Interest Grows in Treatment of Mood Disorders by Classic Psychedelics

There is a buzz surrounding the potential use of psychedelic drugs as novel treatments in mental health—both for the public and within the scientific community. Although this buzz may be akin to a similar, less regulated boom that occurred in the 1950s and 1960s, psychedelic drugs have been used for spiritual and folk healing rituals for thousands of years. In particular, the use of naturally occurring compounds such as N,N-dimethyltryptamine (DMT), ibogaine, psilocybin (“magic mushrooms”), and mescaline have dated to 10,500 BP or earlier, in various locations throughout the world.^1,2 These compounds share similarities in their pharmacologic and psychotropic properties, namely due to their agonistic effects on postsynaptic serotoninergic (5-HT) receptors and consequent hallucinogenic properties. Evidence suggests that the 5-HT2A receptor mediates drug effects, as there is a very strong correlation between receptor affinity and human hallucinogenic potency.³ Together with other synthetically manufactured drugs such as lysergic acid diethylamide (LSD), these substances make up a family of compounds known as classic psychedelics.

Classic psychedelics induce altered states of consciousness that are experienced through visual effects, changes in perception, and distortions in sense of time and space. They can produce a sense of awe and connectedness, as well as personal insights and strong emotions. Research into classic serotonergic psychedelics began in the late 1930s when Albert Hofmann synthesized LSD for use as a cardiorespiratory stimulant only to accidentally ingest it and realize its psychotropic properties.⁴ This event, coupled with an article by R. Gordon Wasson in Life in 1957 entitled “Seeking the Magic Mushroom,” catapulted psychedelics into public and scientific awareness. Numerous research studies were carried out over a decade in various patient cohorts including alcohol use disorder, schizophrenia, and depression before the work was abruptly halted. Growing concerns over the mainstream use of psychedelics, their impact on individuals’ health, and the enactment of the Controlled Substances Act in the United States led to an embargo on research.

Although this initial wave of psychedelic research would not hold up to the rigorous scientific methods and ethical policies of today, it has helped inform the development of present-day trials, both positively and negatively. Current protocols involve intensive screening procedures followed by several hours of psychological support provided before, during, and after the dosing session(s). Psychedelic research has increased exponentially over the past 10 years (Figure), with the market value projected to grow from $2 billion in 2020 to $10.75 billion by 2027.⁵ Besides 3,4-methylenedioxymethamphetamine (MDMA, ecstasy), classic psychedelics—especially psilocybin—are at the forefront of this growth with increasing interest in their therapeutic potential as fast-acting antidepressants.

Depression

Depression is one of the most common psychiatric illnesses throughout the world, affecting more than 290 million individuals.⁶ In 2010, it was reported that depressive disorders alone were the second-leading cause of years lived with disability,6 and the rates of diagnosis are expected to increase as the repercussions from the COVID-19 pandemic become more apparent.⁷ The current standard of care involves antidepressants and/or second-generation antipsychotics along with structured psychotherapy. Unfortunately, for some individuals, these options are sometimes ineffective; current medication options can come with undesirable adverse effects (AEs) and high rates of relapse, in addition to delays in therapeutic effects.

More recently, several clinical trials have demonstrated positive response and remission rates for intravenous and intranasal ketamine, which are thought to produce their antidepressant effects through NMDA receptor antagonism.⁸ Larger-scale studies with longer follow-up periods and larger, representative sample sizes are needed before any concrete conclusions can be made.⁹ Finally, neurostimulation treatments including repetitive transcranial magnetic stimulation have emerged with promising results; however, optimal treatment parameters have yet to be determined and accessibility remains a barrier. Thus, psychedelic drugs have experienced a resurgence in interest as a potential treatment for mood disorders.

Mechanism of Action

Depression is characterized by negativity bias, rigid thought patterns, rumination, and cognitive inflexibility. The brain’s default mode network (DMN)—made up of the ventromedial prefrontal cortex, the perigenual anterior cingulate cortex, and the posterior cingulate cortex—is involved in introspection and self-referential thinking. Altered activity, specifically overactivity, of the DMN has been demonstrated in depression^10,11 in addition to hypoconnectivity with other higher- order cognitive networks such as the executive network and the salience network.^12,13

Although there is some debate in the field, it is believed that classic psychedelics may exert their effects—at least in part—by disrupting activity in these networks.^14,15 Evidence from ayahuasca and psilocybin imaging studies has demonstrated decreases in activity in key regions of the DMN.^16-18 Connectivity alterations may also be strengthened by the promotion of structural and functional neuronal plasticity.¹⁹ Taken together, it is theorized that classic psychedelics exert their effects through differential changes in connectivity, which can result in increased cognitive flexibility and disruptions to maladaptive patterns of thoughts and behavior.

Clinical Trials

Several trials investigating the use of psilocybin for major depression have been conducted using open-label or wait-list controlled designs.^20,21 Results were promising, with rapid and significant antidepressant effects 1 week^20,21 post treatment that were largely sustained at follow-up periods of 3,^20,22-23 6,^22,23 and 12 months²²; a study found that 58% of participants maintained remission at 12 months.²² Likewise, trials have been conducted in patients in end-of-life care who are experiencing depression/anxiety, with similar beneficial outcomes.^24,25 Most AEs reported in the trials were mild and transient, with the most common being a headache following the dosing session.

More recently, a phase 2, double-blind, randomized, controlled trial of escitalopram vs psilocybin-assisted therapy for major depressive disorder (MDD) was conducted.²⁶ Participants randomized to the psilocybin group had 2 dosing sessions separated by 3 weeks, where they received 1 dose of 25 mg of psilocybin at each session and were given placebo pills to take between treatments. Participants in the escitalopram group received 10 to 20 mg of escitalopram administered over 6 weeks. All participants had moderate to severe depression at baseline (mean scores of 14.5 in the psilocybin group and 16.4 in the escitalopram group, as determined by the Quick Inventory of Depressive Symptomatology Self-Report [QIDS-SR-16]).

At the 6-week follow-up, participants in both groups had lower QIDS-SR scores compared with baseline, but the scores did not significantly differ between the escitalopram and psilocybin groups (difference, –2.0; 95% CI, –5.0 to 0.9; P = .17). Similar results between the groups were seen for response (decrease in score of ≥ 50% from baseline) and remission (score of 0-5 using the QIDS-SR-16) rates. Secondary measures of depression (Beck Depression Inventory, Hamilton Depression Rating Scale, Montgomery-Asberg Depression Rating Scale [MADRS]) favored psilocybin over escitalopram. However, the authors did not correct for multiple comparisons, so these results must be interpreted with caution.²⁶

Psilocybin is not the only serotonergic psychedelic being investigated as a potential treatment for depression. The “vine of the souls” plant traditionally found in South America and commonly known as ayahuasca has also demonstrated antidepressant properties in clinical and nonclinical trials.^27-29 In one randomized, controlled trial, patients with treatment-resistant depression who were given a single dose of ayahuasca had significantly lower MADRS scores compared with the placebo group at day 1 (P = .04), day 2 (P = .004), and day 7 (P = .0001) post dose.²⁸ Likewise, 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT), a potent, short-acting psychedelic, and LSD, a serotonergic and dopaminergic partial agonist, have ongoing or completed clinical trials investigating their therapeutic benefits for depression (Table).

Although this evidence demonstrates positive results, the data on efficacy and safety of psychedelics in the treatment of MDD are preliminary and should be considered in the context of several challenges facing the field.²⁹

Ethical Considerations

It appears that research into the therapeutic effects of serotonergic psychedelics will grow in the coming years. As more data become available, establishing clear guidelines for psychedelic-assisted psychotherapy (PAP) will be important. Discussions regarding therapist training, burden of cost, accessibility, and participant safety are needed. Psychedelic therapy is resource intensive and necessitates several hours of specialized therapy. Innovative study protocols aimed at reducing cost and resource burdens will be important in facilitating this research into clinical practice, especially in underresourced communities.

Recent studies have found serious AEs to be rare if proper screening, monitoring, and safety protocols are in place. However, increasing attention to these drugs suggests that investigators need to be cautiously aware of how results of clinical trials are communicated to the public. Transparency regarding AEs, rigorous reviews of study data, and critiques from the scientific community should not be overshadowed by positive results.

Expectancy effects also require consideration—previous experience using psychedelics and enthusiasm in the media may predispose study participants to expect positive treatment outcomes. This issue is further confounded by difficulties in blinding for both participants and therapists. Blinding helps prevent bias and ensures an equal distribution of placebo effects. Current protocols have tried to mitigate these challenges through active placebos or drug comparisons using standard-of-care treatment, but more work is required.

Investigators should also pay special attention to informed consent. It can be difficult to fully prepare someone for a psychedelic experience; it necessitates a thorough consent and preparatory process in which participant boundaries (eg, hand-holding when feeling distressed during the dosing sessions) are established in advance of treatment.

Finally, more research needs to be conducted in participants with diverse ethnic and socioeconomic backgrounds. To date, most studies investigating PAP have been conducted in North America and western Europe with patient cohorts being predominantly white.³⁰ Study samples more representative of the general population need to be a focus in future work.

Future Research

Psychedelic research is expanding into other areas of psychiatry including obsessive-compulsive disorder (OCD), body dysmorphic disorder, substance use disorders, posttraumatic stress disorder, anorexia nervosa, and binge eating disorder (Table). Two exploratory studies have conducted thematic analyses on the psychological effects of and participant perspectives regarding use of ayahuasca for eating disorder (ED) symptoms.^31,32 Both studies reported reductions in ED symptoms along with increased self-love and acceptance. There are now several registered trials investigating the use of psilocybin for various EDs (Table). In addition, a preliminary open-label trial assessed the use of psilocybin for the treatment of OCD.³³ Although the sample size was small (n = 9), there were marked decreases in OCD symptom severity for all participants. To date, there are 4 registered trials investigating psilocybin for the treatment of OCD (Table).

There has also been a large expansion into addictions research (eg, cocaine, alcohol, opioids). Although psilocybin remains the most-studied agent in substance use disorders, ibogaine is also receiving attention. Ibogaine is an indole alkaloid with dissociative properties that may exert therapeutic benefit for substance use disorders by reducing drug cravings, improving mood, and preventing withdrawal symptoms. Promising case reports and open-label trials in opioid addiction have demonstrated elimination of withdrawal symptoms and anticraving capacities following ibogaine administration.^34-37 There are 3 ongoing trials registered in Spain, Brazil, and the United States to investigate ibogaine treatment in methadone detoxification, opioid withdrawal, and alcoholism (Table).

Concluding Thoughts

Classic psychedelic research is rapidly expanding, and preliminary evidence demonstrates therapeutic potential especially for the treatment of major depression and end-of-life distress. However, the field is facing several ethical and methodological challenges that need to be addressed. Larger, well-designed prospective trials are needed to confirm preliminary evidence for the therapeutic actions of psychedelics in individuals with mood and anxiety disorders, including depression and OCD.

Ms Ledwos is research coordinator for psychedelic studies in the Centre for Complex Interventions (CCI) at the Centre for Addiction and Mental Health (CAMH) in Canada. Dr Husain is a clinician scientist and lead of the Mood Disorders Service at CAMH, and associate professor of psychiatry at the University of Toronto in Canada. Dr Castle is scientific director of the CCI at CAMH and professor of psychiatry at the University of Toronto. Dr George is a professor of psychiatry at the University of Toronto and a clinician-scientist at CAMH. He is also a member of the Editorial Board at Psychiatric Times™, and incoming coprincipal editor of Neuropsychopharmacology, the journal of the American College of Neuropsychopharmacology.

References

1. Samorini G. The oldest representations of hallucinogenic mushrooms in the world (Sahara Desert, 9000-7000 BP). Semantic Scholar. 2016. Accessed June 20, 2022. https://www.semanticscholar.org/paper/The-oldest-Representations-of-Hallucinogenic-in-the-Samorini/249dd61313bc743fee0a556d6a6252a1a541c1cb

2. Adovasio JM, Fry GF. Prehistoric psychotropic drug use in Northeastern Mexico and Trans-Pecos Texas. Econ Bot. 1976;30:94-96.

3. Halberstadt AL. Recent advances in the neuropsychopharmacology of serotonergic hallucinogens. Behav Brain Res. 2015;277:99-120.

4. Hofmann A. LSD: My Problem Child. McGraw-Hill Book Company; 1980.

5. Phelps J, Shah RN, Lieberman JA. The rapid rise in investment in psychedelics-cart before the horse. JAMA Psychiatry. 2022;79(3):189-190.

6. Ferrari AJ, Charlson FJ, Norman RE, et al. Burden of depressive disorders by country, sex, age, and year: findings from the global burden of disease study 2010. PLoS Med. 2013;10(11):e1001547.

7. Tang F, Liang J, Zhang H, et al. COVID-19 related depression and anxiety among quarantined respondents. Psychol Health. 2021;36(2):164-178.

8. Bahji A, Vazquez GH, Zarate CA Jr. Comparative efficacy of racemic ketamine and esketamine for depression: a systematic review and meta-analysis. J Affect Disord. 2021;278:542-555. Published correction in J Affect Disord. 2021;281:1001.

9. Rosenblat JD, Ishrat MH, Lee Y, et al. The Canadian Network for Mood and Anxiety Treatments (CANMAT) Task Force report: serotonergic psychedelic treatments for major depressive disorder. Can J Psychiatry. In press.

10. Hamilton JP, Furman DJ, Chang C, et al. Default-mode and task-positive network activity in major depressive disorder: implications for adaptive and maladaptive rumination. Biol Psychiatry. 2011;70(4):327-333.

11. Sheline YI, Barch DM, Price JL, et al. The default mode network and self-referential processes in depression. Proc Natl Acad Sci U S A. 2009;106(6):1942-1947.

12. Goodman ZT, Bainter SA, Kornfeld S, Chang C, Nomi JS, Uddin LQ. Whole-brain functional dynamics track depressive symptom severity. Cereb Cortex. 2021;31(11):4867-4876.

13. Lydon-Staley DM, Kuehner C, Zamoscik V, et al. Repetitive negative thinking in daily life and functional connectivity among default mode, fronto-parietal, and salience networks. Transl Psychiatry. 2019;9(1):234.

14. Smigielski L, Scheidegger M, Kometer M, Vollenweider FX. Psilocybin-assisted mindfulness training modulates self-consciousness and brain default mode network connectivity with lasting effects. Neuroimage. 2019;196:207-215.

15. Pasquini L, Palhano-Fontes F, Araujo DB. Subacute effects of the psychedelic ayahuasca on the salience and default mode networks. J Psychopharmacol. 2020;34(6):623-635.

16. Daws RE, Timmermann C, Giribaldi B, et al. Increased global integration in the brain after psilocybin therapy for depression. Nat Med. 2022;28(4):844-851.

17. Palhano-Fontes F, Andrade KC, Tofoli LF, et al. The psychedelic state induced by ayahuasca modulates the activity and connectivity of the default mode network. PLoS One. 2015;10(2):e0118143.

18. Carhart-Harris RL, Erritzoe D, Williams T, et al. Neural correlates of the psychedelic state as determined by fMRI studies with psilocybin. Proc Natl Acad Sci U S A. 2012;109(6):2138-2143.

19. Ly C, Greb AC, Cameron LP, et al. Psychedelics promote structural and functional neural plasticity. Cell Rep. 2018;23(11):3170-3182.

20. 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(7):619-627.

21. Davis AK, Barrett FS, May DG, et al. Effects of psilocybin-assisted therapy on major depressive disorder: a randomized clinical trial. JAMA Psychiatry. 2021;78(5):481-489. Published correction in JAMA Psychiatry. 2021;78(5):569.

22. Gukasyan N, Davis AK, Barrett FS, et al. Efficacy and safety of psilocybin-assisted treatment for major depressive disorder: prospective 12-month follow-up. J Psychopharmacol. 2022;36(2):151-158.

23. Carhart-Harris RL, Bolstridge M, Day CMJ, et al. Psilocybin with psychological support for treatment-resistant depression: six-month follow-up. Psychopharmacology (Berl). 2018;235(2):399-408.

24. Griffiths RR, Johnson MW, Carducci 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(12):1181-1197.

25. Ross S, Bossis A, Guss J, 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(12):1165-1180.

26. Carhart-Harris R, Giribaldi B, Watts R, et al. Trial of psilocybin versus escitalopram for depression. N Engl J Med. 2021;384(15):1402-1411.

27. Osório Fde L, Sanches RF, Macedo LR, et al. Antidepressant effects of a single dose of ayahuasca in patients with recurrent depression: a preliminary report. Braz J Psychiatry. 2015;37(1):13-20.

28. Palhano-Fontes F, Barreto D, Onias H, et al. Rapid antidepressant effects of the psychedelic ayahuasca in treatment-resistant depression: a randomized placebo-controlled trial. Psychol Med. 2019;49(4):655-663.

29. Sanches RF, de Lima Osório F, Dos Santos RG, et al. Antidepressant effects of a single dose of ayahuasca in patients with recurrent depression: a SPECT study. J Clin Psychopharmacol. 2016;36(1):77-81.

30. Fogg C, Michaels TI, de la Salle S, et al. Ethnoracial health disparities and the ethnopsychopharmacology of psychedelic-assisted psychotherapies. Exp Clin Psychopharmacol. 2021;29(5):539-554.

31. Lafrance A, Loizaga-Velder A, Fletcher J, et al. Nourishing the spirit: exploratory research on ayahuasca experiences along the continuum of recovery from eating disorders. J Psychoactive Drugs. 2017;49(5):427-435.

32. Renelli M, Fletcher J, Tupper KW, et al. An exploratory study of experiences with conventional eating disorder treatment and ceremonial ayahuasca for the healing of eating disorders. Eat Weight Disord. 2020;25(2):437-444.

33. 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(11):1735-1740.

34. Alper KR, Lotsof HS, Frenken GM, et al. Treatment of acute opioid withdrawal with ibogaine. Am J Addict. 1999;8(3):234-242.

35. Brown TK, Alper K. Treatment of opioid use disorder with ibogaine: detoxification and drug use outcomes. Am J Drug Alcohol Abuse. 2018;44(1):24-36.

36. Davis AK, Barsuglia JP, Windham-Herman AM, et al. Subjective effectiveness of ibogaine treatment for problematic opioid consumption: short- and long-term outcomes and current psychological functioning. J Psychedelic Stud. 2017;1(2):65-73.

37. Noller GE, Frampton CM, Yazar-Klosinski B. Ibogaine treatment outcomes for opioid dependence from a twelve-month follow-up observational study. Am J Drug Alcohol Abuse. 2018;44(1):37-46.