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 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

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. Salvia 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 minutes for 60 minutes after inhalation. Orderly time- and dose-related effects were observed. Drug strength ratings peaked at 2 minutes (first time point) and definite subjective effects were no longer present at approximately 20 minutes after inhalation. Dose-related increases were observed on questionnaire measures of mystical-type experience (Mysticism Scale) and subjective effects associated with classic serotonergic (5-HT2A) 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

Tobacco\u27s 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 (0.2-0.8 mg/kg), cotinine (0.5-5.0 mg/kg), anatabine (0.5-5.0 mg/kg), and myosmine (5.0-20.0 mg/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 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 as- sociations 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 12–17 years from Wave 1 (2013–2014) of the nationally representative Population Assessment of Tobacco and Health (PATH) Study. Participants self-reported ever cigarette, e-cigar- ette, smokeless tobacco, traditional cigar, cigarillo, filtered cigar, hookah, and other tobacco product use; al- cohol, 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 pro- blems and tobacco users were more likely to report internalizing (AOR = 1.6, 95% CI: 1.4–1.8) and ex- ternalizing (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

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 as- sociations 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 12–17 years from Wave 1 (2013–2014) of the nationally representative Population Assessment of Tobacco and Health (PATH) Study. Participants self-reported ever cigarette, e-cigar- ette, smokeless tobacco, traditional cigar, cigarillo, filtered cigar, hookah, and other tobacco product use; al- cohol, 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 pro- blems and tobacco users were more likely to report internalizing (AOR = 1.6, 95% CI: 1.4–1.8) and ex- ternalizing (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

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 interalizing (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 tabacco (AOR=1.6, 95% C1=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 exter- nalizing 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