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Recent research with classic psychedelics suggests significant therapeutic potential, particularly for neuropsychiatric disorders. A mediating influence behind symptom resolution is thought to be the personal insight - at times, bordering on the mystical - one acquires during the acute phase of a psychedelic session. Indeed, current clinical trials have found strong correlations between the acute subjective effects (ASE) under the influence of psychedelics and their enduring therapeutic properties. However, with potential barriers to widespread clinical implementation, including the healthcare resource-intensive nature of psychedelic sessions and the exclusion of certain at-risk patient groups, there is an active search to determine whether ASE elimination can be accompanied by the retention of persisting therapeutic benefits of these class of compounds. Recognizing the aberrant underlying neural circuitry that characterizes a range of neuropsychiatric disorders, and that classic psychedelics promote neuroplastic changes that may correct abnormal circuitry, investigators are rushing to design and discover compounds with psychoplastogenic, but not hallucinogenic (i.e., ASE), therapeutic potential. These efforts have paved the discovery of 'non-psychedelic/subjective psychedelics', or compounds that lack hallucinogenic activity but with therapeutic efficacy in preclinical models. This review aims to distill the current evidence - both clinical and preclinical - surrounding the question: can the ASE of classic psychedelics be dissociated from their sustained therapeutic properties? Several plausible clinical scenarios are then proposed to offer clarity on and potentially answer this question., (© 2024. The Author(s).)

Rationale: 4-Thio-substituted phenylalkylamines such as 2,5-dimethoxy-4-ethylthiophenethylamine (2C-T-2) and 2,5-dimethoxy-4-n-propylthiophenethylamine (2C-T-7) produce psychedelic effects in humans and have been distributed as recreational drugs. Objectives: The present studies were conducted to examine the structure–activity relationships (SAR) of a series of 4-thio-substituted phenylalkylamines using the head twitch response (HTR), a 5-HT2A receptor-mediated behavior induced by psychedelic drugs in mice. The HTR is commonly used as a behavioral proxy in rodents for human psychedelic effects and can be used to discriminate hallucinogenic and non-hallucinogenic 5-HT2A agonists. Methods: HTR dose–response studies with twelve different 4-thio-substituted phenylalkylamines were conducted in male C57BL/6 J mice. To detect the HTR, head movement was recorded electronically using a magnetometer coil and then head twitches were identified in the recordings using a validated method based on artificial intelligence. Results: 2C-T, the parent compound of this series, had relatively low potency in the HTR paradigm, but adding an α-methyl group increased potency fivefold. Potency was also increased when the 4-methylthio group was extended by one to three methylene units. Fluorination of the 4-position alkylthio chain, however, was detrimental for activity, as was the presence of a 4-allylthio substituent versus a propylthio group. 2C-T analogs containing a 4-benzylthio group showed little or no effect in the HTR paradigm, which is consistent with evidence that bulky 4-substituents can dampen agonist efficacy at the 5-HT2A receptor. Binding and functional studies confirmed that the compounds have nanomolar affinity for 5-HT2 receptor subtypes and act as partial agonists at 5-HT2A. Conclusions: In general, there were close parallels between the HTR data and the known SAR governing activity of phenylalkylamines at the 5-HT2A receptor. These findings further support the classification of 2C-T compounds as psychedelic drugs. [ABSTRACT FROM AUTHOR]

Rationale: The nonmedical use of new psychoactive substances (NPS) is a worldwide public health concern. The so-called "benzofury" compounds, 5-(2-aminopropyl)benzofuran (5-APB) and 6-(2-aminopropyl)benzofuran (6-APB), are NPS with stimulant-like properties in human users. These substances are known to interact with monoamine transporters and 5-HT receptors in transfected cells, but less is known about their effects in animal models. Methods: Here, we used in vitro monoamine transporter assays in rat brain synaptosomes to characterize the effects of 5-APB and 6-APB, together with their N-methyl derivatives 5-MAPB and 6-MAPB, in comparison with 3,4-methylenedioxyamphetamine (MDA) and 3,4-methylenedioxymethamphetamine (MDMA). In vivo neurochemical and behavioral effects of 5-APB (0.3 and 1.0 mg/kg, i.v.) and 6-APB (0.3 and 1.0 mg/kg, i.v.) were assessed in comparison with MDA (1.0 and 3.0 mg/kg, i.v.) using microdialysis sampling in the nucleus accumbens of conscious male rats. Results: All four benzofuran derivatives were substrate-type releasers at dopamine transporters (DAT), norepinephrine transporters (NET), and serotonin transporters (SERT) with nanomolar potencies, similar to the profile of effects produced by MDA and MDMA. However, the benzofurans were at least threefold more potent than MDA and MDMA at evoking transporter-mediated release. Like MDA, both benzofurans induced dose-related elevations in extracellular dopamine and serotonin in the brain, but benzofurans were more potent than MDA. The benzofuran derivatives also induced profound behavioral activation characterized by forward locomotion which lasted for at least 2 h post-injection. Conclusions: Overall, benzofurans are more potent than MDA in vitro and in vivo, producing sustained stimulant-like effects in rats. These data suggest that benzofuran-type compounds may have abuse liability and could pose risks for adverse effects, especially if used in conjunction with abused drugs or medications which enhance monoamine transmission in the brain. [ABSTRACT FROM AUTHOR]

Rationale: The availability and abuse of synthetic analogues of cathinone have increased dramatically around the world. Synthetic cathinones, such as 3,4-methylenedioxypyrovalerone [MDPV] and α-pyrrolidinopentiophenone [α-PVP], are cocaine-like inhibitors of monoamine transporters and common constituents of "bath salts" or "flakka" preparations. Studies in rats suggest that MDPV and α-PVP are 3 to 4-fold more effective reinforcers than cocaine; however, comparisons of the relative reinforcing effectiveness of MDPV and α-PVP have not been reported in other species. Objectives: Accordingly, in the present study, 4 adult male rhesus monkeys responding under a progressive ratio schedule of reinforcement were used to characterize the reinforcing effects of MDPV and α-PVP and to compare directly these effects with those of cocaine and methamphetamine. Results: MDPV was the most potent reinforcer, followed by α-PVP, methamphetamine, and cocaine. α-PVP was the most effective reinforcer, followed by MDPV, cocaine, and methamphetamine. In addition to making more responses to obtain MDPV and α-PVP, monkeys also responded for longer periods of time when MDPV or α-PVP was available compared with when either cocaine or methamphetamine was available for infusion. Conclusions: These studies confirm recent reports from rodents and provide strong evidence that the synthetic cathinones MDPV and α-PVP are capable of maintaining high levels of responding for prolonged periods of time, and that they function as more effective reinforcers than either cocaine or methamphetamine. The relative strength of these reinforcing effects may account for the high rates of "bath salts" use reported in humans. [ABSTRACT FROM AUTHOR]

Rationale: Tobacco use is highly prevalent among individuals with posttraumatic stress disorder (PTSD), depressive disorders, and pain. Research has revealed pairwise relationships among these conditions but has not examined more complex relationships that may influence symptom severity, chronicity, and treatment outcome. Objective: To examine the clustering of current PTSD, depressive disorders, and clinically significant pain according to current tobacco use and dependence among post-9/11 deployed veterans. Methods: Logistic regression was used to examine the clustering of these conditions in relationship to current tobacco use/dependence, while adjusting for age and total combat exposure, in 343 post-9/11 deployed veterans enrolled in the Translational Research Center for TBI and Stress Disorders (TRACTS) cohort (Mage = 32.1 + 8.3 years; 38% current tobacco use; 25% low and 12% moderate/high tobacco dependence). Results: A three-way clustering of PTSD, depressive disorder, and pain was more likely than any single or pairwise combination of these conditions in moderate/high tobacco-dependent veterans compared to tobacco non-users (adjusted ORs = 3.50 to 4.18). This multi-morbidity cluster also was associated with increased PTSD severity. Conclusions: Moderate to high dependence on tobacco is associated with substantially increased clustering of PTSD, depression, and clinically significant pain in veterans. Research examining synergistic interactions among these conditions, biological vulnerabilities shared among them, and the direct impact of tobacco use on the pathophysiology of PTSD, depression, and pain is needed. The results of such work may spur development of more effective integrated treatments to reduce the negative impact of these multi-morbid conditions on veterans' wellbeing and long-term health. [ABSTRACT FROM AUTHOR]

Rationale: New psychoactive substances (NPSs), including substituted cathinones and other stimulants, are synthesized, sold on the Internet, and ingested without knowledge of their pharmacological activity and/or toxicity. In vitro pharmacology plays a role in therapeutic drug development, drug-protein in silico interaction modeling, and drug scheduling. Objectives: The goal of this research was to determine mechanisms of action that may indicate NPS abuse liability. Methods: Affinities to displace the radioligand [125I]RTI-55 and potencies to inhibit [3H]neurotransmitter uptake for 22 cathinones, 6 benzofurans and another stimulant were characterized using human embryonic kidney cells stably expressing recombinant human transporters for dopamine, norepinephrine, or serotonin (hDAT, hNET, or hSERT, respectively). Selected compounds were tested for potencies and efficacies at inducing [3H]neurotransmitter release via the transporters. Computational modeling was conducted to explain plausible molecular interactions established by NPS and transporters. Results: Most α-pyrrolidinophenones had high hDAT potencies and selectivities in uptake assays, with hDAT/hSERT uptake selectivity ratios of 83–360. Other substituted cathinones varied in their potencies and selectivities, with N-ethyl-hexedrone and N-ethyl-pentylone having highest hDAT potencies and N-propyl-pentedrone having highest hDAT selectivity. 4-Cl-ethcathinone and 3,4-methylenedioxy-N-propylcathinone had higher hSERT selectivity. Benzofurans generally had low hDAT selectivity, especially 1-(2,3-dihydrobenzofuran-5-yl)-N-methylpropan-2-amine, with 25-fold higher hSERT potency. Consistent with this selectivity, the benzofurans were releasers at hSERT. Modeling indicated key amino acids in the transporters' binding pockets that influence drug affinities. Conclusions: The α-pyrrolidinophenones, with high hDAT selectivity, have high abuse potential. Lower hDAT selectivity among benzofurans suggests similarity to methylenedioxymethamphetamine, entactogens with lower stimulant activity. [ABSTRACT FROM AUTHOR]

Rationale: Drug addiction is a complex disease that is impacted by numerous factors. One such factor, time of day, influences drug intake, but there have been no investigations of how time of day affects the amount of drug taken and the development of addiction-like behavior. Previous data from our group show circadian disruption in rats given access to heroin during the light phase, which is important because circadian disruption, itself, can increase drug intake. Thus, the goal of this experiment was to determine how time of day of access affects heroin self-administration and the development of addiction-like behaviors including escalation of heroin intake, willingness to work for heroin on a progressive ratio schedule of reinforcement, seeking during extinction, incubation of seeking, and reinstatement of heroin-seeking behavior.Materials and methods: Male Sprague Dawley rats were given the opportunity to self-administer heroin for 6 h per trial during the second half of either the light or dark phase for 18 trials, including one progressive ratio challenge. Rats then underwent 14 days of abstinence, with a 5-h extinction test occurring on both the first and the 14th days of abstinence. The second extinction test was followed by a heroin prime and 1 h of reinstatement testing. On the following day, a subset of rats were tested in an additional extinction test where rats were tested either at the same time of the day as their previous self-administration sessions or during the opposite light/dark phase.Results: Relative to Light Access rats, Dark Access rats took more heroin, exhibited more goal-directed behavior, exhibited more seeking during the dark phase, failed to extinguish seeking during the 5-h extinction test in the dark phase, and exhibited greater incubation of heroin seeking following abstinence. However, Dark Access rats did not escalate drug taking over trials, work harder for drug, or seek more during drug-induced reinstatement than Light Access rats.Conclusions: These results show that time of access to heroin affects overall heroin intake and seeking in extinction, but does not affect other addiction-like behaviors in rats. [ABSTRACT FROM AUTHOR]

Rationale: Consideration by the US Drug Enforcement Administration and Food and Drug Administration of placing kratom into Schedule I of the Controlled Substances Act (CSA) requires its evaluation of abuse potential in the context of public health.Objective: The objective of the study is to provide a review of kratom abuse potential and its evaluation according to the 8 factors of the CSA.Results: Kratom leaves and extracts have been used for centuries in Southeast Asia and elsewhere to manage pain and other disorders and, by mid-twentieth century, to manage opioid withdrawal. Kratom has some opioid effects but low respiratory depression and abuse potential compared to opioids of abuse. This appears due to its non-opioid-derived and resembling molecular structure recently referred to as biased agonists. By the early 2000s, kratom was increasingly used in the US as a natural remedy to improve mood and quality of life and as substitutes for prescription and illicit opioids for managing pain and opioid withdrawal by people seeking abstinence from opioids. There has been no documented threat to public health that would appear to warrant emergency scheduling of the products and placement in Schedule I of the CSA carries risks of creating serious public health problems.Conclusions: Although kratom appears to have pharmacological properties that support some level of scheduling, if it was an approved drug, placing it into Schedule I, thus banning it, risks creating public health problems that do not presently exist. Furthermore, appropriate regulation by FDA is vital to ensure appropriate and safe use. [ABSTRACT FROM AUTHOR]

Given the plethora of new studies and published papers in the scientific press and the increasingly emerging presence of articles about positive psychedelic experiences appearing in the popular media, there is little doubt that we are in the midst of a Psychedelic Renaissance. The classical psychedelic drugs LSD and psilocybin and the entactogen MDMA are showing promise as tools to assist psychotherapy for a wide range of mental disorders, with multiple pilot studies demonstrating their safety and efficacy. In this article, the author describes how MDMA in particular has inherent characteristics that make it well suited for assisting trauma-focused psychotherapy in a population of patients who have experienced child abuse. But despite these advances, there remain many obstacles ahead of the widespread mainstream acceptance of psychedelic medicines. The author argues that the Misuse of Drugs Act 1971 is one such obstacle. Other impediments include a prevailing attitude of pseudoscience and rigidity from within the non-scientific psychedelic community itself. Resolution of these conflicts must be sought if medicine and society are to see psychedelics gaining a place in mainstream culture and science. [ABSTRACT FROM AUTHOR]

Rationale: Withdrawal symptoms stand as a core feature of alcohol dependence. Our previous results have shown that inhibition of phosphodiesterase-4 (PDE4) decreased ethanol seeking and drinking in alcohol-preferring rodents. However, little is known about whether PDE4 is involved in ethanol abstinence-related behavior. Objective: The objective of this study was to characterize the role of PDE4 in the development of anxiety- and depressive-like behavior induced by abstinence from ethanol exposure in different animal models. Methods: Using three rodent models of ethanol abstinence, we examined the effects of rolipram, a prototypical, selective PDE4 inhibitor, on (1) anxiety-like behavior induced by repeated ethanol abstinence in the elevated plus maze test in fawn-hooded (FH/Wjd) rats, (2) anxiety-like behavior in the open-field test and light-dark transition test following acute ethanol abstinence in C57BL/6J mice, and (3) anxiety- and depressive-like behavior induced by protracted ethanol abstinence in the elevated plus maze, forced-swim, and tail-suspension tests in C57BL/6J mice. Results: Pretreatment with rolipram (0.1 or 0.2 mg/kg) significantly increased entries and time spent in the open arms of the elevated plus maze test in rats with repeated ethanol abstinence. Similarly, in mice with acute ethanol abstinence, administration of rolipram (0.25 or 0.5 mg/kg) dose-dependently increased the crossings in the central zone of the open-field test and duration and transitions on the light side of the light-dark transition test, suggesting anxiolytic-like effects of rolipram. Consistent with these, chronic treatment with rolipram (0.1, 0.3, or 1.0 mg/kg) increased entries in the open arms of the elevated plus maze test; it also reduced the increased duration of immobility in both the forced-swim and tail-suspension tests in mice after protracted ethanol abstinence, suggesting antidepressant-like effects of rolipram. Conclusions: These results provide the first demonstration for that PDE4 plays a role in modulating the development of negative emotional reactions associated with ethanol abstinence, including anxiety and depression. PDE4 inhibitors may be a novel class of drugs for treatment of alcoholism. [ABSTRACT FROM AUTHOR]

Preclinical and clinical research supports a role for neuroactive steroids in the pathophysiology of posttraumatic stress disorder (PTSD). We investigated ganaxolone (a synthetic 3β-methylated derivative of allopregnanolone, a GABAergic neuroactive steroid) for treatment of PTSD in a proof-of-concept, multisite, double-blind, placebo-controlled trial. Veteran and non-veteran participants ( n = 112) were randomized to ganaxolone or placebo at biweekly escalating doses of 200, 400, and 600 mg twice daily for 6 weeks. During an open-label 6-week extension phase, the initial ganaxolone group continued ganaxolone, while the placebo group crossed over to ganaxolone. Eighty-six and 59 participants, respectively, completed the placebo-controlled and open-label phases. A modified intent-to-treat mixed model repeated measures analysis revealed no significant differences between the effects of ganaxolone and placebo on Clinician Administered PTSD Symptom (CAPS) scores, global well-being, negative mood, or sleep. Dropout rates did not differ between groups, and ganaxolone was generally well tolerated. Trough blood levels of ganaxolone at the end of the double-blind phase were, however, lower than the anticipated therapeutic level of ganaxolone in >35% of participants on active drug. Pharmacokinetic profiling of the ganaxolone dose regimen used in the trial and adverse event sensitivity analyses suggest that under-dosing may have contributed to the failure of ganaxolone to out-perform placebo. Future investigations of ganaxolone may benefit from higher dosing, rigorous monitoring of dosing adherence, a longer length of placebo-controlled testing, and targeting of treatment to PTSD subpopulations with demonstrably dysregulated pre-treatment neuroactive steroid levels. Clinicaltrials.gov identifier: NCT01339689. [ABSTRACT FROM AUTHOR]

Rationale: Anecdotally, both acute and chronic cannabis use have been associated with apathy, amotivation, and other reward processing deficits. To date, empirical support for these effects is limited, and no previous studies have assessed both acute effects of Δ-9-tetrahydrocannabinol (THC) and cannabidiol (CBD), as well as associations with cannabis dependence. Objectives: The objectives of this study were (1) to examine acute effects of cannabis with CBD (Cann + CBD) and without CBD (Cann-CBD) on effort-related decision-making and (2) to examine associations between cannabis dependence, effort-related decision-making and reward learning. Methods: In study 1, 17 participants each received three acute vaporized treatments, namely Cann-CBD (8 mg THC), Cann + CBD (8 mg THC + 10 mg CBD) and matched placebo, followed by a 50 % dose top-up 1.5 h later, and completed the Effort Expenditure for Rewards Task (EEfRT). In study 2, 20 cannabis-dependent participants were compared with 20 non-dependent, drug-using control participants on the EEfRT and the Probabilistic Reward Task (PRT) in a non-intoxicated state. Results: Cann-CBD reduced the likelihood of high-effort choices relative to placebo ( p = 0.042) and increased sensitivity to expected value compared to both placebo ( p = 0.014) and Cann + CBD ( p = 0.006). The cannabis-dependent and control groups did not differ on the EEfRT. However, the cannabis-dependent group exhibited a weaker response bias than the control group on the PRT ( p = 0.007). Conclusions: Cannabis acutely induced a transient amotivational state and CBD influenced the effects of THC on expected value. In contrast, cannabis dependence was associated with preserved motivation alongside impaired reward learning, although confounding factors, including depression, cannot be disregarded. This is the first well powered, fully controlled study to objectively demonstrate the acute amotivational effects of THC. [ABSTRACT FROM AUTHOR]

Rationale: Recent reports on the abuse of novel synthetic cathinone derivatives call attention to serious public health risks of these substances. In response to this concern, a growing body of preclinical research has characterized the psychopharmacology of these substances, particularly mephedrone (MEPH) or methylenedioxypyrovalerone (MDPV), noting their similarities to 3,4-methylenedioxymethamphetamine (MDMA) and cocaine. Few studies have utilized drug discrimination methodology to characterize the psychopharmacological properties of these substances. Objectives: The present study employed a rodent drug discrimination assay to further characterize the stimulus effects of MEPH and MDPV in comparison to MDMA and to a drug mixture comprised of d-amphetamine and MDMA. Methods: Eight male Sprague-Dawley rats were trained to discriminate 1.5 mg/kg MDMA, and eight rats were trained to discriminate a mixture of 1.5 mg/kg MDMA and 0.5 mg/kg d-amphetamine (MDMA + AMPH) from vehicle. Substitution tests were conducted with MDMA, d-amphetamine, MDPV, MEPH, and cocaine. Results: Dose-response curves generated with MDMA and MEPH were comparable between training groups. In contrast, AMPH, MDPV, and cocaine produced only partial substitution in animals trained to discriminate MDMA but produced full substitution in animals trained to discriminate the MDMA + AMPH mixture. Conclusions: These findings indicate that MDPV's effects may be more similar to those of traditional psychostimulants, whereas MEPH exerts stimulus effects more similar to those of MDMA. Additional experiments with selective DA and 5-hydroxytryptamine (5-HT) receptor antagonists are required to further elucidate specific receptor mechanisms mediating the discriminative stimulus effects of MDPV and mephedrone. [ABSTRACT FROM AUTHOR]

Rationale: Lysergic acid diethylamide (LSD) has a history of use as a psychotherapeutic aid in the treatment of mood disorders and addiction, and it was also explored as an enhancer of mind control. Objectives: The present study sought to test the effect of LSD on suggestibility in a modern research study. Methods: Ten healthy volunteers were administered with intravenous (i.v.) LSD (40-80 μg) in a within-subject placebo-controlled design. Suggestibility and cued mental imagery were assessed using the Creative Imagination Scale (CIS) and a mental imagery test (MIT). CIS and MIT items were split into two versions (A and B), balanced for 'efficacy' (i.e. A≈B) and counterbalanced across conditions (i.e. 50 % completed version 'A' under LSD). The MIT and CIS were issued 110 and 140 min, respectively, post-infusion, corresponding with the peak drug effects. Results: Volunteers gave significantly higher ratings for the CIS ( p = 0.018), but not the MIT ( p = 0.11), after LSD than placebo. The magnitude of suggestibility enhancement under LSD was positively correlated with trait conscientiousness measured at baseline ( p = 0.0005). Conclusions: These results imply that the influence of suggestion is enhanced by LSD. Enhanced suggestibility under LSD may have implications for its use as an adjunct to psychotherapy, where suggestibility plays a major role. That cued imagery was unaffected by LSD implies that suggestions must be of a sufficient duration and level of detail to be enhanced by the drug. The results also imply that individuals with high trait conscientiousness are especially sensitive to the suggestibility-enhancing effects of LSD. [ABSTRACT FROM AUTHOR]

Rationale and objective: Prevalence of alcohol use is markedly influenced by socioeconomic conditions and is therefore subject to cohort effects. The common genetic variation 5-HTTLPR (serotonin transporter gene-linked polymorphic region) has been related to several aspects of alcohol use and addiction but with mixed results, probably due to different environmental interaction effects. We aimed at assessing whether the association between alcohol use and 5-HTTLPR genotype is subject to cohort effects as birth cohorts may be raised in significantly different environments. Methods: We used the database of the Estonian Children Personality Behaviour and Health Study (beginning in 1998). Cohorts of initially 9-year-old (recalled at ages 15 and 18) and 15-year-old (recalled at ages 18 and 25) children provided self-reports on their alcohol use in all data collection waves (complete data available n = 1,075). Results: A significant genotype × gender × cohort interaction effect on the age of consuming the first alcoholic drink was found [ F(2, 1,063) = 7.2, p < 0.001]. Females with the s/s genotype in the older cohort were the latest experimenters with alcohol, while the s/s females of younger cohort had tried alcohol earlier than any other group. In males, there was no significant cohort × genotype interaction, but the 5-HTTLPR genotype was associated with alcohol use, the s/s subjects reporting the highest consumption. Conclusion: Expression of genetic vulnerability to alcohol use is influenced by birth cohort effects. The 5-HTTLPR genotype is associated with alcohol consumption in general population, but the effect depends on gender and birth cohort. [ABSTRACT FROM AUTHOR]

Background: Several theories propose alternative explanations for drug addiction. Objectives: We propose a general theory of transition to addiction that synthesizes knowledge generated in the field of addiction into a unitary explanatory frame. Major principles of the theory: Transition to addiction results from a sequential three-step interaction between: (1) individual vulnerability; (2) degree/amount of drug exposure. The first step, sporadic recreational drug use is a learning process mediated by overactivation of neurobiological substrates of natural rewards that allows most individuals to perceive drugs as highly rewarding stimuli. The second, intensified, sustained, escalated drug use occurs in some vulnerable individuals who have a hyperactive dopaminergic system and impaired prefrontal cortex function. Sustained and prolonged drug use induces incentive sensitization and an allostatic state that makes drugs strongly wanted and needed. Habit formation can also contribute to stabilizing sustained drug use. The last step, loss of control of drug intake and full addiction, is due to a second vulnerable phenotype. This loss-of-control-prone phenotype is triggered by long-term drug exposure and characterized by long-lasting loss of synaptic plasticity in reward areas in the brain that induce a form of behavioral crystallization resulting in loss of control of drug intake. Because of behavioral crystallization, drugs are now not only wanted and needed but also pathologically mourned when absent. Conclusions: This general theory demonstrates that drug addiction is a true psychiatric disease caused by a three-step interaction between vulnerable individuals and amount/duration of drug exposure. [ABSTRACT FROM AUTHOR]

Rationale: Most studies on the subjective effects of ecstasy are based on the assumption that the substance that was taken is 3,4-methylenedioxymethamphetamine (MDMA). However, many tablets sold as ecstasy contain other substances and MDMA in varying doses. So far, few attempts have been made to take this into account while assessing subjective effects. Objectives: This study aims to link the pharmacological content of tablets sold as ecstasy to the subjective experiences reported by ecstasy users. Methods: Self-reported effects on ecstasy tablets were available from 5,786 drug users who handed in their tablets for chemical analysis at the Drug Information and Monitoring System (DIMS) in the Netherlands. Logistic regression was employed to link the pharmacological content of ecstasy tablets to the self-reported subjective effects and compare effects with MDMA to other substances present. Results: MDMA showed a strong association with desirable subjective effects, unparalleled by any other psychoactive substance. However, the association of MDMA was dose-dependent, with higher doses (>120 mg/tablet) likely to evoke more adverse effects. The novel psychostimulants mephedrone and p-fluoroamphetamine were considered relatively desirable, whereas meta-chlorophenylpiperazine (mCPP) and p-methoxymethamphetamine (PMMA) were strongly associated with adverse subjective effects. Also, 3,4-methylene-dioxyamphetamine (MDA) and benzylpiperazine (BZP) were not appreciated as replacement for MDMA. Conclusion: Linking the pharmacological content of ecstasy sold on the street to subjective experiences contributes to a better understanding of the wide range of subjective effects ascribed to ecstasy and provides a strong rationale for the prolonged endurance of MDMA as the key ingredient of the ecstasy market. [ABSTRACT FROM AUTHOR]

±3,4-Methylenedioxymethamphetamine (MDMA, “ecstasy”) reportedly produces unique subjective effects, including increased sociability, feelings of closeness with others, and reduced interpersonal defensiveness. Despite their apparent importance in recreational and potential psychotherapeutic use of MDMA, the defining characteristics and neurobiological mechanisms of these interpersonal effects are poorly understood. We investigated acute effects of MDMA on self-reported sociability and neuronal activation in response to socially threatening (angry and fearful faces) and socially rewarding (happy faces) stimuli. Assessment of social threat response focused on amygdala activation, whereas assessment of social reward focused on ventral striatum activation. Healthy volunteers ( N = 9) reporting past ecstasy use completed three experimental sessions, receiving MDMA (0.75 and 1.5 mg/kg) and placebo (PBO) under double-blind conditions. During peak drug effects, participants underwent functional magnetic resonance imaging while viewing standardized images depicting emotional facial expressions including angry, fearful, happy, and neutral expressions. They also completed standardized self-report measures of sociability. MDMA (1.5 mg/kg) increased self-reported sociability compared to MDMA (0.75 mg/kg) and PBO. MDMA (1.5 mg/kg) attenuated left amygdala response to angry facial expressions compared to PBO, but MDMA did not affect amygdala reactivity to fearful expressions. MDMA (0.75 mg/kg) enhanced ventral striatum response to happy expressions relative to PBO. These data present the first evidence that MDMA may increase sociability in humans both by diminishing responses to threatening stimuli and enhancing responses to rewarding social signals. [ABSTRACT FROM AUTHOR]

The purpose of this study was to review whether methylenedioxymethamphetamine (MDMA) has the appropriate pharmacodynamic profile to be a therapeutic agent. Empirical descriptions of MDMA’s subjective effects in humans will be reviewed to evaluate the proposal that MDMA has psychotherapeutic properties. The focus will be published evidence on its functional effects in therapeutic, medical, and other situations. MDMA is a powerful central nervous system (CNS) stimulant which affects several neurotransmitter systems and intensifies a range of psychobiological functions. Its acute mood effects can be very positive and life enhancing, and the affirmative cognitions engendered during MDMA therapy may well endure afterwards. However, MDMA also has a number of potential anti-therapeutic characteristics. Acutely, it can also intensify negative cognitions, and these may similarly endure over time. Psychotherapists have found that setting, intention, and expectancy are crucial for a positive outcome, but these factors cannot be guaranteed. Post-MDMA, there is a period of neurotransmitter recovery when low moods predominate, and these may exacerbate psychiatric distress. The explanations proposed for MDMA-assisted therapy are all psychodynamic, and a neurochemical model needs to be outlined. It has been suggested that enduring therapeutic gains can follow a single session, but again, this lacks a clear psychopharmacological rationale. Finally, diathesis–stress models suggest that psychiatric individuals are more prone to acute and chronic abreactions to CNS stimulants such as MDMA. There are a number of issues which need to be addressed before it can be argued that MDMA might be clinically useful for psychotherapy. [ABSTRACT FROM AUTHOR]

A number of studies have compared ecstasy users to control groups on various measures of neuropsychological function in order to determine whether ecstasy use results in lasting cognitive deficits. However, few of those studies controlled adequately for non-ecstasy illicit drug use. The aim of this study was to investigate neuropsychological function in chronic ecstasy users while controlling for polydrug use. Neuropsychological function was assessed in four groups—30 current 3,4-methylenedioxymethamphetamine (MDMA) users with a little history of illicit drug use other than ecstasy and cannabis, 30 polydrug controls, 30 drug-naïve controls and 20 ex-MDMA users—using a battery of well-validated, computerized neuropsychological tests. The battery focused on memory, executive function, impulsivity and risk-taking. Few differences were apparent between the groups, and on no measure were the current MDMA users impaired significantly relative to the polydrug controls. However, within the current MDMA users, questionnaire-measured impulsivity correlated with performance on a number of tests—a relationship that was not apparent in the controls. These data highlight the complexity in understanding the current ecstasy literature and suggest that some individuals may be particularly vulnerable to cognitive impairment following chronic use. Although no differences were identified between the current MDMA users and the controls, trait impulsiveness was significantly correlated with impairment on a number of neuropsychological outcome measures in the MDMA users, but not in the controls. These data suggest that impulsive individuals may be those most at risk for the development of cognitive impairment following chronic ecstasy use. [ABSTRACT FROM AUTHOR]

Determining whether, under what circumstances, and to what extent 3,4-methylenedioxymethamphetamine (MDMA) exposure produces chronic changes in human brain function is a critical public health issue. MDMA is a widely used recreational drug commonly sold as “Ecstasy”. Because findings from the animal literature have indicated that specific dosage regimens of MDMA can produce long-lasting alterations in serotonergic function, existing studies of MDMA effects in humans have examined brain serotonin (5-HT) transporters (5-HTT) and receptors or have examined brain structures or functions potentially affected by MDMA. The objectives of this review are to provide a background for interpreting human MDMA neuroimaging research, to examine existing neuroimaging data regarding the rationale for and limitations to human MDMA research, and to provide suggestions for improving the design and interpretation of future neuroimaging approaches. Of the existing neuroimaging studies in human MDMA users, few experimental designs have been replicated across different research groups. Only investigations employing nuclear imaging methods to assay brain 5-HTT levels have been replicated across methods and research laboratories. These studies have found reduced levels of the 5-HTT in recently abstinent MDMA users with some evidence for normalization of 5-HTT levels with prolonged abstinence. However, the sensitivity of these methods is unknown. The current state of neuroimaging in human MDMA users does not permit conclusions regarding the long-term effects of MDMA exposure. Future study designs might benefit from improved sample homogeneity, increased length of MDMA abstinence, longitudinal study design, test–retest measures, serotonergic specificity, and multimodal approaches. [ABSTRACT FROM AUTHOR]

Many animal models relevant to the persistent effects of drugs of abuse necessitate the application of interspecies dose scaling procedures to approximate drug administration regimens in humans, but drug self-administration procedures differ in that they allow animal subjects to control their own drug intake. This report reviews the reinforcing effects of 3,4-methylenedioxymethamphetamine (MDMA), its enantiomers, and several structural analogs in rhesus monkeys, paying particular attention to the pharmacological mechanisms of such reinforcing effects, the development of structure activity relationships among these compounds, the stability of MDMA self-administration behavior over time, and the persistent effects of self-administered MDMA on monoamines. The methylenedioxy amphetamine congeners MDMA, 3,4-methylenedioxyamphetamine, N-ethyl-3,4-methylenedioxyamphetamine, and N-methyl-1-(3,4-methylenedioxyphenyl)-2-butanamine function as reinforcers in rhesus monkeys, maintaining self-administration behavior greater than that engendered by contingent saline but less than that engendered by traditional psychostimulants. These findings are remarkable as structurally distinct serotonergic hallucinogen-like drugs do not maintain reliable self-administration in laboratory animals. During prolonged MDMA self-administration, MDMA-maintained responding progressively weakens, and MDMA eventually fails to maintain significant self-administration. The neurochemical correlates of this effect have not yet been identified. Procedures in which MDMA and related compounds are self-administered can be established in rhesus monkeys. These techniques can be used to engender contingent MDMA exposure without resorting to controversial methods of interspecies dose scaling. As such, further application of self-administration methods may provide important new insights into the persistent effects of MDMA on brain and behavior in nonhuman primates. [ABSTRACT FROM AUTHOR]

Rationale: Systemic injections of the selective corticotropin-releasing factor 1 (CRF1) receptor antagonist CP-154,526 attenuate footshock-stress-induced reinstatement of heroin and cocaine seeking and morphine conditioned place preference (CPP). Intracranial injections of the nonselective CRF receptor antagonist D-Phe-CRF into the bed nucleus of the stria terminalis (BNST), but not the amygdala, attenuate footshock-induced reinstatement of cocaine seeking. However, the brain sites involved in the effect of CP-154,526 on footshock-induced reinstatement of opiate seeking are unknown. Objective: We used a CPP version of the reinstatement model to examine the role of CRF1 receptors in the BNST, amygdala, and nucleus accumbens (NAc) in footshock- or drug-priminginduced reinstatement of extinguished morphine CPP. Methods: Rats acquired morphine CPP over a period of 8 days during which they were given four morphine (10 mg/kg s.c.) and four saline injections and were subsequently confined to distinct chambers for 50 min. Subsequently, the morphine CPP was extinguished in 14 daily sessions during which rats were given saline injections and given access to both the saline- and morphine-paired chambers. The rats were then tested for reinstatement of morphine CPP induced by priming injections of morphine (0 or 3.0 mg/kg s.c.) or by exposure to intermittent footshock (15 min, 0.5 mA). Prior to the test sessions, the rats were given intracranial injections of CP-154,526 (1.0 µg) or vehicle into the BNST, amygdala, or NAc. Results: CP-154,526 injections into the BNST, but not the amygdala or NAc, attenuated footshock-stress-induced reinstatement of morphine CPP. In contrast, CP-154,526 injections into the amygdala or NAc, but not the BNST, attenuated morphine-priming-induced reinstatement of morphine CPP. Conclusion: The present results demonstrate dissociable roles of CRF1 receptors in the BNST, amygdala, and NAc in footshock-stress- vs morphine-priming-induced reinstatement of drug CPP. [ABSTRACT FROM AUTHOR]

Rationale/Objectives: Recent theoretical models suggest that the central executive may not be a unified structure. The present study explored the nature of central executive deficits in ecstasy users. Methods: In study 1, 27 ecstasy users and 34 non-users were assessed using tasks to tap memory updating (computation span; letter updating) and access to long-term memory (a semantic fluency test and the ChicagoWord Fluency Test). In study 2, 51 ecstasy users and 42 non-users completed tasks that assess mental set switching (number/letter and plus/minus) and inhibition (random letter generation). Results: MANOVA revealed that ecstasy users performed worse on both tasks used to assess memory updating and on tasks to assess access to long-term memory (C- and S-letter fluency). However, notwithstanding the significant ecstasy group-related effects, indices of cocaine and cannabis use were also significantly correlated with most of the executive measures. Unexpectedly, in study 2, ecstasy users performed significantly better on the inhibition task, producing more letters than non-users. No group differences were observed on the switching tasks. Correlations between indices of ecstasy use and number of letters produced were significant. Conclusions: The present study provides further support for ecstasy/polydrug-related deficits in memory updating and in access to long-term memory. The surplus evident on the inhibition task should be treated with some caution, as this was limited to a single measure and has not been supported by our previous work. [ABSTRACT FROM AUTHOR]

Rationale: Like amphetamine, a locomotoractivating dose of 3,4-methylenedioxymethamphetamine (MDMA) predominantly excites striatal single-unit activity in freely moving rats. Although both D1- and D2-like dopamine (DA) receptors play important roles in this effect, MDMA, unlike amphetamine, strongly increases both DA and serotonin (5-HT) transmission. Objectives: This study was conducted to investigate the 5-HT receptor mechanisms underlying the striatal effects of MDMA. Methods: We recorded the activity of >200 single units in the striatum of awake, unrestrained rats in response to acute MDMA administration (5 mg/kg) combined with the selective blockade of either 5-HT2A or 5-HT2C/B receptors. Results: Prior administration of SR-46349B (a 5-HT2A antagonist 0.5 mg/kg) blocked nearly all MDMA-induced striatal excitations, which paralleled its significant attenuation of MDMA-induced locomotor activation. Conversely, prior administration of SB-206553 (a 5-HT2C/B antagonist 2.0 mg/kg) had no effect on the amount of MDMA-induced locomotor activation or the distribution of single-unit responses to MDMA. However, a coefficient-of-variation analysis indicated significantly less variability in the magnitude of both MDMA-induced neuronal excitations and inhibitions in rats that were pretreated with SB-206553 compared to vehicle. Analysis of concurrent single-unit activity and behavior confirmed that MDMA-induced striatal activation was not merely due to behavioral feedback, indicating a primary action of MDMA. Conclusion: These results support and extend our previous findings by showing that 5-HT2A and 5-HT2C/B receptors differentially regulate the expression of MDMA-induced behavioral and striatal neuronal responses, either directly or through the modulation of DA transmission. [ABSTRACT FROM AUTHOR]

Presents a study which discussed the nature of ecstasy-group related deficits in associative learning. Definition of associative learning; List of patterns of drug use and other relevant lifestyle variables investigated in the study; Conclusion of the study.

Rationale. The issue of ecstasy-related fatalities has extensively attracted the attention of both the media and the general public, but less so of the scientific literature. Objectives. The aim of the present review is to focus on the epidemiological, clinical and pharmacological issues related to ecstasy fatalities. Results. Possibly due to a number of different reasons, the rates of ecstasy-related deaths seem to have peaked in recent years. MDMA metabolism is regulated by the levels of CYP2D6 and COMT (both exhibit some genetic polymorphism), and range of activity of these enzymes may account for some inter-individual differences in terms of toxic responses to the drug. A small increase in MDMA dosage can lead to a significant rise in drug plasma concentration. Due to their tolerance to MDMA psychoactive effects, some individuals may binge with dosages that may be the cause of serious concern. In experienced users, a reverse tolerance phenomenon can also be observed. Together with ecstasy, most of the misusers take a number of different compounds and the possible rationale of this style of consumption is commented upon here. Frequently, the lethal complications observed after acute MDMA administration can be the consequence of the occurrence of a serotonin syndrome and/or of sympathomimetic overstimulation (both conditions are exacerbated by environmentally induced overheating). Conclusions. A number of methodological problems can contribute to making difficult the interpretation of the role played by ecstasy in so-called ecstasy-related deaths, especially so if accurate information is not available. [ABSTRACT FROM AUTHOR]

Aims. Not every tablet sold as "ecstasy" contains MDMA (3,4-methylenedioxymethamphetamine). The historical origins and evolution of this mismatch will be reviewed, in order to estimate the proportions of ecstasy tablets containing MDMA at different periods over the past 30 years. Methods. Surveys into the pharmacological constituents of ecstasy tablets, dosage levels, and empirical reports of their perceived purity, provide the main data for this review. Results. During the 1980s and early 1990s there were few problems with the purity of ecstasy tablets, and the biochemical evidence shows that they nearly always contained MDMA. During the mid-1990s, the majority of ecstasy tablets continued to contain MDMA, while many others comprised MDA (3,4-methylenedioxyamphetamine), MDEA (3,4-methylenedioxyethylamphetamine), or amphetamine drug mixtures. However, a small proportion (4-20% according to survey, time and place), comprised non-amphetamine drugs such as caffeine, ephedrine, ketamine, paracetamol, or placebo. During the late 1990s, the proportion of ecstasy tablets containing MDMA increased to around 80-90%. The latest reports suggest that non-MDMA tablets are now very infrequent, with purity levels between 90% and 100%. Dosage levels of tablets are also highly variable, with low dose tablet often encountered during the mid-1990s, and high dose tablets now seen more frequently. The theoretical and practical implications of these findings will be debated. Conclusions. The ecstasy purity problem was predominantly a phenomenon of the mid to late 1990s, when many tablets contained substances other than MDMA. Before and since then, the proportion of ecstasy tablets containing MDMA has been very high. [ABSTRACT FROM AUTHOR]

Abstract Rationale: MDMA is a serotonergic neurotoxin but few pre-clinical studies have found long-term behavioural consequences. As human users of MDMA are polydrug users, it is important to investigate whether the behavioural effects of other drugs are modulated by prior exposure to MDMA. Objectives: This study investigated whether pretreatment with a multiple high dose regimen of MDMA altered the rewarding effects of other drugs of abuse. Methods: Adult male Lister Hooded rats (n=10/ group) were pretreated with 10 mg/kg MDMA or 1 ml/kg saline vehicle IP every 2 h for 6 h. Fourteen days later, conditioned place preference (CPP) to d-amphetamine (3 mg/kg), cocaine (20 mg/kg), ethanol (2.0 g/kg), heroin (0.5 mg/kg), or MDMA (10 mg/kg) was assessed. Results: In general, MDMA pretreatment had no effect on drug reward or habituation to the place conditioning apparatus. However, in contrast to saline pretreated rats, those animals receiving MDMA failed to show CPP after ethanol. Conclusion: MDMA pretreatment reduced the rewarding properties of ethanol. This finding may represent a functional consequence of MDMA-induced neurotoxicity. By extrapolation, human users of MDMA may be exposed to an increase in risks associated with alcohol abuse. [ABSTRACT FROM AUTHOR]