Many other serotonergic drugs are often classified as hallucinogens, but either do not have significant 5-HT2A agonist activity or have other effects that are important. The best-known example is MDMA (methylenedioxymethamphetamine), a drug that has only weak 5-HT2A activity but is a potent releaser of serotonin. It has few typical hallucinogenic effects and is more accurately classified as an empathogen or entactogen. Although this drug can cause significant harm when used illicitly, it has produced very promising results and has shown an excellent safety profile in a series of trials that investigated its effects in the treatment of PTSD.5
Another important group is the NMDA receptor antagonist hallucinogens, including ketamine and phencyclidine (PCP). Ketamine is a Schedule III drug used widely as a dissociative anesthetic. In sub-anesthetic doses, it is a powerful hallucinogen. The discovery of its short-term antidepressant effects has generated much excitement, and it is now seeing significant off-label use for treatment-resistant depression. More limited research has investigated ketamine as a possible treatment for opioid use disorder, alcohol use disorder, and cocaine use disorder. Although their primary molecular target is different, classic hallucinogens stimulate some of the same signaling pathways as the NMDA receptor antagonists, which suggests that there could be some overlap in mechanisms of action.
Two other classes of hallucinogen with possible relevant effects in substance use disorders are the iboga alkaloids and the kappa opioid agonists. Ibogaine and related alkaloids occur naturally in the African shrub Tabernanthe iboga. These alkaloids bind to a broad range of receptors. Although ibogaine is a Schedule I substance in the US, it is used clinically in some addiction treatment centers in other countries, and underground in the US. Although anti-addictive effects of ibogaine have been demonstrated in preclinical studies, drug development has been stalled by toxicity concerns. The analog 18-methoxycoronaridine (18-MC) is currently under study as an anti-addictive agent and is thought to lack the psychoactive properties of ibogaine.
The kappa opioid agonist salvinorin A is found in a species of sage called Salvia divinorum. It causes profound but brief alterations in consciousness when inhaled in quantities under 1 mg. Although there is preclinical evidence for anti-addictive effects of salvinorin A and related compounds, no clinical trials of these drugs for the treatment of substance use disorders have been conducted.
Classic hallucinogens in the treatment of substance use disorders
Following Albert Hoffman’s accidental discovery of the psychoactive effects of LSD in 1943, the 1950s through the early 1970s saw an explosion of research on classic hallucinogens. LSD, psilocybin, and other hallucinogens were legally available for clinical use as an experimental treatment until the mid to late 1960s. Over 1000 articles published during this period documented the treatment of more than 40,000 people with classic hallucinogens. In reaction to concerns about increasing misuse of psychedelics in the context of the cultural upheaval of this period, clinical research on hallucinogens was halted in the early 1970s. The Controlled Substances Act, passed in 1970, placed all the major classic hallucinogens into Schedule I, and clinical research with classic hallucinogens became essentially impossible.
Although there were no further clinical trials with classic hallucinogens for more than 30 years, interest in the therapeutic potential of these drugs has steadily increased in the past decade or so. Extensive evidence supports the relative safety of classic hallucinogens (particularly psilocybin and LSD) in clinical research settings. Early-stage clinical trials of psilocybin or LSD for obsessive-compulsive disorder, anxiety and depression associated with a life-threatening cancer diagnosis, major depression, tobacco use disorder, and alcohol use disorder have recently been published.6-13
In the 1950s through the early 1970s, there was extensive research on the effects of LSD in the treatment of alcoholism. At least a dozen trials with some form of control group were conducted, but these studies were under-powered, and results were mixed. A 2012 meta-analysis of the 6 randomized trials of LSD for alcoholism included 325 participants who received LSD and 211 who received control treatment.14 At the first post-treatment follow-up, 59% of the LSD-treated group were significantly improved compared with 38% of the control participants (odds ratio, 1.96; P = .0003). Moreover, the beneficial effect of LSD remained significant after 6 months. Although these findings are not conclusive evidence of efficacy, they provide a strong argument for renewed clinical investigation of classic hallucinogens for the treatment of alcoholism.
Dr. Bogenschutz is Professor of Psychiatry, New York University School of Medicine, New York.
1. Rehm J, Taylor B, Room R. Global burden of disease from alcohol, illicit drugs and tobacco. Drug Alcohol Rev. 2006;25:503-513.
2. Rosner S, Hackl-Herrwerth A, Leucht S, et al. Opioid antagonists for alcohol dependence. Cochrane Database Syst Rev. 2010;12:CD001867.
3. Rosner S, Hackl-Herrwerth A, Leucht S, et al. Acamprosate for alcohol dependence. Cochrane Database Syst Rev. 2010;9:CD004332.
4. Cahill K, Stevens S, Lancaster T. Pharmacological treatments for smoking cessation. JAMA. 2014;311:193-194.
5. Mithoefer MC, Grob CS, Brewerton TD. Novel psychopharmacological therapies for psychiatric disorders: psilocybin and MDMA. Lancet Psychiatry. 2016;3:481-488.
6. Moreno FA, Wiegand CB, Taitano EK, Delgado PL. Safety, tolerability, and efficacy of psilocybin in 9 patients with obsessive-compulsive disorder. J Clin Psychiatry. 2006;67:1735-1740.
7. Grob CS, Danforth AL, Chopra GS, et al. Pilot study of psilocybin treatment for anxiety in patients with advanced-stage cancer. Arch Gen Psychiatry. 2011;68:71-78.
8. Gasser P, Hostein D, Michel Y, et al. Safety and efficacy of lysergic acid diethylamide-assisted psychotherapy for anxiety associated with life-threatening diseases. J Nerv Ment Dis. 2014;202:513-520.
9. Johnson MW, Garcia-Romeu A, Cosimano MP, et al. Pilot study of the 5-HT2AR agonist psilocybin in the treatment of tobacco addiction. J Psychopharmacol. 2014;28:983-992.
10. Bogenschutz MP, Forcehimes AA, Pommy JA, et al. Psilocybin-assisted treatment for alcohol dependence: a proof-of-concept study. J Psychopharmacol. 2015;29:289-299.
11. Carhart-Harris RL, Bolstridge M, Rucker J, et al. Psilocybin with psychological support for treatment-resistant depression: an open-label feasibility study. Lancet Psychiatry. 2016;3:619-627.
12. Ross S, Bossis A, Guss G, et al. Rapid and sustained symptom reduction following psilocybin treatment for anxiety and depression in patients with life-threatening cancer: a randomized controlled trial. J Psychopharmacol. 2016;30:1165-1180.
13. Griffiths RR, Johnson MW, Carduccci MA, et al. Psilocybin produces substantial and sustained decreases in depression and anxiety in patients with life-threatening cancer: a randomized double-blind trial. J Psychopharmacol. 2016;30:1181-1197.
14. Krebs TS, Johansen PO. Lysergic acid diethylamide (LSD) for alcoholism: meta-analysis of randomized controlled trials. J Psychopharmacol. 2012;26:994-1002.
15. Grof S, Soskin RA, Richards WA, Kurkland AA. DPT as an adjunct in psychotherapy of alcoholics. Int Pharmacopsychiatry. 1973;8:104-115.
16. Rhead JC, Soskin RA, Ibrahim T, et al. Psychedelic drug (DPT)-assisted psychotherapy with alcoholics: a controlled study. J Psych Drugs. 1977;9:287-300.
17. Ludwig AM, Levine J. A controlled comparison of five brief treatment techniques employing LSD, hypnosis, and psychotherapy. Am J Psychother. 1965;19:417-435.
18. Savage C, McCabe OL. Residential psychedelic (LSD) therapy for the narcotic addict: a controlled study. Arch Gen Psychiatry. 1973;28:808-814.
19. Garcia-Romeu A, Griffiths RR, Johnson MW. Psilocybin occasioned mystical experiences in the treatment of tobacco addiction. Curr Drug Abuse Rev. 2014;7:157-164.
20. Halpern JH, Sherwood AR, Passie T, et al. Evidence of health and safety in American members of a religion who use a hallucinogenic sacrament. Med Sci Monit. 2008;14:SR15-22.
21. Fabregas JM, Gonzalez D, Fondevila S, et al. Assessment of addiction severity among ritual users of ayahuasca. Drug Alcohol Depend. 2010;111:257-261.
22. PubChem Compound. https://www.ncbi.nlm.nih.gov/pccompound. Accessed February 21, 2017.