and energy.

The effects generally last between 15 and 30 minutes , but shorter with crack.

Cocaine and crack cocaine are illegal drugs. This is because they involve health risks.

Cocaine is a highly addictive drug.

Long-term use can gradually change the brain’s reward system, increasing the risk of addiction .

In occasional cocaine users, social or physical problems are rare, but scientists insist there is no safe amount of cocaine.

People who are addicted may eventually prefer taking cocaine to any other activity. Their lifestyles may alter completely as the addiction takes hold.

The person may lose their job, home, family, and become bankrupt. The consequences can be fatal.

An overdose of cocaine can lead to seizures, life-threatening heart failure , cerebral hemorrhage, stroke , and respiratory failure.

Regular usage, even without overdosing, increases the risk of negative health consequences.

There is no specific medication to treat cocaine overdose.

Some studies have shown that those who inject or smoke cocaine have a greater risk of complications than individuals who snort it. Smokers tend to develop an addiction more rapidly than those who snort.

Smoking cocaine also increases the risk of developing respiratory problems, such as shortness of breath, coughing, and lung trauma, including bleeding.

Physical changes

Scientists at the University of Cambridge in England identified abnormal brain structure in the frontal lobe of the brain of cocaine users.

The team scanned the brains of 120 individuals , half of whom were addicted to cocaine. Results showed a widespread loss of gray matter among cocaine users. The loss was greater among those who had used the drug for longer.

The basal ganglia, a part of the brain that houses the reward system, was found to be larger among individuals who were dependent on cocaine.

The scientists believe that the basal ganglia were already enlarged before the addiction began. This would suggest that some people might be more vulnerable to the addictive effects of cocaine.

Risk of stroke and heart attack

Research indicates that cocaine use can significantly increase the risk of a heart attack or stroke.

Recreational cocaine users have been found to have harder arteries, thicker heart muscle walls, higher blood pressure , and up to a 35 higher risk of a hardened aorta, compared with people who have never used the drug.

Other health risks

Cocaine use can also have the following effects:

• constricted blood vessels
• high body temperature
• rapid heart rate
• high blood pressure , heart failure, and stroke
• abdominal pain
• decreased appetite, with a risk of malnourishment among chronic users
• severe paranoia, an impaired sense of reality
• hallucinations, or hearing things that are not there
• upper respiratory tract problems from regular snorting, including a loss of the sense of smell, nosebleeds, nasal septum decay, swallowing problems, persistent runny nose, and hoarseness
• severe bowel gangrene caused by a reduction in blood flow among those who ingest regularly
• injecting increases the risk of severe allergic reactions and blood-borne diseases, such as HIV and hepatitis

Binge pattern cocaine use can lead to irritability, anxiety , and restlessness.

Cocaethylene: Cocaine and alcohol

People who abuse substances often take more than one drug at the same time. When a person consumes cocaine and alcohol together, the liver produces cocaethylene.

Cocaethylene prolongs the euphoric effects of cocaine and makes them more intense.

For that reason, drug users sometimes take cocaethylene as a recreational drug itself.

However, cocaethylene use is linked to a significantly greater risk of sudden death, compared with cocaine alone.

Treating addiction

Recognizing an addiction is the first step to losing it.

Depending on the nature of the abuse, some patients who seek help will be advised to attend a residential rehabilitation program, or a structured day program.

Medications can treat the symptoms related to cocaine withdrawal, but there is no substitute drug that can effectively help a patient recover from a cocaine dependency.

Individuals who stop using the drug will have powerful cravings that can last for years.

Counseling, social support, and some specialist medications may help .

The National Treatment Agency for Substance Misuse (NTA) says that 70 percent of people who go into treatment for powder cocaine problems either stop completely or significantly reduce their consumption within 6 months.

Anyone who is concerned about cocaine use should see a doctor or a local support group for beating addiction.

Last medically reviewed on May 15, 2017

• Alcohol / Addiction / Illegal Drugs
• Neurology / Neuroscience

How we reviewed this article:

• Abnormal brain structure linked to chronic cocaine abuse. (2011, June 21) http://www.cam.ac.uk/research/news/abnormal-brain-structure-linked-to-chronic-cocaine-abuse
• Cocaine: get help. (2014, October 9) http://www.nhs.uk/Livewell/drugs/Pages/drugs-recovery.aspx
• Ersche, K.D., Barnes, A., Jones, P.S., Morein-Zamir, S., Robbins, T.W., & Bullmore E.T. (2011, July). Abnormal structure of frontostriatal brain systems is associated with aspects of impulsivity and compulsivity in cocaine dependence. Brain, 134, 7, 2013-24 https://www.ncbi.nlm.nih.gov/pubmed/21690575
• Kaye S., Darke S. (2004, October). Non-fatal cocaine overdose among injecting and non-injecting cocaine users in Sydney, Australia. Addiction . 99(10):1315-22 http://www.ncbi.nlm.nih.gov/pubmed/15369570
• Markel, H. (2011, April 6). Über Coca: Sigmund Freud, Carl Koller, and Cocaine. Journal of the American Medical Association, 305, 13, 1360-1361 http://jamanetwork.com/journals/jama/article-abstract/896143
• Nestler E.J. (2005, December). The Neurobiology of Cocaine Addiction. Science & Practice Perspectives. 3, 1, 4-10 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2851032/
• Powder cocaine: How the treatment system is responding to a growing problem. (n.d.) http://www.nta.nhs.uk/uploads/ntapowdercocaine1march2010d.pdf
• Pereira, R. B., Andrade, P. B., & Valentão, P. (2015, October). A comprehensive view of the neurotoxicity mechanisms of cocaine and ethanol. Neurotoxicity Research . 253-267 http://link.springer.com/article/10.1007/s12640-015-9536-x
• The neurobiology of drug addiction. (2007, January) https://www.drugabuse.gov/publications/teaching-packets/neurobiology-drug-addiction/section-iv-action-cocaine/2-snorting-vs-smoking-cocaine-different-a
• What are the short-term effects of cocaine use? (2016, May) https://www.drugabuse.gov/publications/research-reports/cocaine/what-are-short-term-effects-cocaine-use

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Drug Addiction Research Paper

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I. introduction, academic writing, editing, proofreading, and problem solving services, get 10% off with fall23 discount code, ii. drug use, misuse, abuse, and addiction, iii. drug administration, absorption, metabolism, and excretion, iv. how drugs work in the brain, v. drug safety and toxicity, vi. tolerance, dependence, and withdrawal, vii. specific psychoactive drugs, a. stimulants, 1. xanthines, 2. nicotine, 3. amphetamines, b. depressants, 3. marijuana and hashish, c. the hallucinogens lsd, mdma, and pcp, viii. summary.

IX. Bibliography

A drug is a chemical substance produced exogenously (outside of the body) that, when taken into the body, changes normal body functions. Psychologists are very interested in psychoactive drugs that change central nervous system (CNS; brain and spinal cord) activity, and thereby affect perception, thought, emotion, and behavior. Although people use many psychoactive drugs for acceptable medicinal reasons, this research paper focuses on those psychoactive drugs that people use primarily for recreational, nonmedicinal reasons (e.g., to feel good, be more alert, alter or avoid reality). An adult drinking alcohol to relax or smoking cigarettes to stop the jitters are examples of recreational use of licit (legal) drugs in this country, and smoking crack to feel euphoric or injecting heroin for the “rush” are examples of illicit (illegal) recreational drug use. Most of the information about how drugs make a person feel come from self-reports of licit and illicit users of drugs, whereas most of the data about how the body affects drugs and how drugs work in the brain comes from well-controlled experimental studies using nonhuman animals.

With pills to treat everything from the symptoms of the common cold to the positive symptoms of schizophrenia, drug use is prevalent in the United States, and pharmaceuticals are a multibillion-dollar industry. Nonetheless, society sends mixed messages about drug use, with commercials warning against the evils of illicit drug use and advertisements offering wonder treatments in a “purple pill.” Drugs in and of themselves are not “evil,” but every drug can be misused and abused. Misuse generally refers to the deviation from instructions on the label of over-the-counter drugs or the doctor’s instructions for prescription drugs. For example, taking more or fewer pills per dose or day, not using the drug the full time course as prescribed (e.g., antibiotics), using the drug past the expiration date, using the drug with other drugs (e.g., alcohol with barbiturates), or sharing prescriptions with others without a doctor’s permission are all forms of drug misuse. Although most of these acts may not seem very serious, they all can lead to very dangerous, even deadly, consequences (e.g., alcohol with other drugs, especially other CNS depressants). Drug abuse, which also can occur with licit and illicit drugs, refers here to use of a psychoactive substance to the extent that it produces some sort of physical, cognitive, behavioral, or social impairment. Keep in mind, however, that the public often thinks of drug abuse as specific to illicit drugs like methamphetamine, cocaine, heroin, and LSD (lysergic acid diethylamide), even though alcohol, for example, is a licit drug that people can abuse. What follows is an introduction to the use, misuse, and abuse of psychoactive drugs and their effects on behavior, beginning with how drugs enter the body and what happens to them once they do.

Pharmacokinetics is the study of how drugs are absorbed into the body, metabolized once in the body, and excreted from the body. The goal of drug absorption is for the drug to circulate in the blood, and more specifically for a psychoactive drug, the goal is for it to circulate in the brain. Administration for the purpose of absorption in blood and brain can take various forms depending on type of substance (lipid soluble vs. water soluble, gaseous vs. solid) and desired rate of absorption (rapid vs. slow, acute vs. continuous). Most humans administer drugs either orally (swallowed by mouth), sublingually (substance placed under the tongue), subcutaneously (injecting under the skin), intramuscularly (injecting into muscle tissue), intravenously (injecting directly into the bloodstream via a vein), transdermally (applied to outer layer of skin), intrarectally (using suppositories), intranasally (sniffed into the nostrils), or by inhalation (breathing gases and solids into the lungs). Intraperitoneal (into the peritoneal cavity), intraventricular (via a cannula into the ventricles of the brain), and intracranial (directly into a target area of the brain) injections are forms of administration used mostly in research with laboratory animals. Psychoactive drugs administered directly into the brain will have the most rapid effects because they will reach their CNS sites of action most quickly. Drugs administered through all other routes must be lipid-soluble in order to get through the formidable solid lipid barrier of the brain known as the blood brain barrier (BBB). Provided the psychoactive drugs administered directly into the bloodstream can pass the BBB, they will reach their CNS sites of action relatively quickly. Inhalation results in fast absorption into the bloodstream because gases and drugs in smoke (e.g., nicotine) are readily absorbed into the intricate network of capillaries that line the large surface area of the elaborately pocketed lungs. Although swallowing a pill is a simple, common method of drug administration, absorption is a tenuous process. Drugs taken orally must survive the harsh environment of the digestive system (e.g., stomach acids and digestive enzymes). Rates of absorption via other routes of administration are somewhere between those of inhalation and oral administration, depending somewhat on the availability of capillaries at the site of administration. Users of psychoactive drugs choose their favorite drug partially because of how quickly the drug exerts its psychoactive effects. For example, heroin is the preferred drug for some opiate addicts because it is more lipid soluble, is absorbed into the brain faster, and produces a faster, more intense “rush” than morphine does.

Before drugs can stop working in the body, they must be either broken down into other substances (metabolized) or removed from the body (excreted). Enzymes in the liver metabolize most of the psychoactive drugs described in this research paper into less lipid-soluble chemical products (metabolites). Some metabolites have their own effects on the body and brain. Several variables affect the rate of metabolism, including species, genetics, age, drug experience, and drug interactions. Regarding the latter, some drugs will inhibit or enhance the activity of enzymes responsible for metabolizing certain drugs—for example, SSRI-type antidepressants like fluoxetine inhibit some of the enzymes responsible for metabolizing codeine into the active analgesic morphine.

Subsequent to metabolism and recirculation in the blood, the kidneys excrete the more water-soluble metabolites from the body in urine, although there is excretion of small amounts of the drugs and their metabolites in exhaled breath, sweat, saliva, feces, and breast milk. Not surprisingly, urine drug tests are frequently used to determine the presence of metabolites some time after the metabolism of the original drug, rather than the presence of the original drug at time of administration.

Pharmacodynamics is the study of how drugs work in the body. Psychoactive drugs work in the CNS. The brain is made of supporting glial (fat) cells and excitable neurons. Neurons are responsible for the electrochemical transmission of information, enabling cells to communicate with one another. The structure and arrangement of neurons allows for the transmission, integration, storage, and interpretation of information received via sensory receptors, as well as the control of bodily organs and muscles. In other words, these specialized cells (neurons) are responsible for everything we think, feel, and do.

Psychoactive drugs work in the brain primarily by affecting neurotransmitter activity at the synapses. Neurons produce neurotransmitters that are stored in vesicles within the terminal buttons. When an action potential reaches the terminal buttons, vesicles release the neurotransmitter into the synaptic cleft. Neurotransmitter molecules then briefly bind to postsynaptic receptors causing ion channels to open, letting ions enter or exit, resulting in either excitatory or inhibitory postsynaptic potentials. Once released from the postsynaptic receptors, the neurotransmitter molecules undergo reuptake into the presynaptic terminal button or are destroyed by enzymes in the synaptic cleft. The effect of psychoactive drugs on synaptic activity can occur anywhere in the process of neurotransmitter production, storage, release, receptor binding, and reuptake or degradation.

More specifically, the administration of neurotransmitter precursors can increase the amount of neurotransmitter molecules available in the brain. For example, physicians prescribe L-DOPA, the precursor of dopamine, to patients with Parkinson’s disease in order to increase levels of dopamine in the brain. Other drugs can destroy or block the enzymes necessary for conversion of the precursors into neurotransmitters (e.g., p-chlorophenylalanine, PCPA, prevents the synthesis of serotonin). The vesicles that house neurotransmitters also can be the target site of drugs. Reserpine, occasionally used to treat high blood pressure, interferes with the transporter molecules that fill vesicles with neurotransmitters, thereby leaving the vesicles empty with no neurotransmitter available for release. A common target site of psychoactive drugs is the postsynaptic receptors where neurotransmitters bind. Drugs that bind to receptors and mimic the actions of a particular neurotransmitter are direct agonists (e.g., nicotine binds to nicotinic acetylcholinergic receptors). Drugs that bind to receptors without stimulating the receptor and prevent neurotransmitter molecules from occupying the receptor binding sites are direct antagonists (e.g., curare causes paralysis by binding to acetylcholinergic receptors). There are also drugs that work as agonists or antagonists by binding to sites other than where the neurotransmitter molecule binds (noncompetitive sites). Finally, drugs can affect what happens to neurotransmitters after they are released from their receptors by interfering with either the enzymes that break the neurotransmitters down (e.g., physostygmine deactivates the enzyme acetylcholinesterase, which breaks down acetylcholine) or reuptake mechanisms (e.g., cocaine deactivates the dopamine reuptake transporters).

Each type of neurotransmitter binds to a specific set of receptors that typically bear their own name (e.g., dopamine to dopaminergic receptors). The set of receptors belonging to a specific neurotransmitter can have quite different reactions to the neurotransmitter. Various drugs bind to receptor sites with different strengths, and may selectively bind to just one or a few receptor subtypes or nonselectively bind to multiple receptor subtypes. The selective serotonin reuptake inhibitors (SSRIs), used as antidepressants, bind specifically to receptor sites on the presynaptic serotonin reuptake pumps. Recent technological advances have allowed scientists to isolate the unique subtypes of receptor proteins, such that they can produce large quantities of each of the specific receptor proteins and then test the affinity of new drugs at each of the receptor subtypes. Drugs that bind to only a very specific receptor subtype or have greatly enhanced affinities for very specific subtypes of receptors will have fewer side effects as compared to drugs that bind less discriminately to an entire set of receptors. A good example is the drugs used to treat Parkinson’s disease. Some of the older drugs (e.g., bromocriptine) that are structurally more similar to dopamine have more negative side effects than the newer developed drugs (e.g., ropinerole) that have more discriminate receptor affinity for D3 than D2 receptors.

Clearly, not all drugs are equal. Scientists who study drugs, pharmacologists, typically measure many participants’ responses to doses so low that they cause no measurable effect to doses so high that they cease to cause any additional effect. They then plot the number (or percent) of participants who respond to the drug at each of the doses tested (dose response curve). The plot indicates the drug’s potency (number of drug molecules required to elicit a given response), efficacy (the maximum effect of the drug, with additional amounts resulting in no increase in response), and variability (individual differences in responsiveness to the drug).

The federal Food and Drug Administration (FDA) has extremely specific guidelines in place for the testing of a new drug’s effectiveness and safety. Safety refers to the drug’s potential to produce everything from predictable, tolerable, unpleasant side effects to unpredictable, intolerable, severe toxicities. Unfortunately, all drugs have multiple effects, with some effects less desirable. Given that undesirable side effects are unavoidable, the goal is the most favorable combination of the most desired drug effects and the least unwanted side effects. The ED50 is the effective dose that produces the desired effect in 50 percent of the participants. The LD50 is the lethal dose that produces death in 50 percent of the subjects. Typically, the ED50 and LD50 are determined in several species and over many trials to reduce the risk of toxicity in humans. The greater the distance between the ED50 and LD50, the less the risk of drug-induced toxicity at beneficial dosages. The margin of safety is the ratio of LD1 to ED99 (effective dose in 99 percent of the participants). Ratios of one or greater suggest greater safety. Be cautious, though—this margin of safety is under the best of controlled testing conditions, far from the circumstances under which many humans may take the drug (e.g., mixing drugs). One drug can alter the effects of another drug in many different ways. A second drug can have an additive effect, a synergistic effect (a greater effect than would be expected when just adding the two drugs), or an antagonistic effect (the second drug reduces or blocks the effect of the target drug). Even drugs not meant to have any effect (placebos) can influence a target drug’s effects because of the user’s expectations.

Tolerance is the need to take increasing doses of a drug in order to achieve the same effects as previously achieved with lower doses. Likewise, when the same dose of drug has less and less of an effect with repeated administrations, tolerance has occurred. A good example is the tolerance that some people have for the caffeine in coffee. A novice coffee drinker may feel the stimulatory effects of coffee after a single cup of coffee containing about 100 mg of caffeine. After drinking coffee daily for a few weeks, it may take two or three cups of caffeinated coffee to feel that same excitation. There are several types of tolerance including metabolic tolerance, cellular tolerance, and behavioral tolerance. Metabolic tolerance occurs when, with repeated administrations of the drug, the body produces more and more metabolic enzymes, thereby speeding up the rate of metabolism of that drug. Thus, one must take more and more drug with each administration to maintain the same concentration of drug in the body as during previous episodes. Cellular tolerance is down regulation (reduction in numbers) of the receptors in the brain or reduced sensitivity of those receptors to the drug because of the continuous or repetitive presence of the drug. The result is the need for more drug in order to get the same level of effect in the brain. Behavioral tolerance involves learning. Behavioral tolerance can be observed in the presence of conditioned drug-taking cues and be absent in novel environments or situations. The drug serves as the unconditioned stimulus (US) and the drug effect as an unconditioned response (UR). Drug administering paraphernalia (e.g., white uniform, syringe and needle, bong and roach clips) and a specific location (e.g., doctor’s office, nightclub, crack house) where the drug is administered can serve as conditioned stimuli (CSs) that, when paired with the drug (US), come to elicit conditioned responses (CRs) that are similar to the UR or opposite the UR (compensatory responses). For example, when Siegel (1975) gave rats morphine (US), they showed reduced sensitivity (UR analgesia) to heat applied to their paws, but with repetitive administrations of morphine in the presence of the same environmental cues (CS), the rats showed increased sensitivity (CR hyperalgesia) to those environmental cues.

A drug may develop different types of tolerance, and to all, some, or none of its effects. Some effects of a drug may even show acute tolerance, which occurs during a single administration of the drug. As a drug is absorbed into the blood, there is a gradual increase in the blood drug concentration, the ascending portion of the blood concentration curve. As long as drug administration has ceased, the blood concentration will eventually reach a peak level. When more metabolism than absorption is occurring, the concentration of drug in the blood begins to decline, depicted as the descending portion of the blood concentration. Acute tolerance is evident when, during a single administration, the measured effect is stronger on the ascending portion of the blood concentration curve than at the same concentration on the descending portion of the curve. Some effects of alcohol show acute tolerance in humans and rats. Finally, cross-tolerance is tolerance that occurs to one specific drug and subsequently tolerance occurs to the first administration of a different drug.

Drug dependence sometimes accompanies tolerance but does not require it. Dependence exists when a person must continue taking a drug in order to function normally and avoid the symptoms of withdrawal (physiological changes associated with the cessation of the drug). In other words, to determine dependence requires one to stop taking the drug. Physical dependence signifies that the body has adjusted physiologically to the repeated or continued presence of the drug. Removing the drug upsets the balance the body has established with the drug present, and results in often-unpleasant symptoms opposite those produced by the drug (e.g., heroin causes constipation whereas withdrawal from heroin causes diarrhea). Interestingly, long-term alcohol consumption can produce considerable tolerance without causing physical dependence; however, abstention from chronic alcoholism can cause life-threatening tremors, nausea, seizures, and delirium. Although the public tends to associate aversive withdrawal symptoms with drug “addiction” (e.g., chills, runny nose, fever, increased sensitivity to pain with opiate addiction), dependence and withdrawal are not unique to illicit drugs. Many legally prescribed and appropriately used therapeutic drugs result in dependence (e.g., SSRI-type antidepressants). It takes the body from several days to several weeks to readjust to the absence of a previously administered drug that has produced dependence. Thus, physiological dependence and withdrawal promote drug-taking behaviors, as people continue to take the drug, at least partially, to avoid the terrible effects of withdrawal. Several drugs that do not cause physiological dependence (e.g., cocaine, marijuana) do, however, produce psychological dependence. That is, an individual may be dependent on a drug for its pleasurable effects (i.e., positive reinforcement). Rats prefer to lever press for cocaine over food, even to the point of starvation.

Psychoactive agents are categorized a number of different ways. For example, drugs are categorized according to their chemical structure (e.g., amphetamines), whether they are legal or illegal (e.g., caffeine and nicotine vs. cocaine and amphetamines), how they affect the CNS (e.g., stimulants and depressants), and the type of behavioral, affective, and/or cognitive effects they produce (e.g., hallucinogens, analgesics). What follows is a description of a few of the most well-studied drugs with emphasis on the use of the drug; behavioral, cognitive, and mood-related effects of the drug; and the CNS mechanisms by which the drug produces its effects on behavior.

Stimulants produce behavioral excitation, increased motor activity, and increased alertness by enhancing excitation at neuronal synapses. The most commonly used stimulants include caffeine (a xanthine), nicotine, amphetamines, and cocaine. Many consider caffeine and nicotine to be “minor” stimulants and amphetamines and cocaine to be “major” stimulants. These stimulants have medicinal purposes, but most people are more familiar with their recreational uses. Stimulants vary greatly in the degree to which they affect behavior and in their potential for dependence and abuse.

Xanthines are a family of stimulants that includes caffeine, theobromine, and theophylline, the most widely used stimulants in the world. Caffeine is in many products (e.g., over-the-counter medications, baked goods, candy) but most commonly is associated with coffee and soft drinks. Tea contains caffeine, theophylline, and trace amounts of theobromine, and both caffeine and theobromine are in chocolate. Caffeine and theophylline are approximately equal with regard to stimulatory effects, but theobromine is only about one-tenth as strong as the other two.

How much caffeine is in coffee depends on the type of coffee bean (coffea robusta having twice the caffeine content of coffee Arabica) and how it is brewed (caffeine in a 5-ounce cup: instant about 60 mg, percolated about 85 mg, drip-brewed about 112 mg). Caffeine content in 12-ounce soft drinks ranges from about 38 mg (Diet Pepsi) to 54 mg (Mountain Dew), and as high as about 110 mg in special “energy” sodas (Red Bull). A 5-ounce cup of medium brewed black tea has about 60 mg of caffeine, and a strong brew of tea contains as much as 100 mg of caffeine. A 5- ounce cup of brewed tea contains a much smaller amount of theophylline (< 1 mg). A 1-ounce piece of milk chocolate contains 1 to 6 mg caffeine and about 40 mg of the 10 times less stimulating theobromine. There is 75 to 150 mg of xanthines in a cup of hot cocoa, and cocoa products contain enough caffeine and theobromine to affect behavior.

Orally consumed caffeine is absorbed in the stomach and mostly intestines, with peak blood levels occurring at 30 to 60 minutes. Caffeine easily crosses the blood brain and placenta barriers. Some foods, alcohol, smoking, hormones, age, and species affect the metabolism of caffeine. Xanthines are antagonists at adenosine A1 and A2a receptors, affecting the release of several neurotransmitters. When activated by adenosine, receptors located on presynaptic terminals inhibit spontaneous and stimulated neurotransmitter release. By blocking activation of adenosine receptors, xanthines lead to increased neurotransmitter release and increased excitation. At high concentrations, xanthines also block benzodiazepine receptors located on the GABA receptor complex, which may account for some of the increased anxiety after consumption of enormous amounts of coffee. Because outside of the CNS theophylline is particularly good at causing smooth muscles to relax, theophylline is useful therapeutically to dilate the bronchi of the lungs in the treatment of asthma.

Often people consume products containing moderate levels of caffeine because of their subjective experiences of increased alertness, improved attention, reduced fatigue, and more clear cognition. Experimental evidence suggests the most prominent effect of caffeine is enhancing performance of noncognitive tasks, like athletic and perceptual tasks, by reducing fatigue and boredom (see review by Weiss & Laties, 1962). Additionally, caffeine augments brainstem reflexes, enhances some visual processing, improves reaction time and self-reported alertness, reduces the detrimental effects of sleep deprivation on psychomotor performance, increases wakefulness, and produces insomnia.

Tolerance develops to some of the subjective effects of caffeine. Small and moderate, but not large, doses of caffeine appear to have reinforcing properties. Most people manage their caffeine intake, avoiding the anxiety, tremors, rapid breathing, and insomnia associated with high doses of caffeine. Within 12 to 24 hours of cessation, caffeine withdrawal often causes mild to severe headaches, drowsiness, muscle aches, and irritability, suggesting caffeine has some potential for producing limited physiological dependence. However, after reviewing caffeine studies, Nehlig (1999) concluded that caffeine does not affect the dopaminergic CNS centers for reward and motivation, as do cocaine and amphetamines.

Nicotine is one of the most-used psychoactive drugs in the world. The primary psychoactive active ingredient in tobacco is nicotine. According to the 2005 National Survey on Drug Use and Health (Department of Health and Human Services, 2006), about 71.5 million Americans (> 12 years old) used a tobacco product within the previous month. Only 30.6 percent of full-time college students ages 18 to 22 reported using in the previous month, as compared to 42.7 percent of same-aged part-time and noncollege students. Many of the toxic chemical compounds, other than nicotine, in tobacco products are the source of serious health problems (e.g., emphysema, chronic lung disease, cancer, cardiovascular disease) and death.

Nicotine is easily absorbed into the body. When inhaled, nicotine in cigarette smoke particles (tar) is quickly absorbed into the bloodstream via the capillaries lining the lungs. Smokers experience a sudden “rush” with that first cigarette of the day because the nicotine-saturated blood rapidly reaches the brain and crosses the BBB. Even though cigarettes contain about 0.5 to 2.0 mg of nicotine, smokers absorb only about 20 percent of that nicotine into blood. Smokers easily avoid nicotine toxicity by controlling the depth and rate of smoke inhalation. The liver metabolizes about 90 percent of the nicotine in the bloodstream before excretion. Urine tests measuring nicotine’s major metabolite cotinine do not distinguish between tobacco use and environmental exposure.

Nicotine is an agonist at acetylcholinergic nicotinic receptors. Peripherally, nicotine’s activation of receptors increases blood pressure, heart rate, and adrenal gland release of adrenaline. Nicotine activation of CNS nicotinic receptors located on presynaptic terminal buttons facilitates release of dopamine, acetylcholine, and glutamate throughout the brain. Physiological and psychological dependence of nicotine is due to nicotinic-induced release of dopamine from neurons projecting from the ventral tegmental area to forebrain regions (mesolimbic system) and prefrontal cortex (mesocortical system), brain areas responsible for reinforcement. Nicotine-induced release of acetylcholine is the likely cause of improved cognition and memory, as well as increased arousal. Increased glutamatergic activity due to nicotinic presynaptic facilitation contributes to enhanced memory of nicotine users.

Plenty of evidence exists regarding nicotine’s facilitating effects on cognition and memory in humans and animals (for reviews see Levin, McClernon, & Rezvani, 2006; Levin & Simon, 1998). Individual differences in the cognitive effects of nicotine may be due to genetic variations in dopaminergic activity. Nicotine administered via a patch to adult carriers of the 957T allele (alters D2 receptor binding in humans) impaired working verbal memory performance and reduced processing efficiency in brain regions important for phonological rehearsal (Jacobsen, Pugh, Mencl, & Gelernter, 2006). Additionally, nicotine stimulates activity in brain regions involved in attention, motivation, mood, motor activity, and arousal.

Tolerance appears to develop to the subjective mood effects of nicotine, but not to nicotine-induced changes in physiology or behavioral performance (for review see Perkins, 2002). However, most smokers do develop both physiological and psychological dependence on nicotine. Typically, withdrawal from cigarettes causes intense persistent cravings, irritability, apprehension, irritation, agitation, fidgeting, trouble concentrating, sleeplessness, and weight gain. Even people deprived of smoking just overnight report higher stress, irritability, and lower pleasure (e.g., Parrott & Garnham, 1998). Abstinence symptoms can last for several months, and many smokers find the cravings to be so intense that they relapse. It is common for smokers to quit smoking many times. Decreased activity in reward brain areas (e.g., dopaminergic mesolimbic system) that occurs during nicotine withdrawal may be responsible for the motivation of cravings, relapse, and continued smoking.

In 1932 amphetamine, a synthetic drug similar in structure to ephedrine, was patented. That amphetamine is a potent dilator of nasal and bronchial passages easily administered as an inhalant made it a viable treatment for asthma in the early 1900s. During World War I and World War II, governments gave amphetamines to soldiers to prevent fatigue and improve mood. Subsequently, college students used amphetamines to stay awake studying for exams, and truck drivers for staying awake on crosscountry hauls. It did not take long for word to spread that amphetamines (speed) caused euphoria, quickly making them an abused recreational drug. As Schedule II drugs, amphetamines have high potential for abuse and dependence, but also have accepted medicinal use with strict restrictions. Currently, treatments for narcolepsy and attention deficit hyperactivity disorder (ADHD) are accepted uses of amphetamines and amphetamine-like drugs (methylphenidate).

Amphetamines are a group of similarly structured synthetic chemicals that cause euphoria and behavioral stimulation. The d form of amphetamine is more potent than the 1 form. Administration is typically oral for current medicinal purposes, and inhalation or injection with a freebase form of methamphetamine (ice, crank) for a faster recreational “rush.” Amphetamines easily cross the BBB and readily disperse throughout the brain. The liver metabolizes about 60 percent of methamphetamine, amphetamine being the major active metabolite, and then the kidneys excrete the metabolites and unchanged methamphetamine.

Amphetamines work both in the periphery and in the CNS. In the CNS, these drugs increase activity at synapses that release epinephrine, norepinephrine, and dopamine by either causing the neurotransmitters to leak out of their vesicles into the synaptic cleft and/or blocking reuptake into presynaptic terminal buttons. Recreational users typically prefer methamphetamine to other amphetamines because it has fewer unpleasant peripheral effects (e.g., increased heart rate, increased blood pressure, dry mouth, headaches) and stronger, longer-lasting CNS.

Amphetamines improve mood, decrease fatigue, increase vigilance, energize, impair ability to estimate time, and diminish the desire for food and drink. “Fen-Phen,” a combination of fenfluramine and the amphetamine phentermine, was widely prescribed as an effective appetite suppressant in the 1990s, at least until it was removed from the market in late 1997 because of its association with heart valve problems and lung disease. Most of the performanceenhancing effects of amphetamines are limited to tasks that are routine, well-rehearsed, and well-practiced activities. Intravenously or intranasally administered high doses of amphetamine cause a “rush” of intense exhilaration and pleasure. The euphoria and strong reinforcing properties of amphetamines are due to increased dopamine activity in the mesolimbic system. Increased repetitive movements (stereotypy in laboratory rats) and behaviors (punding in humans) to the exclusion of eating, grooming, and sleeping are probably due to amphetamine stimulation in the nigrostriatal dopamine system. High acute doses and chronic use probably over stimulate the mesolimbic dopamine system, producing violently aggressive paranoia and amphetamine psychosis, delusions, hallucinations, and a split from reality. The sensation that insects are crawling under the skin (formication) may be the basis for the self-mutilation observed in laboratory animals. Long-term chronic use of methamphetamines is particular neurotoxic, leading to irreversible brain damage and psychosis.

Acute and chronic tolerance to amphetamines’ desired effects of enhanced mood and euphoria occurs rapidly. The positively rewarding feelings associated with intravenously injected amphetamine, especially methamphetamine, leads to overwhelming psychological dependence. Physiological dependence on amphetamines is evident from the withdrawal symptoms of ravenous hunger, fatigue, lethargy, depression, and suicidal tendencies. Many of the characteristics of amphetamines are similar to those of cocaine.

For thousands of years, the natives of the South American Andes have increased endurance and stamina as they traveled the harsh mountain terrain by chewing the leaves of the coca plant. The plant became of interest to Europeans and Americans in the mid to late 1800s when entrepreneurs began adding the extract of the coca leaves to many products (e.g., wine, nerve tonics, home remedies, teas, and colas). In the 1860s Dr. W. S. Halstead discovered cocaine’s local anesthetic properties. Because cocaine is readily absorbed in mucous membranes, it is still a local anesthetic of choice in some surgeries (e.g., nasal, esophageal). Currently, U.S. federal law categorizes cocaine as a Schedule II drug (high potential for abuse and dependence, but has currently accepted medicinal use with strict restrictions). In 2005 an estimated 2.4 million people were using cocaine, and about 2,400 persons per day used cocaine for the first time (Department of Health and Human Services, 2006).

Cocaine administration takes several forms, all with fairly quick but short-lived results (1 to 2 hours’ duration). Users snort the powdered hydrochloride salt form of cocaine, and when they dissolve that in water, they can inject the drug. In the 1970s users developed a smokeable free-base form of cocaine by extracting the hydrochloride with the very volatile gas ether. The safer smokeable rock crystal crack cocaine forms when producers treat cocaine with baking soda and water. The crack user inhales the vapors as the rock heats and makes a crackling sound. When inhaled, cocaine is rapidly absorbed by capillaries in the lungs, whereas snorted cocaine hydrochloride is absorbed more slowly into mucous membranes. Cocaine readily crosses the BBB and quickly distributes throughout the brain, where it remains for as long as 8 hours. The major metabolite benzoylecgonine is inactive and, when excreted by the kidneys in urine, is detectable for 48 hours, even as long as 2 weeks in chronic cocaine users. Cometabolism of cocaine and alcohol produces the pharmacologically active, longer-lasting, and toxic metabolite cocaethylene.

Cocaine blocks presynaptic reuptake transporters for dopamine, epinephrine, norepinephrine, and serotonin. This blockade prolongs the presence of these neurotransmitters in the synapse, allowing the neurotransmitters to bind repetitively to postsynaptic receptors. Cocaine’s enhancement of dopaminergic activity in the reward/reinforcement centers of the brain (e.g., the nucleus accumbens and other mesolimbic systems) is responsible for the highly addictive nature and powerful psychological dependence of cocaine. Serotonin receptors also play a role in the reinforcing effects of cocaine.

Cocaine is an extremely addictive psychostimulant that in low to moderate doses produces euphoria and increases alertness, mental acuity, self-consciousness, talkativeness, and motor behavior. Moderate to high doses cause more intense confusion, agitation, paranoia, restlessness, tremors, and seizures. Chronic use of cocaine produces impulsive and repetitive behavior. High-dose cocaine use can cause cocaine-induced psychosis characterized by extreme agitation and anxiety; exaggerated compulsive motor behaviors; delusions of paranoia and persecution; visual, auditory and tactile hallucinations; loss of touch with reality; and permanent brain damage. Medical risks associated with cocaine use include increased risk of cerebral ischemia, intracranial bleeding, heart attack and heart complications due to cocaine’s vasoconstrictive properties, respiratory failure, strokes, seizures, and risks with snorting that include nasal lesions, perforations, bleeding, and infections.

Tolerance to cocaine’s effects and physiological dependence to high doses of cocaine can occur. Regarding withdrawal syndrome, as the stimulatory CNS effects of cocaine subside, the user experiences depression, anxiety, lingering sleepiness, boredom, reduced motivation, and an intense craving for the drug. Much more powerful is the development of psychological dependence, because of cocaine’s strong reinforcing properties, and therefore relapse.

Depressants decrease CNS neuronal activity such that behavior is depressed, anxiety is lessened, and sedation and sleep are increased. This group of drugs includes barbiturates, benzodiazepines, some abused inhalants, and alcohol. Many of these drugs work at the GABA receptor complex, and all have potential for misuse, abuse, and dependence.

Alcohol (ethanol) is a CNS depressant used throughout the world and history. In the United States, alcohol sales are an important part of the economy, with Americans spending over a hundred billion dollars annually on beer, wines, and distilled liquors. Based on alcohol sales in the Unites States, total ethanol consumption in 2004 was 377,002,000 gallons, including 4,368,000 gallons of ethanol and 97,065,000 gallons of beer (National Institute on Alcohol Abuse and Alcoholism, n.d.). Alcohol consumption in the United States costs in terms of increased risky behavior, injuries on the job, relational strain, and hospitalization. Chronic users develop vitamin deficiencies because alcohol is high in calories and not nutritious, and they are at risk for pancreatitis, chronic gastritis, gastric ulcers, stomach and intestinal cancers (alcohol is a gastric irritant), as well as death due to cirrhosis of the liver. Alcohol is involved in costly traffic-related injuries and fatalities. According to the National Highway Traffic Safety Administration, automobile crashes involving alcohol in 2000 cost the public almost $115 billion, with an estimated 513,000 people injured and 16,792 killed (Pacific Institute for Research and Evaluation, n.d.).

People typically absorb alcohol orally, and ethanol is easily absorbed via the gastrointestinal system. Generally, beers have 3.2 to 5 percent ethanol, wines 12 to 14 percent, and hard liquors (distilled spirits) 40 to 50 percent. An adult can metabolize the amount of ethanol contained in a 12-ounce, 3.2 percent beer, a 3 ½-ounce, 12 percent wine, or 1-ounce, 40 percent (80 proof) hard liquor in approximately one hour. The enzyme alcohol dehydrogenase metabolizes about 95 percent of the ethanol consumed into acetaldehyde at a constant rate of 0.25 ounces/hour, and that metabolizes to acetyl-coenzyme, which then converts to water and carbon dioxide. The other 5 percent is excreted unchanged mostly through breath (hence the use of Breathalyzers to estimate alcohol concentration). Women have less ethanol-metabolizing enzyme in their stomach wall and therefore absorb more ethanol than men do. Water and fat-soluble ethanol easily crosses the BBB and placental barriers. Ethanol diffuses rapidly throughout the brain, and ethanol concentrations in a fetal brain reach those of the alcohol-drinking mother.

Ethanol nonspecifically affects neuronal membranes and directly affects synaptic activity and ionic channels of several neurotransmitters. Ethanol dose dependently inhibits NMDA-type glutamate receptors (reduces postsynaptic excitation) and enhances inhibition produced by GABAA receptor-mediated influx of chloride ions (increases postsynaptic inhibition). Ethanol also induces synaptic release of opioids that trigger dopamine release in the brain reinforcement areas, explaining how the antagonist naltrexone reduces cravings for alcohol and relapse in alcoholdependent persons attempting to abstain. Specific serotonin receptors (5HT2, 5HT3) located in the nucleus accumbens may also be a site of ethanol action. Antagonists of those receptors reduce ethanol consumption in some persons with alcoholism. Additionally, ethanol leads to a decrease in the number of cannabinoid receptors (down-regulation) affecting the craving of alcohol.

Water excretion in urine increases (diuretic) as the blood alcohol concentration (BAC) rises, and water is retained (antidiuretic) as the BAC declines, causing swelling in the extremities. Although it makes the drinker feel warmer to the touch, ethanol actually causes hypothermia. Because ethanol causes blood vessels in skin to dilate, persons with white skin appear flushed. Behaviorally, ethanol has a biphasic effect, with low doses inhibiting inhibitions (disinhibition), and high doses depressing all behaviors. Alcohol reduces the latency to fall to sleep and inhibits REM sleep. Generally, low to moderate doses increase rate and tone of speech, impair visual perception, disrupt balance, worsen reaction time, exaggerate mood, reduce fear and apprehension (anxiolytic), and affect learning and memory in a state-dependent manner. However, there are huge individual differences in ethanol-induced effects because genetics, motivation, environment, experience with alcohol, and tolerance vary greatly. Chronic consumption of higher doses of alcohol can lead to memory storage problems, with heavy drinkers experiencing blackouts, periods during which they cannot remember events even though they were awake and active. Long-term heavy drinking can cause irreversible neuronal damage, producing dementia and severe cognitive deficits known as Korsakoff’s Syndrome.

Each of the forms of tolerance can develop to some of the effects of ethanol (e.g., depression of REM) depending on pattern of drinking and amount consumed, with tolerance more apparent in regular and heavy drinkers. Physiological dependence is evident when withdrawal from ethanol results in agitation, confusion, tremors, cramps, sweating, nausea, and vomiting. Persons with severe alcoholism may experience delirium tremens (DTs) characterized by disorientation, hallucinations, and life threatening seizures.

The opiates, also known as narcotics, are a class of potent analgesics that have similar behavioral effects, including opium, opium extracts (e.g., morphine, codeine), several opiate derivatives (e.g., heroin), and several chemically unrelated synthetic opiates (e.g., methadone). Opium is harvested from the opium poppy, and has been used for centuries. In the 1800s, women and children alike ingested opium in everything from cure-alls to cough syrups. In the mid-1800s morphine as a medical analgesic increased with the invention of the hypodermic needle during the Civil War. When heroin was put on the market in the late 1890s it was considered a powerful and safe cough suppressant, and it was at least a decade before its full potential for abuse and dependence was realized. In the United States, opium, morphine, codeine, and methadone are all Schedule II drugs (high potential for abuse and dependence with acceptable medicinal uses with strict restrictions), whereas heroin is a Schedule I drug (high potential for abuse and dependence with no acceptable medicinal use). Although it is illegal in this country, it is widely used as a recreational drug. An estimated 108,000 persons age 12 and older used heroin for the first time in 2005 (Department of Health and Human Services, 2006).

Opiates are administered orally, as rectal suppositories, or as is most common with medicinal and recreational use, via injection. Morphine, because it is more water than fat soluble, crosses the BBB slowly, whereas more lipid soluble heroin crosses the BBB much more rapidly and produces a faster more intense “rush.” Metabolism of morphine in the liver produces the metabolite morphine- 6-glucuronide that is an even more potent analgesic. Heroin, which is three times more potent than morphine, metabolizes to monoacetylmorphine, which then converts to morphine. Urine tests detect the opiates as well as their metabolites, and therefore are not useful in determining the exact form of the drug used. Furthermore, poppy seeds and cough syrups contain ingredients that metabolize and test positive for opiate metabolites.

Exogenous opioids (produced outside of the body) bind to opioid receptors and mimic the actions of endogenous opioids (endorphins). Most of their analgesic effects are due to their presynaptic inhibition of pain-producing neurotransmitter release. There are Mu, Kappa, and Delta opiate receptors. Morphine is an agonist at Mu receptors located in several brain areas including the nucleus accumbens (addiction and abuse), thalamus, striatum, and brainstem (respiratory depression, nausea and vomiting), in the spinal cord (analgesia), and periphery. In the brain, Delta receptors in the nucleus accumbens and limbic system are involved in opioid-related emotional responses, and Kappa receptors may be Mu receptor–antagonists.

Opiates alter the perception of pain without affecting consciousness. They also produce a feeling of drowsiness, putting the person in a sort of mental fog that impairs cognitive processing. Opiates cause the user to feel carefree, content, and euphoric. Respiration becomes slow, shallow, and irregular, at therapeutic doses, and breathing may stop with high doses. Combined use of opiates and depressants can be particularly hazardous. Other physiological effects of opiate use include constricted pupils, histamine-induced red eyes and itching, lowered blood pressure, constipation, cough suppression, nausea and vomiting, and changes in the immune system.

Key features of frequent repetitive opiate use are tolerance to analgesia and euphoria, and cross-tolerance to other opiates. The severity of the withdrawal symptoms— anxiety, agitation, despair, irritability, physical pain, cramping, and diarrhea—depends on how long, how often, and how much of the opiate was used. Depression and intense cravings for the drug last for several months after the individual has stopped using heroin, for example.

For centuries, people in many parts of the world have used some form of the Cannabis sativa hemp plant as a recreational drug. The plant grows as a weed in many parts of the United States, and is cultivated in other countries. Marijuana production consists of drying and shredding the leaves of the plant, whereas hashish is a dried form of the resin from the flowers of the plant. Marijuana and hashish are both Schedule I drugs in the United States. Each day in 2005, an estimated 6,000 persons, 59.1 percent under 18, used marijuana for the first time (Department of Health and Human Services, 2006). The main psychoactive substance in these products is delta-9- tetrahydocaanabinol (THC). Most marijuana has a THC content of about 4 to 8 percent.

Often THC is ingested via hand-rolled marijuana cigarettes called joints or reefers, but it is also consumed in cookies and brownies. Only about half of the THC in a marijuana cigarette is absorbed, but absorption via the capillaries in the lining of the lungs is very rapid. Peak blood levels of THC occur within 10 minutes of the beginning of smoking, and detectable blood levels continue for 12 hours after a single cigarette. Absorption and onset of effects after oral ingestion is slower, with peak THC blood levels not occurring for at least 2 hours. THC easily crosses the BBB and placenta barrier, and collects in fatty parts of the body. It slowly metabolizes into active 11-hydroxy-delta- 9-THC, which then converts into inactive metabolites detectable in urine tests for as long as a month in heavy or chronic smokers.

The actions of THC in the brain were unknown until the 1990s identification of the weaker and shorter-lasting endogenous THC-like substance, anandamide, and the cannabinoid receptor. THC is an anandamide agonist that, when bound to cannabinoid receptors, inhibits the release of other neurotransmitters at those synapses, especially GABA. These g-protein-linked receptors are located mostly on presynaptic terminals and exist in large numbers throughout the brain, but not in the brainstem. That there are none of these receptors in the brainstem, where regulations of major life-support functions are controlled (e.g., heart rate, respiration), is probably why even high doses of marijuana are not likely lethal, although they can peripherally affect the cardiovascular and immune systems.

The psychoactive effects of THC are dependent upon type of administration, experience with the drug, environment, and expectations. Interestingly, the effects of marijuana on appetite and sexual behavior are culturally dependent, with Americans experiencing “the munchies” and Jamaicans decreased appetite, Americans enhanced sexual responsiveness and persons of India reduced sexual interest. Generally, people use marijuana because it has a mellowing, mildly euphoric effect. Other psychoactive effects include poorer attention, distorted perception of time and colors, altered auditory and gustatory perceptions, diminished anxiety, slowed reaction time, and impaired cognitive processing. Poor learning and memory are due to the numerous cannabinoid receptors in the hippocampus. Impaired balance and abnormal movements occur because of THC’s activation of receptors in the basal ganglia, and the cognitive effects are due to receptors in the cerebral cortex. Poor reaction time, decreased attention to peripheral visual stimuli, difficulty concentrating, and impairment of complex motor tasks under the influence of marijuana hinders driving ability. High doses of marijuana produce panic and anxiety, and extremely high doses produce additional disorientation, delusions, and hallucinations.

Tolerance, receptor-down regulation with repeated use, develops to THC. Withdrawal symptoms, which begin about 48 hours after the last marijuana use, include restlessness, irritability, despair, apprehension, difficulty sleeping, nausea, cramping, and poor appetite. Withdrawal symptoms are mild as compared to those that occur with most other drugs (e.g., alcohol, opiates) and occur for only about half of regular users. Thus, physiological dependence does occur for many, and most experience craving for marijuana when they stop using the drug.

Although the hallucinogens lysergic acid diethylamide (LSD), methylene-dioxy-methamphetamine (MDMA; Ecstasy), and phencyclidine (PCP; Angel Dust) affect very different neurotransmitter systems, they are grouped here because of their similar psychological effects at nontoxic doses. The commonality among hallucinogens (psychedelic drugs) is their ability to cause users to disconnect from reality and hallucinate. Although there are a large number of natural hallucinogenics, LSD, MDMA, and PCP are all synthetic drugs originally synthesized with hopes of medicinal value. Albert Hoffman accidentally experienced a “psychedelic trip” in 1943, and since then LSD has become one of the most widely known hallucinogens. PCP was used as an anesthetic prior to being taken off the market in 1965, when it made it to the streets as a recreational drug, and MDMA became a club drug in the 1960s. Estimates of first time users of hallucinogens for each year from 2000 to 2005 have been close to one million people age 12 and older per year, with about 615,000 first-time Ecstasy users in 2005 (Department of Health and Human Services, 2006).

Users ingest LSD orally, and the drug is absorbed in about 60 minutes with peak blood levels within 3 hours. LSD easily crosses both brain and placenta barriers. Metabolism takes place in the liver, where LSD is converted to 2-oxo-3phydroxy-LSD, and then excreted in urine. People use MDMA orally, snort it, smoke it, and inject it, with absorption being slowest with oral use. Most of MDMA metabolizes to 3,4-dihydroxymethamphetamine (DHMA), and urine tests detect metabolites for up to 5 days. People either take PCP orally (peak blood levels in 2 hours) or smoke the drug (peak blood levels in 15 minutes), and it is well absorbed into blood with both methods. Urine tests detect PCP for as long as a week after use.

LSD is a serotonergic receptor agonist, and most of the psychoactive effects of LSD are thought to be due to agonist actions at serotonin receptors in the pontine raphe (filters sensory stimuli). MDMA is structurally similar to but more potent than mescaline and metamphetamine, and stimulates release of both serotonin and dopamine in the CNS. Prolonged use of MDMA results in serotonergic neurotoxicity, and can lead to long-term verbal and visual memory loss. PCP blocks the ionic channels of glutamatergic-NMDA receptors, preventing calcium ions from entering into the dendrites of postsynaptic neurons when glutamate binds to these receptors, and blocking synaptic excitation.

Very small doses of LSD cause vivid visual hallucinations like colorful kaleidoscope lights and distorted images, lights to be heard and sounds to be seen, moods that oscillate from jubilation to dread, and frightening cognitions that surface. The LSD “trip” is often unpleasant, resulting in panic and confusion. A unique feature of LSD use is the infamous “flashback,” a reoccurrence of the drug’s effects without warning, even a long time after LSD use. At low doses MDMA has behavioral effects similar to those of methamphetamines, but at higher doses it has the psychoactive effects of LSD. Low doses of PCP produce agitation, dissociation from self and others, a “blank stare,” and major alterations in mood and cognition. Higher doses of PCP can cause the user to have violent reactions to stimuli in his or her environment, along with analgesia and memory loss. Extremely high doses of PCP result in coma.

Tolerance and cross-tolerance develops to the psychological and physiological effects of most hallucinogens rather quickly, making it difficult to stay repetitively “high” on these drugs. Furthermore, there are few if any withdrawal symptoms and therefore little or no physiological dependence with LSD, MDMA, and PCP in most users.

Psychoactive drugs change cognitions, emotions, and behavior. Drugs, per se, are neither good nor bad. People use psychoactive drugs for medicinal and recreational reasons. Regardless of the initial reason for using a drug, some people misuse and even abuse some psychoactive drugs because of the drugs’ effects on mood, thought, and behavior. How people administer the drug (by ingestion, injection, inhalation, or absorption through the skin) affects how fast and intense the drug’s effects are. The route of administration can affect how quickly the drug is absorbed into the bloodstream, how rapidly it is broken down, and how long it takes to be excreted from the body. The primary site of action for psychoactive drugs is the synapse of neurons in the brain. Often drugs work by either mimicking or blocking the actions of one or more neurotransmitters in the CNS. All drugs have multiple effects, and most are toxic at some dose. Dependence, withdrawal, and/or tolerance develop to some of the effects of most, but not all, psychoactive drugs.

Psychoactive drugs can be categorized many different ways. For example, by chemical structure, whether their use is legal or illegal, or the type of CNS or behavioral effects they produce. Stimulants, like cocaine and amphetamines, increase neuronal and behavioral activity. Depressants, like alcohol, reduce neuronal and behavioral activity. Opiates, some having legal uses (e.g., morphine) and others not (e.g., heroin), reduce pain and, in high enough doses, cause an addictive “rush.” Low doses of marijuana have a mellowing, mildly euphoric effect, whereas very high doses can cause hallucinations. Drugs like LSD, MDMA, and PCP are all classified as hallucinogens because at even low doses they cause sensory and perceptual distortions. Although a great deal is known about how many psychoactive drugs act in the brain and affect behavior, researchers continue to identify the most effective pharmacological, cognitive, and behavioral treatments for persons who abuse these drugs.

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• Nehlig, A. (1999). Are we dependent upon coffee and caffeine? A review on human and animal data. Neuroscience and Biobehavioral Reviews, 23, 563–576.
• Pacific Institute for Research and Evaluation. (n.d.). Impaired driving in the United States.
• Parrott, A. C., & Garnham, N. J. (1998). Comparative mood states and cognitive skills of cigarette smokers, deprived smokers, and nonsmokers. Human Psychopharmacology: Clinical and Experimental, 13, 367–376.
• Patat, A., Rosenzweig, P., Enslen, M., Trocherie, S., Miget, N., Bozon, M. C., et al. (2000). Effects of new slow release formulation of caffeine on EEG, psychomotor and cognitive functions in sleep-deprived subjects. Human Psychopharmacology: Clinical and Experimental, 15, 153– 170.
• Perkins, K. A. (2002). Chronic tolerance to nicotine in humans and its relationship to tobacco dependence. Nicotine and Tobacco Research, 4, 405–422.
• Pickens, R., & Thompson, T. (1968). Cocaine-reinforced behavior in rats: Effects of reinforcement magnitude and fixedratio size. The Journal of Pharmacology and Experimental Therapeutics, 161, 122–129.
• Roth, M. E., Cosgove, K. P., & Carroll, M. E. (2004). Sex differences in the vulnerability to drug abuse: A review of preclinical studies. Neuroscience and Biobehavioral Reviews, 28, 533–546.
• Siegel, S. (1975). Evidence from rats that morphine tolerance is a learned response. Journal of Comparative and physiological psychology, 89, 498–506.
• Siegel, S. (2005). Drug tolerance, drug addiction, and drug anticipation. Current Directions in Psychological Science, 14, 296–300.
• Siegel, S., & Ramos, B. M. C. (2002). Applying laboratory research: Drug anticipation and the treatment of drug addiction. Experimental and Clinical Psychopharmacology, 10, 162–183.
• Walsh, J. K., Muehlbach, M. J., Humm, T. M., Dickins, Q. S., Sugerman, J. L., & Schweitzer, P. K. (1990). Effect of caffeine on physiological sleep tendency and ability to sustain wakefulness at night. Psychopharmacology, 101, 271–273.
• Weiss, B., & Laties, V. G. (1962). Enhancement of human performance by caffeine and the amphetamines. Pharmacologic Review, 14, 1–36.

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CocaineEssays (Examples)

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Cocaine botanical origins cocaine is synthesized from.

Cocaine Botanical Origins Cocaine is synthesized from the leaves of the coca plant. These plants grow in Bolivia, Peru, Columbia, Africa, Taiwan, Indonesia, and Formosa. The leaf contains between 0.5% and 1.5% cocaine and the processing methods extract pure cocaine from the leaves. In the late 15th century, the Incan people thought coca leaves were direct gifts from the gods in order to help them through the brutal physical abuse of working long days and nights in the gold and silver mines at very high altitudes. These people used the leaves during their burial ceremonies and religious rituals; they were controlled as a very special blessing from supreme beings. By mixing the coca leaf with lime or ash, the chewers could "graze" for days - offsetting the effects of physical and mental exhaustion. Invaders to the Incan and Andean cultures were divided over the "permitted" use of the coca leaves by these people. One….

Honer, W.G., Gewirtz, G., Tuey, M. "Psychosis and violence in cocaine smokers." Lancet 288:451.

Budd, R.D. "Cocaine abuse and violent death." Am J. Drug Alcohol Abuse 15:375(1989):82.

Licata, A., Taylor, S., Berman, M., et al. "Effects of cocaine on human aggression." Pharmacol Biochem Behav 45 (1993):549-552.

Cocaine and Crack Proletariat Hunger

There is no valuable sustenance in crack or cocaine, and is used mainly as a recreational drug by many. This, in some ways, leaves the inner cities and crime and moves to the wealthier middle and upper middle classes who use the cocaine and not the crack version for recreation. This is the society of Jay McInerney's seminal 1980s fictional tale of New York 20-something lives, "right Lights, ig City." Cocaine users have and have had their "scene" for quite some time, and for the, the currency is still money, rather than the drug itself. That is how recreational cocaine users differ from the crime-influenced hunger satisfier described in the proletariat hunger killer definition. There is not the sense of urgent necessity outside of the biological influence of the drug itself, of course. In other words, recreational cocaine users may indeed get addicted and the drug may indeed replace their hunger,….

Bibliography

Canadian Drug Addiction Information:

 http://www.drugaddiction.ca/EnglishPage/Drug_addiction_Impact.htm 

Cocaine.org's Web page:

www.cocaine.org

Cocaine Addiction and Effects Cocaine May Not

Cocaine Addiction and Effects Cocaine may not be a problem in itself but its overdose and consistent abuse leads to numerous behavioral and psychological changes, which are often undesirable. Cocaine alters chemical processes in the brain giving the person an illusion of happiness and well-being. This is dangerous since a person needs to maintain a proper perspective on things in his life but cocaine can hide the pain, keeping the person in a state of elation. However this effect doesn't last very long and there comes a stage when cocaine stops producing this effect on brain but by then it is impossible to quit since one becomes addicted to it. National Institute on Drug Abuse states: "As cocaine abuse continues, tolerance often develops. This means that higher doses and more frequent use of cocaine are required for the brain to register the same level of pleasure experienced during initial use. ecent studies….

1) Cocaine Abuse and Addiction Retrieved online 17th Dec 2004:  http://www.focusas.com/Cocaine.html 

2) National Institute on drug Abuse: Research report: Retrieved online 17th Dec 2004:  http://www.nida.nih.gov/ResearchReports/Cocaine/Cocaine.html

Cocaine the Long-Term and Short-Term

The good news for those keeping an eye on the health of students in secondary school is that there has been a "…significant decline in the 30-day prevalence of powder cocaine use among 8th, 10th, and 12th graders from its peak use in the late 1990s" (nida). Sexual Addiction Author Paul Earley writes in the Cocaine Recovery Book that cocaine stimulates the part of the brain that stirs a sexual feeling along while decreasing a person's inhibitions. So, given the heightened sexual arousal, and a decrease in inhibition, the cocaine addict can become addicted to sexual behaviors that can be "…compulsive and bizarre… [and hence the person may] progress from compulsive and ritualistic sex to shame and remorse" (Earley, 1991). In fact Earley asserts that some male cocaine addicts try to get females addicted to the drug, engendering "…a dual addiction to sex and cocaine" (147). Treatments for Cocaine Addiction According to the….

Works Cited

Drugabuse.com. (2012). What are the short-term effects of cocaine use? Retrieved April 25,

2013, from  http://www.drugabuse.gov .

Drugabuse.com. (2012). What is Cocaine? Retrieved April 25, 2013, from

Cocaine Market Since the Late

Part of the reason for cocaine's rise in popularity was due to the fact that early on, many people didn't understand that the drug could have harmful side effects for those who use it. It wasn't until the early 1970's that the drug was made illegal and by that time there was already millions of Americans who were using cocaine. This allowed drug dealers such as those in Colombia to set up cartels that operated out of Colombia and made huge profits from the drug trade throughout the 70's and 80's and even continuing in to the present. Although the United States Government has done a lot in the past few decades to educate the public and restrict cocaine's distribution, I believe it's popularity and marketability before that time has made it a major player in the financing of the nation's overall drug market throughout the years. COCAINE USE FACTS Percent….

Brecher, Edward. Front Line. A Social History of America's Most Popular Drugs.

Licit and Illicit Drugs. Pg 282.

Business Heroes. John Stith Pemberton: The Inventor of Coca Cola. Pgs. 4-6. 1998.

Drug Facts. Study Conducted by the Office of National Drug Control Policy. June 2005.  http://www.cocaine.org .

Cocaine in California Cocaine Production

African-American street gang members, primarily affiliates of Bloods and Crips, distribute crack cocaine and marijuana in the HIDTA region. Asian street gangs dominate distribution of MDMA and high-potency marijuana at the retail level.[footnoteRef:10] Members of the OMGs, most notably Hells Angels Motorcycle Club (HAMC), are the ones that are really known to distribute powder cocaine, methamphetamine, and marijuana at the midlevel and retail level. [9: Vega, .A., Alderete, E., Kolody, B., & Aguilar-Gaxiola, S. "Illicit drug use among mexicans and mexican-Americans in california: The effects of gender and acculturation." Addiction 12.9 (2009): 12-54.] [10: "The Pursuit of Oblivion: A Global History of Narcotics." Davenport-Hines, Richard. New York City .. Norton & Company; First edition, 2002. 1-576.] Distribution The Central Valley HIDTA region is considered to be a regional and regional-level distribution center for ice methamphetamine and cocaine created in the region as well as ice cocaine, marijuana, and heroin trafficked all….

Callaghan, R.C., Cunningham, J.K., Allebeck, P., Arenovich, T., Sajeev, G., Remington, G., Kish, S.J. "Methamphetamine use and schizophrenia: A population-based cohort study in california." The American Journal of Psychiatry 19.5 (2012): 23-28.

"The Pursuit of Oblivion: A Global History of Narcotics." Davenport-Hines, Richard. New York City W.W. Norton & Company; First edition, 2002. 1-576.

Forster, G. "Quotas in the drug war." Policy Review 29.9 (2004): 21-28.

Hernandez, M.T., Sanchez, M.A., Ayala, L., Magis-RodrAguez, C. "METHAMPHETAMINE AND COCAINE USE AMONG MEXICAN MIGRANTS IN CALIFORNIA: THE CALIFORNIA-MEXICO EPIDEMIOLOGICAL SURVEILLANCE PILOT." AIDS Education and Prevention 21.9 (2009): 34-44.

Heroin and Cocaine Addiction and Overdose and How it Effects Families

Cocaine is a crystalline alkaloid obtained from the leaves of the coca plant. It is a stimulant, appetite suppressant and a sodium channel blocker that causes it to be an anesthetic at low doses. It is highly addictive because of its effect on the brain's reward pathways. Cocaine is more dangerous than many other stimulants because of its effect on the sodium channel in the body's chemistry, which, under higher dosages may cause sudden cardiac arrest. Cocaine is unique as a molecule because it has pockets that allow it to cross the blood-brain barrier quite quickly and easily (Sommers, 2008). High dosages or repeated use may also cause a breakdown in the blood-brain barrier, allowing the user to experience greater psychoactive episodes from other substances (Sharma, H., et al., 2009). Historical Background - From a historical perspective, the use of cocaine and other psychoactive substances is neither novel nor new. In….

Anthenelli, D. (2010). Vaccine for Cocaine Addiction: A Promising new Immunotherapy. Current Psychiatry, 9(9), 16-19.

Clarke, P., & Myers, J. (2012). Developmental Counseling and Therapy. Journal of Mental Health Counseling, 34(4), 23-37. Retrieved from Journal of Mental Health Counseling.

Goldbaum, E. (2012, May 9). Chronic Cocaine Use Triggers Changes in Brain's Neuron Structure. Retrieved from University at Buffalo News Center:  http://www.buffalo.edu/news/releases/2012/05/13420.html 

Gootenberg, P. (2008). Cocaine: The Making of a Global Drug. Chapel Hill, NC: University of North Carolina Press.

Redux Beverages LLC and Cocaine

To cope with the FDA uproar, Cocaine was forced to add a "humorous slogan…explaining that the beverage did not contain the illegal drug cocaine" (Thompson 2012: 1). But although government regulations have occasionally thwarted Cocaine, other developing conditions have enhanced its appeal. It has a vibrant social media presence. Its ability to engage with users, posting pictures of people getting Cocaine under a Christmas tree or making edgy status updates that play upon the company name, has been a boon to the company. Also, given that availability has been challenging in some areas, given that Cocaine has been pulled from the shelves by retailers who have had customer complaints about the name, social media enables loyal patrons to more easily find where Cocaine is being sold. Conclusion: Positioning The driving tangible reason that consumers buy Cocaine is primarily its caffeine content. Taste is hardly an issue, given that many loyalists prefer shots….

"Cocaine Energy Drink." Amazon.com reviews. [2 Apr 2013]

 http://www.amazon.com/Cocaine-Energy-Drink-Strong-Bulls/dp/B000RI8GI8 

"FDA finds Cocaine energy drink illegal." CADCA. 2007. [2 Apr 2013]

 http://www.cadca.org/resources/detail/fda-finds-%E2%80%98cocaine%E2%80%99-energy-drink-illegal

Vigabatrin for Treatment of Cocaine

These therapies are widely used to overcome patients with drugs problems which include male or female patients. These are psychological and medical treatments to decrease the use of cocaine and sedative drugs in the patient. These include therapies, and use of the medical drugs to reduce the patients impulsive desire to use cocaine regularly. Female patients could not treat in the case of pregnancy positive test results. Patients treated with vigabatrin therapies were reported more positive result compared to other similar available therapies. Background: Cocaine is sedative drug which causes brain damage and nervous blockage. Many studies have been done on cocaine addiction, which are very promising these days across different countries of the world. The two widely used treatments are vigabatrin and placebo therapies. These are psychological and medical treatments to decrease the use of cocaine and sedative drugs in the patient. These include therapies, and use of the medical….

Brodie J.D., Figueroa E., Laska E.M. And Dewey S.L. Safety and efficacy of gamma-vinyl GABA (GVG) for the treatment of methamphetamine and/or cocaine addiction. Synapse 2005; 55:122 -- 125

Brodie J.D., Figueroa E. And Dewey S.L. Treating cocaine addiction: from preclinical to clinical trial experience with gamma-vinyl GABA. Synapse 2003; 50:261 -- 265

Jonathan D. Brodie, Brady G. Case, Emilia Figueroa, Stephen L. Dewey, James a. Robinson, Joseph a. Wanderling, Eugene M. Laska. Randomized, Double-Blind, Placebo-Controlled Trial of Vigabatrin for the Treatment of Cocaine Dependence in Mexican Parolees

Outpatient Programs Mental Depression Cocaine Dependence Treatment

Outpatients With Depression and Cocaine Dependence Outpatient Programs, Mental Depression, Cocaine Dependence, Treatment Increasing Treatment Adherance Among Outpatients with Depression and Cocaine Dependence: esults of a Pilot Study This research study by Dennis C. Daley et.al (1998) was conducted to examine the effect of a modified motivational therapy intervention on outpatient treatment adherence and completion for patients with co morbid depressive disorder and cocaine dependence. This study was located using EBSCOhost, data: academic search premier, field: TI -- title, key words; outpatient, cocaine, dependence. The significance of this study lies in the finding that an outpatient program combining individual and group motivational therapy sessions holds promise for improving treatment adherence and completion among depressed patients with cocaine dependence. Depression is common among cocaine-dependent patients and poor adherence with outpatient treatment among cocaine-dependent patients is well documented. The majority of these patients drop out within 1 month of treatment. Cocaine-dependent patients treated on an inpatient….

Daley, D.C., Salloum, I.M., Zuckoff, A., Kirisci, L., & Thase, M.E. (1998, November) Increasing treatment adherance among outpatients with depression and cocaine dependence: Results of a pilot study. American journal of psychiatry, 155:1611-1613. Retrieved September 19, 2011, from  http://ajp.psychiatryonline.org/cgi/content/full/155/11/1611

Counselling Marijuana Cocaine Heroin Ecstasy

They are the ones who handle jobs that require expertise. Their job itself is difficult that not everybody can accept the responsibility. With this continuously growing number of addicts and/or substance-abused people, indeed, we need to have more and more credible substance abuse counselors to somehow alleviate this problem. eferences Block I, Ghoneim. MM 1993. Effects of chronic marijuana use on human cognition. Psychopharmacology 100(1-2):219-228, Brook JS, Balka EB, Whiteman M. 1999.: The risks for late adolescence of early adolescent marijuana use. Am J. Public Health 89(10):1549-1554 Fisher. Gary, Harrison, T. 2004. Substance Abuse: Information for School Counselors, Social Workers, Therapists, and Counselors (3rd Edition). Allyn and Bacon. Gruber, AJ, Pope HG, Hudson HI, Yurgelun-Todd D. 2003. Attributes of long-term heavy cannabis users: A case control study. Psychological Medicine 33:1415-1422. Lehman WE, Simpson DD. 1992. Employee substance abuse and on-the-job behaviors. Journal of Applied Psychology 77(3):309-321. Marijuana and Health. 2001. Syndistar Inc. http://www.intheknowzone.com/marijuana/lterm.htm Pope HG, Yurgelun-Todd D.….

Block RI, Ghoneim. MM 1993. Effects of chronic marijuana use on human cognition. Psychopharmacology 100(1-2):219-228,

Brook JS, Balka EB, Whiteman M. 1999.: The risks for late adolescence of early adolescent marijuana use. Am J. Public Health 89(10):1549-1554

Fisher. Gary, Harrison, T. 2004. Substance Abuse: Information for School Counselors, Social Workers, Therapists, and Counselors (3rd Edition). Allyn and Bacon.

Gruber, AJ, Pope HG, Hudson HI, Yurgelun-Todd D. 2003. Attributes of long-term heavy cannabis users: A case control study. Psychological Medicine 33:1415-1422.

Physiological Effects and Treatments for

Different routes of cocaine administration can produce different adverse effects. egularly snorting cocaine, for example, can lead to loss of sense of smell, nosebleeds, problems with swallowing, hoarseness, and an overall irritation of the nasal septum, which can lead to a chronically inflamed, runny nose. Ingested cocaine can cause severe bowel gangrene, due to reduced blood flow. Persons who inject cocaine have puncture marks and tracks, most commonly in their forearms. Intravenous cocaine users may also experience an allergic reaction, either to the drug, or to some additive in street cocaine, which can result, in severe cases, in death. Because cocaine has a tendency to decrease food intake, many chronic cocaine users lose their appetites and can experience significant weight loss and malnourishment. The human liver combines cocaine and alcohol and manufactures a third substance, cocaethylene, which intensifies cocaine's euphoric effects 3. The mixture of cocaine and alcohol is the….

1. Quaglio G, Lugoboni F, Pajusco B, Fornasiero a, Mezzelani P, Lechi a. [Clinical manifestations of cocaine abuse]. Ann Ital Med Int. Oct-Dec 2004;19(4):291-301; quiz 302-293.

2. White SM, Lambe CJ. The pathophysiology of cocaine abuse. J Clin Forensic Med. Mar 2003;10(1):27-39.

3. Velasquez EM, Anand RC, Newman WP, 3rd, Richard SS, Glancy DL. Cardiovascular complications associated with cocaine use. J La State Med Soc. Nov-Dec 2004;156(6):302-310; quiz 311.

4. Sofuoglu M, Kosten TR. Novel approaches to the treatment of cocaine addiction. CNS Drugs. 2005;19(1):13-25.

Drug Abuse in Eastern Kentucky

drug use and abuse in the United States and presents differing approaches that are used (or proposed) to get a handle on the problem. There is no doubt that the drug abuse issue is not new and it is not being reduced by any significant amount. This paper presents statistics and scholarly research articles that delve into various aspects of the drug abuse issue in the United States, with particular emphasis on drugs that are abused in eastern Kentucky and generally in the Appalachian communities. History of Drug Use & Availability The history of illegal drug use in the United States goes back to the 19th Century, according to the U.S. Drug Enforcement Agency (DEA). The DEA has a Museum in Arlington, Virginia, that illustrates the history of drug discoveries, drug use, and drug abuse through the years. The DEA reports that morphine, heroin, and cocaine were "discovered" in the 19th….

Bureau of Justice Statistics. (2008). Drugs and Crime Facts / Drug Use / Youth. Retrieved November 30, 2012, from http://bjs.ojp.usdog.gov.

Drug Enforcement Agency. (2012). Illegal Drugs in America: A Modern History. Retrieved November 30, 2012, from  http://www.deamuseum.org .

Grant, Judith. (2007). Rural women's stories of recovery from addition. Addiction Research and Theory, 15(5), 521-541.

Havens, Jennifer R., Oser, Carrie B., and Leukefeld, Carl G. (2011). Injection risk behaviors

Disparity in Sentencing for Crack

It is a matter of opinion as to whether this is actually accurate, but it does appear to be logical (Payne, 1997). This is an important analogy because of the fact that many individuals who are targeted for a particular reason will often attempt to find a disparity issue that they can use to insist that they have been treated unfairly. In drug use or sale issues, these people are targeted because of the offense that they have committed, but when sentencing is handed down, those who feel that they received too harsh of a sentence will work to find reasons that they believe their sentencing to be unfair. Race is only one reason that these individuals use. Others include gender, age, and whether the amount of drug that they had is a felony or should be a misdemeanor instead. Some of the speculation into why some individuals feel that they….

Banks, C. (2004). Criminal Justice Ethics: Theory and Practice. Thousand Oaks: Sage.

Blumstein, a. et. al. (1983). Research on sentencing: The Search for Reform.

Drug Use Trends. (1997, September-October). Slow development in "crack babies" may be caused by conditions of urban poverty, says new study. Retrieved at  http://www.ndsn.org/sepoct97/poverty.html 

Education Reforms and Students at Risk: A review of the current state of the art. (1994, January). Chapter 2: Student Background. Retrieved at  http://www.ed.gov/pubs/edreformstudies/edreforms/chap2a.html

Contingency Management Alcohol & Marijuana

" (1995) The authors state: "The amphetamines occasioned dose-related increases in d- amphetamine-appropriate responding, whereas hydromorphone did not. Amphetamines also occasioned dose-related increases in reports of the drug being most like "speed," whereas hydromorphone did not. However, both amphetamines and hydromorphone occasioned dose-related increases in reports of drug liking and in three scales of the ARCI. Thus, some self-report measures were well correlated with responding on the drug-appropriate lever and some were not. Lamb and Henningfield (1994) suggest that self-reports are complexly controlled by both the private event and the subject's history of experience with the drug. Some of the self-reports they observed (e.g., feels like speed) are probably occasioned by a relatively narrow range of stimuli because in the subject's experience with drug administration, these reports have been more selectively reinforced by the verbal community relative to other reports (e.g., drug liking). They also suggest that these results imply that….

Budney, Alan J. et al. (2006) Clinical Trial of Abstinence-Based Vouchers and Cognitive-Behavioral Therapy for Cannabis Dependence. Journal of Consulting and Clinical Psychology 2006. Vol.. 74 No. 2. 2006 American Psychological Association.

McRae, a.; Budney, a.; & Brady, K. (2002) Treatment of Marijuana Dependence: A Review of the Literature. Journal of Substance Abuse Treatment 24 (2003)

Pathways of Addiction: Opportunities in Drug Abuse Research (1996) Institute of Medicine (IOM)

Kamon, J; Budney, a. & Stanger, C. (2005)a Contingency Management Intervention for Adolescent Marijuana Abuse and Conduct Problems. Journal of the American Academy of Child & Adolescent Psychiatry. 44(6):513-521, June 2005.

Sports - Drugs

Cocaine Botanical Origins Cocaine is synthesized from the leaves of the coca plant. These plants grow in Bolivia, Peru, Columbia, Africa, Taiwan, Indonesia, and Formosa. The leaf contains between 0.5% and…

There is no valuable sustenance in crack or cocaine, and is used mainly as a recreational drug by many. This, in some ways, leaves the inner cities and…

Cocaine Addiction and Effects Cocaine may not be a problem in itself but its overdose and consistent abuse leads to numerous behavioral and psychological changes, which are often undesirable. Cocaine…

The good news for those keeping an eye on the health of students in secondary school is that there has been a "…significant decline in the 30-day prevalence…

Part of the reason for cocaine's rise in popularity was due to the fact that early on, many people didn't understand that the drug could have harmful side…

Research Paper

African-American street gang members, primarily affiliates of Bloods and Crips, distribute crack cocaine and marijuana in the HIDTA region. Asian street gangs dominate distribution of MDMA and high-potency…

Cocaine is a crystalline alkaloid obtained from the leaves of the coca plant. It is a stimulant, appetite suppressant and a sodium channel blocker that causes it to be…

Marketing Plan

To cope with the FDA uproar, Cocaine was forced to add a "humorous slogan…explaining that the beverage did not contain the illegal drug cocaine" (Thompson 2012: 1). But although…

Article Critique

These therapies are widely used to overcome patients with drugs problems which include male or female patients. These are psychological and medical treatments to decrease the use of…

Article Review

Outpatients With Depression and Cocaine Dependence Outpatient Programs, Mental Depression, Cocaine Dependence, Treatment Increasing Treatment Adherance Among Outpatients with Depression and Cocaine Dependence: esults of a Pilot Study This research study by…

They are the ones who handle jobs that require expertise. Their job itself is difficult that not everybody can accept the responsibility. With this continuously growing number of…

Different routes of cocaine administration can produce different adverse effects. egularly snorting cocaine, for example, can lead to loss of sense of smell, nosebleeds, problems with swallowing, hoarseness, and…

drug use and abuse in the United States and presents differing approaches that are used (or proposed) to get a handle on the problem. There is no doubt…

It is a matter of opinion as to whether this is actually accurate, but it does appear to be logical (Payne, 1997). This is an important analogy because of…

" (1995) The authors state: "The amphetamines occasioned dose-related increases in d- amphetamine-appropriate responding, whereas hydromorphone did not. Amphetamines also occasioned dose-related increases in reports of the drug being most…

Cocaine Essays (Examples)

Pablo Escobar

Violent crime control and law enforcement act of 1994.

The Establishment. (2016, April 12). About That Controversial 1994 Crime Bill. A Medium Corporation. Retrieved from   https://medium.com/the-establishment/about-that-controversial-1994-crime-bill-c17ccfcc25fa

Effectiveness Of The War On Drugs

ACLU (2020). Against drug prohibition. Retrieved from:   https://www.aclu.org/other/against-drug-prohibition  " target="_blank" REL="NOFOLLOW">

War On Drugs

Marijuana is an addictive drug, transgender the behaviors acts and transitions.

Jellestad, L., Jäggi, T., Corbisiero, S., Schaefer, D. J., Jenewein, J., Schneeberger, A., ... & Garcia Nuñez, D. (2018). Quality of life in transitioned trans persons: a retrospective cross-sectional cohort study. BioMed research international, 2018.

Positive And Negative Effects Athletic Performance And Caffeine

Mishra, D. (2018). Caffeine For Athletic Performance: Good Or Avoid? Sideline Sports. Retrieved from: https://www.sidelinesportsdoc.com/caffeine-for-athletic-performance-good-or-avoid/

Private Security And Law

Sexual addiction and treatment.

Young, K., Pistner, M.,O’Mara, J., & Buchanan, J. (2009). Cyber disorders: the mental health concern for the new millennium. CyberPsychology & Behavior, 2(5), 475-479.

Race And Incarceration Rates

Plessy v. Ferguson. 1896. Retrieved July 30, 2019 (  https://www.oyez.org/cases/1850-1900/163us537  ).

Related Topics

• Crack Cocaine

Category Topics

• Drug Testing
• Illegal Drugs

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Max rohde is first author on new gene therapy research paper.

Posted by cullum1 on Wednesday, November 15, 2023 in News .

PhD candidate Max Rohde is first author on “ Practical and Statistical Considerations for the Long Term Follow-Up of Gene Therapy Trial Participants ” published recently in  Clinical Pharmacology & Therapeutics . The paper outlines “some of the key considerations for designing long term follow-up protocols in the gene therapy setting” and offers “guidance for innovative operational and statistical methods that can help assess the safety profile and durability of response for these novel therapeutics.” Co-authors include Seoan Huh (Pfizer), Vanessa D’Souza (Google), Steven Arkin (Pfizer), Erika Roberts   (ELR Lab Services), and Avery McIntosh (Pfizer).  

Max’s research interests include adaptive clinical trial design, reproducible research, and statistics education. He was the 2022 winner of the Distinguished Teaching Assistant award .

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