Recreational abuse of newly emerging """"""""club drugs"""""""" including atypical hallucinogens, which is exacerbated by internet websites, is a significant and growing national problem. Abuse of these drugs among adolescents and young adults is a particular concern. A series of studies in human volunteers will provide new information about the pharmacological mechanisms of action, comparative pharmacology, and abuse liability of three mechanistically different hallucinogen compounds that are of concern to national authorities and about which there are major gaps in our current understanding: salvinorin A (a ? opioid agonist), N,N-dimethyltryptamine (DMT, a 5-HT2A agonist), and dextromethorphan (an NMDA antagonist). For all three compounds, dose-effect studies using low to high doses in participants with histories of hallucinogen drug abuse will provide new information about subjective effects, psychiatric symptoms, behavioral/cognitive impairment, physiological effects, relative abuse liability, and possible persisting toxic consequences of use. Pharmacological mechanisms of action will be investigated by examining the effects of selective receptor antagonists and by systematically comparing pairs of drugs acting at different receptor sites. Specifically, the first three studies will focus on two short-acting, atypical hallucinogens: salvinorin A and DMT. The first study will use a double- blind, double-dummy design to compare the effects of inhaled vaporized salvinorin A and intravenous DMT across a wide range of doses and measures, characterizing both robust and subtle differences between the two compounds. The second and third studies will further explore mechanisms of action by examining interactions of both drugs with naltrexone (a selective opioid receptor antagonist) and ketanserin (a selective 5-HT2A antagonist). The subsequent three studies will focus on the relatively longer-acting compound dextromethorphan, which is a noncompetitive NMDA-antagonist found in over-the-counter cough and cold medications and abused at high doses as a hallucinogen. The fourth study will compare the dose-effects of oral dextromethorphan with oral psilocybin (a classic 5-HT2A-mediated hallucinogen with a duration of action similar to dextromethorphan) characterizing both robust and subtle differences between the two compounds. The fifth and sixth studies will further explore the mechanisms of action of dextromethorphan (vs. psilocybin) by examining interactions with naltrexone (opioid antagonists are used clinically to treat dextromethorphan overdose) and ketanserin. Overall, this research program exploring the comparative pharmacology and specific mechanisms of action of salvinorin A, DMT, and dextromethorphan will have relevance to the development of prevention and treatment strategies for the abuse of these emerging abused hallucinogen drugs. Regarding public health more generally, this research has potentially wide-ranging implications for understanding the neurobiological basis of psychiatric and neurological disorders that involve the ? opioid, 5- HT, and NMDA receptor pathways.

Public Health Relevance

Recreational abuse of club drugs including hallucinogens is a significant and growing national problem, particularly in adolescents and young adults, and internet websites encourage abuse by describing how some of these drugs can be readily obtained as naturally-occurring plants or in over-the-counter cough and cold medications. This project will investigate the physical, behavioral, cognitive, and subjectively rewarding effects of three abused hallucinogens with different mechanisms of action in the brain, and will also examine whether certain pharmacological compounds can block the effects of each drug. The project has important implications for prevention and treatment strategies for the abuse of these hallucinogen drugs, as well as for understanding the brain mechanisms of psychiatric and neurological disorders.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Project (R01)
Project #
5R01DA003889-30
Application #
8675809
Study Section
Biobehavioral Regulation, Learning and Ethology Study Section (BRLE)
Program Officer
Kautz, Mary A
Project Start
1984-07-01
Project End
2018-02-28
Budget Start
2014-03-01
Budget End
2015-02-28
Support Year
30
Fiscal Year
2014
Total Cost
$450,470
Indirect Cost
$172,402
Name
Johns Hopkins University
Department
Psychiatry
Type
Schools of Medicine
DUNS #
001910777
City
Baltimore
State
MD
Country
United States
Zip Code
21218
Johnson, Matthew W; Garcia-Romeu, Albert; Griffiths, Roland R (2016) Long-term follow-up of psilocybin-facilitated smoking cessation. Am J Drug Alcohol Abuse :1-6
Barrett, Frederick S; Bradstreet, Matthew P; Leoutsakos, Jeannie-Marie S et al. (2016) The Challenging Experience Questionnaire: Characterization of challenging experiences with psilocybin mushrooms. J Psychopharmacol 30:1279-1295
Johnson, Matthew W; MacLean, Katherine A; Caspers, Michael J et al. (2016) Time course of pharmacokinetic and hormonal effects of inhaled high-dose salvinorin A in humans. J Psychopharmacol 30:323-9
Maqueda, Ana Elda; Valle, Marta; Addy, Peter H et al. (2016) Naltrexone but Not Ketanserin Antagonizes the Subjective, Cardiovascular, and Neuroendocrine Effects of Salvinorin-A in Humans. Int J Neuropsychopharmacol 19:
Carbonaro, Theresa M; Bradstreet, Matthew P; Barrett, Frederick S et al. (2016) Survey study of challenging experiences after ingesting psilocybin mushrooms: Acute and enduring positive and negative consequences. J Psychopharmacol 30:1268-1278
Griffiths, Roland R; Johnson, Matthew W; Carducci, Michael A et al. (2016) Psilocybin produces substantial and sustained decreases in depression and anxiety in patients with life-threatening cancer: A randomized double-blind trial. J Psychopharmacol 30:1181-1197
Maqueda, Ana Elda; Valle, Marta; Addy, Peter H et al. (2015) Salvinorin-A Induces Intense Dissociative Effects, Blocking External Sensory Perception and Modulating Interoception and Sense of Body Ownership in Humans. Int J Neuropsychopharmacol 18:
Hendricks, Peter S; Johnson, Matthew W; Griffiths, Roland R (2015) Psilocybin, psychological distress, and suicidality. J Psychopharmacol 29:1041-3
Barrett, Frederick S; Johnson, Matthew W; Griffiths, Roland R (2015) Validation of the revised Mystical Experience Questionnaire in experimental sessions with psilocybin. J Psychopharmacol 29:1182-90
Reissig, Chad J; Harrison, Joseph A; Carter, Lawrence P et al. (2015) Inhaled vs. oral alprazolam: subjective, behavioral and cognitive effects, and modestly increased abuse potential. Psychopharmacology (Berl) 232:871-83

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