Considerations in assessing the abuse potential of psychedelics during drug development.

The recent increase in clinical research on the potential therapeutic uses of classic psychedelics has prompted the need to revisit the assessment of the abuse potential of these drugs. The term "classic psychedelic" is used in this manuscript to describe serotonergic 5-HT2A agonists that alter perception, cognition, and mood (i.e., psychedelic effects) and that are currently controlled in Schedule I of the Controlled Substances Act (CSA). Schedule I drugs are subject to the most restrictive controls under the CSA, as they are considered to have a high abuse potential and no currently accepted medical use in the United States (USA). However, these classic psychedelics were placed in Schedule I at the time the CSA was enacted in 1970, and their abuse potential has not been systematically assessed using modern methodology. This paper provides an overview of scientific evaluation of the abuse potential of classic psychedelics and delineates the data that will be needed in support of a recommendation for the rescheduling, if a drug product containing a classic psychedelic gains FDA approval. This article is part of the Special Issue on 'National Institutes of Health Psilocybin Research Speaker Series'.

Mental Health Problems and Onset of Tobacco Use Among 12- to 24-Year-Olds in the PATH Study.

OBJECTIVE: To examine whether mental health problems predict incident use of 12 different tobacco products in a nationally representative sample of youth and young adults. METHOD: This study analyzed Wave (W) 1 and W2 data from 10,533 12- to 24-year-old W1 never tobacco users in the Population Assessment of Tobacco and Health (PATH) Study. Self-reported lifetime internalizing and externalizing symptoms were assessed at W1. Past 12-month use of cigarettes, electronic nicotine delivery systems (ENDS), traditional cigars, cigarillos, filtered cigars, pipe, hookah, snus pouches, other smokeless tobacco, bidis and kreteks (youth only), and dissolvable tobacco was assessed at W2. RESULTS: In multivariable regression analyses, high-severity W1 internalizing (adjusted odds ratio [AOR] = 1.5, 95% CI = 1.3-1.8) and externalizing (AOR = 1.3, 95% CI = 1.1-1.5) problems predicted W2 onset of any tobacco use compared to no/low/moderate severity. High-severity W1 internalizing problems predicted W2 use onset across most tobacco products. High-severity W1 externalizing problems predicted onset of any tobacco (AOR = 1.6, 95% CI = 1.3-1.8), cigarettes (AOR = 1.4, 95% CI = 1.0-2.0), ENDS (AOR = 1.8, 95% CI = 1.5-2.1), and cigarillos (AOR = 1.5, 95% CI = 1.0-2.1) among youth only. CONCLUSION: Internalizing and externalizing problems predicted onset of any tobacco use. However, findings differed for internalizing and externalizing problems across tobacco products, and by age, gender, and race/ethnicity. In addition to screening for tobacco product use, health care providers should screen for a range of mental health problems as a predictor of tobacco use. Interventions addressing mental health problems may prevent youth from initiating tobacco use.

Longitudinal associations between youth tobacco and substance use in waves 1 and 2 of the Population Assessment of Tobacco and Health (PATH) Study.

BACKGROUND: While evidence suggests bidirectional associations between cigarette use and substance (alcohol or drug) use, how these associations are reflected across the range of currently available tobacco products is unknown. This study examined whether ever tobacco use predicted subsequent substance use, and ever substance use predicted subsequent tobacco use among 11,996 U.S. youth (12-17 years) from Waves 1 (2013-2014) and 2 (2014-2015) of the Population Assessment of Tobacco and Health (PATH) Study. METHODS: Ever use of cigarettes, e-cigarettes, traditional cigars, cigarillos, filtered cigars, pipe, hookah, snus pouches, smokeless tobacco excluding snus pouches, dissolvable tobacco, bidis, kreteks, alcohol, marijuana, prescription drugs, and other drugs (cocaine and other stimulants, heroin, inhalants, solvents, and hallucinogens) was assessed at Wave 1 followed by past 12-month use assessments at Wave 2. The analyses included covariates (demographics, mental health, sensation seeking, prior use) to mitigate confounding. RESULTS: Ever tobacco use predicted subsequent substance use. The magnitude of the associations was lowest for alcohol, higher for marijuana, and highest for other drugs. Ever substance use also predicted subsequent tobacco use. Specifically, ever alcohol, marijuana, and non-prescribed Ritalin/Adderall use predicted tobacco-product use. Ever e-cigarette and cigarette use exclusively and concurrently predicted subsequent any drug (including and excluding alcohol) use. E-cigarette and cigarette use associations in the opposite direction were also significant; the strongest associations were observed for exclusive cigarette use. CONCLUSION: Tobacco and substance use prevention efforts may benefit from comprehensive screening and interventions across tobacco products, alcohol, and drugs, and targeting risk factors shared across substances.

Co-occurrence of tobacco product use, substance use, and mental health problems among youth: Findings from wave 1 (2013-2014) of the population assessment of tobacco and health (PATH) study.

INTRODUCTION: Cigarette use is associated with substance use and mental health problems among youth, but associations are unknown for non-cigarette tobacco product use, as well as the increasingly common poly-tobacco use. METHODS: The current study examined co-occurrence of substance use and mental health problems across tobacco products among 13,617 youth aged 12-17years from Wave 1 (2013-2014) of the nationally representative Population Assessment of Tobacco and Health (PATH) Study. Participants self-reported ever cigarette, e-cigarette, smokeless tobacco, traditional cigar, cigarillo, filtered cigar, hookah, and other tobacco product use; alcohol, marijuana, and other drugs; and lifetime substance use, internalizing and externalizing problems. RESULTS: In multivariable regression analyses, use of each tobacco product was associated with substance use, particularly cigarillos and marijuana (AOR=18.9, 95% CI: 15.3-23.4). Cigarette (AOR=14.7, 95% CI: 11.8-18.2) and cigarillo (AOR=8.1, 95% CI: 6.3-10.3) use were strongly associated with substance use problems and tobacco users were more likely to report internalizing (AOR=1.6, 95% CI: 1.4-1.8) and externalizing (AOR=1.4, 95% CI: 1.3-1.6) problems. Female tobacco users were more likely to have internalizing problems than male tobacco users. Poly-tobacco users were more likely than exclusive users to use substances (AOR=3.4, 95% CI: 2.7-4.3) and have mental health (AOR=1.2, 95% CI: 1.0-1.5) and substance use (AOR=4.7, 95% CI: 3.4-6.6) problems. CONCLUSIONS: Regardless of the tobacco product used, findings reveal high co-occurrence of substance use and mental health problems among youth tobacco users, especially poly-tobacco users. These findings suggest the need to address comorbidities among high risk youth in prevention and treatment settings.

Tobacco's minor alkaloids: Effects on place conditioning and nucleus accumbens dopamine release in adult and adolescent rats.

Tobacco products are some of the most commonly used psychoactive drugs worldwide. Besides nicotine, alkaloids in tobacco include cotinine, myosmine, and anatabine. Scientific investigation of these constituents and their contribution to tobacco dependence is less well developed than for nicotine. The present study evaluated the nucleus accumbens dopamine-releasing properties and rewarding and/or aversive properties of nicotine (0.2-0.8mg/kg), cotinine (0.5-5.0mg/kg), anatabine (0.5-5.0mg/kg), and myosmine (5.0-20.0mg/kg) through in vivo microdialysis and place conditioning, respectively, in adult and adolescent male rats. Nicotine increased dopamine release at both ages, and anatabine and myosmine increased dopamine release in adults, but not adolescents. The dopamine release results were not related to place conditioning, as nicotine and cotinine had no effect on place conditioning, whereas anatabine and myosmine produced aversion in both ages. While the nucleus accumbens shell is hypothesized to play a role in strengthening drug-context associations following initiation of drug use, it may have little involvement in the motivational effects of tobacco constituents once these associations have been acquired. Effects of myosmine and anatabine on dopamine release may require a fully developed dopamine system, since no effects of these tobacco alkaloids were observed during adolescence. In summary, while anatabine and myosmine-induced dopamine release in nucleus accumbens may play a role in tobacco dependence in adults, the nature of that role remains to be elucidated.

Co-occurrence of tobacco product use, substance use, and mental health problems among adults: Findings from Wave 1 (2013-2014) of the Population Assessment of Tobacco and Health (PATH) Study.

BACKGROUND: Although non-cigarette tobacco product use is increasing among U.S. adults, their associations with substance use and mental health problems are unclear. This study examined co-occurrence of tobacco use, substance use, and mental health problems, and its moderation by gender, among 32,202U.S. adults from Wave 1 (2013-2014) of the nationally representative longitudinal Population Assessment of Tobacco and Health (PATH) Study. METHODS: Participants self-reported current cigarette, e-cigarette, traditional cigar, cigarillo, filtered cigar, hookah, smokeless tobacco and other tobacco product use; past year alcohol, marijuana, and other drug use; and past year substance use, internalizing and externalizing problems. RESULTS: Compared to non-current tobacco users, current users were more likely to report alcohol or drug use (adjusted odds ratio (AOR)=2.6; 95% confidence interval (CI): 2.3, 2.9), with the strongest associations observed for cigarillo and hookah users. Across all tobacco product groups, users were more likely to report internalizing (AOR=1.9; 95% CI: 1.7, 2.1), externalizing (AOR=1.6; 95% CI: 1.5, 1.8), and substance use (AOR=3.4; 95% CI: 2.9, 4.1) problems than non-users. Gender moderated many of these associations and, of these, all non-cigarette tobacco product associations were stronger among females. CONCLUSIONS: This nationally representative study of U.S. adults is the first to comprehensively document tobacco use, substance use, and mental health comorbidities across the range of currently available tobacco products, while also demonstrating that female tobacco users are at increased risk for substance use and mental health problems. These findings may point to gender differences in vulnerability and suggest that interventions incorporate gender-specific approaches.

Nicotine reinforcement in never-smokers.

RATIONALE: Global tobacco-related mortality dwarfs that of all other drugs. Nicotine is believed to be the primary agent responsible for tobacco use and addiction. However, nicotine is a relatively weak and inconsistent reinforcer in nonhumans and nicotine reinforcement has not been demonstrated in never-smokers. OBJECTIVES: This study investigated the discriminative, subjective, and reinforcing effects of nicotine in never-smokers. METHODS: Eighteen never-smokers (< 50 lifetime nicotine exposures) participated in a double-blind study. During a drug discrimination phase, volunteers ingested oral nicotine and placebo capsules (quasi-random order) at least 2 h apart and rated subjective effects repeatedly for 2 h after ingestion in daily sessions. Blocks of 10 sessions were continued until significant discrimination was achieved (p ≤ 0.05, binomial test; ≥ 8 of 10). Following discrimination, nicotine choice was tested by having volunteers choose which capsule set to ingest on each daily session. Successive blocks of 10 sessions were conducted until choice for nicotine or placebo met significance within each volunteer (≥ 8 of 10 sessions). RESULTS: All 18 volunteers significantly discriminated nicotine from placebo; the lowest dose discriminated ranged from 1.0 to 4.0 mg/70 kg. Nine volunteers significantly chose nicotine (choosers) and nine significantly chose placebo (nicotine avoiders). The choosers reported predominately positive nicotine subjective effects (e.g., alert/attentive, good effects, liking), while avoiders tended to report negative effects (e.g., dizzy, upset stomach, disliking). Both choosers and avoiders attributed their choice to the qualitative nature of drug effects. CONCLUSIONS: These results provide the first evidence that nicotine can function as a reinforcer in some never-smokers.

Inhaled vs. oral alprazolam: subjective, behavioral and cognitive effects, and modestly increased abuse potential.

RATIONALE: Infrahuman and human studies suggest that a determinant of the abuse potential of a drug is rate of onset of subjective effects. OBJECTIVES: This study sought to determine if the rate of onset of subjective effects and abuse potential of alprazolam would be increased when administered via inhalation vs. the oral route. METHODS: Placebo, inhaled alprazolam (0.5, 1, and 2 mg), and oral alprazolam (1, 2, and 4 mg) were administered under double-blind, double-dummy conditions using a crossover design in 14 healthy participants with histories of drug abuse. Participant and observer ratings and behavioral and cognitive performance measures were assessed repeatedly during 9-h sessions. RESULTS: Both routes of administration produced orderly dose and time-related effects, with higher doses producing greater and longer-lasting effects. Onset of subjective effects following inhaled alprazolam was very rapid (e.g., 2 vs. 49 min after 2 mg inhaled vs. oral). On measures of abuse potential (e.g., liking and good effects), inhaled alprazolam was more potent, as evidenced by a leftward shift in the dose-response curve. Despite the potency difference, at the highest doses, peak ratings of subjective effects related to abuse potential (e.g., "drug liking") were similar across the two routes. On other measures (e.g., sedation and performance), the routes were equipotent. CONCLUSIONS: The inhaled route of administration modestly increased the abuse potential of alprazolam despite significantly increasing its rate of onset. If marketed, the reduced availability and increased cost of inhaled alprazolam may render the societal risk of increased abuse to be low.

Acute cognitive effects of high doses of dextromethorphan relative to triazolam in humans.

BACKGROUND: Although concerns surrounding high-dose dextromethorphan (DXM) abuse have recently increased, few studies have examined the acute cognitive effects of high doses of DXM. The aim of this study was to compare the cognitive effects of DXM with those of triazolam and placebo. METHODS: Single, acute, oral doses of DXM (100, 200, 300, 400, 500, 600, 700, 800 mg/70 kg), triazolam (0.25, 0.5mg/70 kg), and placebo were administered p.o. to twelve healthy volunteers with histories of hallucinogen use, under double-blind conditions, using an ascending dose run-up design. Effects on cognitive performance were examined at baseline and after drug administration for up to 6h. RESULTS: Both triazolam and DXM produced acute impairments in attention, working memory, episodic memory, and metacognition. Impairments observed following doses of 100-300 mg/70 kg DXM were generally smaller in magnitude than those observed after 0.5mg/70 kg triazolam. Doses of DXM that impaired performance to the same extent as triazolam were in excess of 10-30 times the therapeutic dose of DXM. CONCLUSION: The magnitude of the doses required for these effects and the absence of effects on some tasks within the 100-300 mg/70 kg dose range of DXM, speak to the relatively broad therapeutic window of over-the-counter DXM preparations when used appropriately. However, the administration of supratherapeutic doses of DXM resulted in acute cognitive impairments on all tasks that were examined. These findings are likely relevant to cases of high-dose DXM abuse.

Dose-related effects of salvinorin A in humans: dissociative, hallucinogenic, and memory effects.

RATIONALE: Salvinorin A is a kappa opioid agonist and the principal psychoactive constituent of the plant Salvia divinorum, which has increased in popularity as a recreational drug over the past decade. Few human studies have examined salvinorin A. OBJECTIVE: This double-blind, placebo-controlled study evaluated the dose-related effects of inhaled salvinorin A in individuals with histories of hallucinogen use. METHODS: Eight healthy hallucinogen-using adults inhaled up to 16 doses of salvinorin A (0.375-21 µg/kg) in ascending order. Physiological, behavioral, and subjective effects were assessed every 2 min for 60 min after administration. Qualitative subjective effects were assessed retrospectively via questionnaires at the end of sessions. Persisting effects were assessed 1 month later. RESULTS: Orderly dose-related effects peaked at 2 min and then rapidly dissipated, replicating previous findings. Subjective effects were intense, with maximal drug strength ratings or unresponsiveness frequently observed at high doses. Questionnaires assessing qualitative effects (Hallucinogen Rating Scale, Pharmacological Class Questionnaire) suggested some overlap with serotonergically mediated classic hallucinogens. Salvinorin A also produced dose-related dissociative effects and impairments in recall/recognition memory. At 1-month follow-up, there was no evidence of persisting adverse effects. Participants reported that salvinorin A effects were qualitatively different from other drugs. CONCLUSIONS: Salvinorin A produces a unique profile of subjective and cognitive effects, including strong dissociative effects and memory impairment, which only partially overlap with classic hallucinogen effects. Along with nonhuman studies of salvinorin A, these results are important for understanding the neurobiology of the kappa opioid system and may ultimately have important therapeutic applications.

High doses of dextromethorphan, an NMDA antagonist, produce effects similar to classic hallucinogens.

RATIONALE: Although reports of dextromethorphan (DXM) abuse have increased recently, few studies have examined the effects of high doses of DXM. OBJECTIVE: This study in humans evaluated the effects of supratherapeutic doses of DXM and triazolam. METHODS: Single, acute oral doses of DXM (100, 200, 300, 400, 500, 600, 700, and 800 mg/70 kg), triazolam (0.25 and 0.5 mg/70 kg), and placebo were administered to 12 healthy volunteers with histories of hallucinogen use, under double-blind conditions, using an ascending dose run-up design. Subjective, behavioral, and physiological effects were assessed repeatedly after drug administration for 6 h. RESULTS: Triazolam produced dose-related increases in subject-rated sedation, observer-rated sedation, and behavioral impairment. DXM produced a profile of dose-related physiological and subjective effects differing from triazolam. DXM effects included increases in blood pressure, heart rate, and emesis; increases in observer-rated effects typical of classic hallucinogens (e.g., distance from reality, visual effects with eyes open and closed, joy, anxiety); and participant ratings of stimulation (e.g., jittery, nervous), somatic effects (e.g., tingling, headache), perceptual changes, end-of-session drug liking, and mystical-type experience. After 400 mg/70 kg DXM, 11 of 12 participants indicated on a pharmacological class questionnaire that they thought they had received a classic hallucinogen (e.g., psilocybin). Drug effects resolved without significant adverse effects by the end of the session. In a 1-month follow-up, volunteers attributed increased spirituality and positive changes in attitudes, moods, and behavior to the session experiences. CONCLUSIONS: High doses of DXM produced effects distinct from triazolam and had characteristics that were similar to the classic hallucinogen psilocybin.

Human psychopharmacology and dose-effects of salvinorin A, a kappa opioid agonist hallucinogen present in the plant Salvia divinorum.

Salvinorin A is a potent, selective nonnitrogenous kappa opioid agonist and the known psychoactive constituent of Salvia divinorum, a member of the mint family that has been used for centuries by Mazatec shamans of Mexico for divination and spiritual healing. S. divinorum has over the last several years gained increased popularity as a recreational drug. This is a double-blind, placebo controlled study of salvinorin A in 4 psychologically and physically healthy hallucinogen-using adults. Across sessions, participants inhaled 16 ascending doses of salvinorin A and 4 intermixed placebo doses under comfortable and supportive conditions. Doses ranged from 0.375 µg/kg to 21 µg/kg. Subject-rated drug strength was assessed every 2 min for 60 min after inhalation. Orderly time- and dose-related effects were observed. Drug strength ratings peaked at 2 min (first time point) and definite subjective effects were no longer present at approximately 20 min after inhalation. Dose-related increases were observed on questionnaire measures of mystical-type experience (Mysticism Scale) and subjective effects associated with classic serotonergic (5-HT2(A)) hallucinogens (Hallucinogen Rating Scale). Salvinorin A did not significantly increase heart rate or blood pressure. Participant narratives indicated intense experiences characterized by disruptions in vestibular and interoceptive signals (e.g., change in spatial orientation, pressure on the body) and unusual and sometimes recurring themes across sessions such as revisiting childhood memories, cartoon-like imagery, and contact with entities. Under these prepared and supportive conditions, salvinorin A occasioned a unique profile of subjective effects having similarities to classic hallucinogens, including mystical-type effects.

Caffeinated energy drinks--a growing problem.

Since the introduction of Red Bull in Austria in 1987 and in the United States in 1997, the energy drink market has grown exponentially. Hundreds of different brands are now marketed, with caffeine content ranging from a modest 50 mg to an alarming 505 mg per can or bottle. Regulation of energy drinks, including content labeling and health warnings differs across countries, with some of the most lax regulatory requirements in the U.S. The absence of regulatory oversight has resulted in aggressive marketing of energy drinks, targeted primarily toward young males, for psychoactive, performance-enhancing and stimulant drug effects. There are increasing reports of caffeine intoxication from energy drinks, and it seems likely that problems with caffeine dependence and withdrawal will also increase. In children and adolescents who are not habitual caffeine users, vulnerability to caffeine intoxication may be markedly increased due to an absence of pharmacological tolerance. Genetic factors may also contribute to an individual's vulnerability to caffeine-related disorders including caffeine intoxication, dependence, and withdrawal. The combined use of caffeine and alcohol is increasing sharply, and studies suggest that such combined use may increase the rate of alcohol-related injury. Several studies suggest that energy drinks may serve as a gateway to other forms of drug dependence. Regulatory implications concerning labeling and advertising, and the clinical implications for children and adolescents are discussed.

d-LSD-induced c-Fos expression occurs in a population of oligodendrocytes in rat prefrontal cortex.

Induction of mRNA or protein for immediate-early genes, such as c-fos, is used to identify brain areas, specific cell types, and neuronal circuits that become activated in response to various stimuli including psychoactive drugs. The objective of the present study was to identify the cell types in the prefrontal cortex in which lysergic acid diethylamide (d-LSD) induces c-Fos expression. Systemic administration of d-LSD resulted in a dose-dependent increase in c-Fos immunoreactivity. Although c-Fos-positive cells were found in all cortical layers, they were most numerous in layers III, IV, and V. d-LSD-induced c-Fos immunoreactivity was found in cells co-labeled with anti-neuron-specific enolase or anti-oligodendrocyte Oligo1. The Oligo1-labeled cells had small, round bodies and nuclear diameters characteristic of oligodendrocytes. Studies using confocal microscopy confirmed colocalization of c-Fos-labeled nuclei in NeuN-labeled neurons. Astrocytes and microglia labeled with glial fibrillary acidic protein antibody and OX-42 antibody, respectively, did not display LSD-induced c-Fos expression. Pyramidal neurons labeled with anti-neurofilament antibody also did not show induction of c-Fos immunoreactivity after systemic d-LSD administration. The present study demonstrates that d-LSD induced expression of c-Fos in the prefrontal cortex occurs in subpopulations of neurons and in oligodendrocytes, but not in pyramidal neurons, astrocytes, and microglia.

Hallucinogen-like effects of N,N-dipropyltryptamine (DPT): possible mediation by serotonin 5-HT1A and 5-HT2A receptors in rodents.

N,N-dipropyltryptamine (DPT) is a synthetic tryptamine hallucinogen which has been used psychotherapeutically in humans, but has been studied preclinically only rarely. In the present studies, DPT was tested in a drug-elicited head-twitch assay in mice, and in rats trained to discriminate lysergic acid diethylamide (LSD), N,N-dimethyl-4-phosphoryloxytryptamine (psilocybin), or 3,4-methylenedioxymethamphetamine (MDMA). A separate group of rats was also trained to recognize DPT itself as a discriminative stimulus, and in all cases, the behavioral effects of DPT were challenged with the selective serotonin (5-HT)2A antagonist M100907, the 5-HT1A selective antagonist WAY-100635, or their combination. In the head-twitch assay, DPT elicited dose-dependent effects, producing a biphasic dose-effect curve. WAY-100635 produced a parallel rightward shift in the dose-effect curve for head twitches, indicative of surmountable antagonism, but the antagonist effects of M100907 were functionally insurmountable. DPT produced partial to full substitution when tested in rats trained to discriminate LSD, psilocybin or MDMA, and served as a discriminative stimulus. In all cases, the antagonist effects of M100907 were more profound than were those of WAY-100635. DPT is thus active in two rodent models relevant to 5-HT2 agonist activity. The effectiveness with which M100907 antagonizes the behavioral actions of this compound strongly suggest that the 5-HT2A receptor is an important site of action for DPT, but the modulatory actions of WAY-100635 also imply a 5-HT1A-mediated component to the actions of this compound.

The behavioral pharmacology of hallucinogens.

Until very recently, comparatively few scientists were studying hallucinogenic drugs. Nevertheless, selective antagonists are available for relevant serotonergic receptors, the majority of which have now been cloned, allowing for reasonably thorough pharmacological investigation. Animal models sensitive to the behavioral effects of the hallucinogens have been established and exploited. Sophisticated genetic techniques have enabled the development of mutant mice, which have proven useful in the study of hallucinogens. The capacity to study post-receptor signaling events has lead to the proposal of a plausible mechanism of action for these compounds. The tools currently available to study the hallucinogens are thus more plentiful and scientifically advanced than were those accessible to earlier researchers studying the opioids, benzodiazepines, cholinergics, or other centrally active compounds. The behavioral pharmacology of phenethylamine, tryptamine, and ergoline hallucinogens are described in this review, paying particular attention to important structure activity relationships which have emerged, receptors involved in their various actions, effects on conditioned and unconditioned behaviors, and in some cases, human psychopharmacology. As clinical interest in the therapeutic potential of these compounds is once again beginning to emerge, it is important to recognize the wealth of data derived from controlled preclinical studies on these compounds.