Psychedelics and the Future of Psychiatry

Over the past several years, we have witnessed a psychedelic renaissance, and a growing body of evidence suggests that several psychedelic compounds hold strong therapeutic potential for a wide array of mental health conditions.

Once dismissed as dangerous and having little therapeutic potential, psychedelic drugs are gaining mainstream acceptance. Research data continue to demonstrate that, on the whole, these medicines are not only safe, but mostly well tolerated. Although more research is needed to better understand safety, especially in the context of at-risk conditions, these favorable safety profiles are enabling deeper exploration of these medicines.

The term psychedelic was coined in the 1950s by psychiatrist Humphry Osmond, MD, and it literally means mind-manifesting. This class of drugs produces changes in perception, thought, and mood with minimal disorientation or confusion. Unlike alcohol, benzodiazepines, and barbiturates, psychedelics do not lead to a slowing of cognitive processes or an acceleration of cognition as seen with stimulants.

Several US states and cities are in the process of legalizing or decriminalizing psychedelics like psilocybin, 3,4-methylenedioxymethamphetamine (MDMA), lysergic acid diethylamide (LSD), and others for therapeutic or recreational purposes. In 2020, the Oregon Ballot Measure 109 was passed,1 allowing licensed service providers to administer psilocybin products to individuals 21 years and older and making Oregon the first state to legalize psilocybin. The drug will not be available commercially or for home-based use, as strict regulations are in place to ensure psilocybin will be used only under the supervision of trained facilitators. This was a major milestone in psychedelic medicine, as it opened the door for more widespread access to psilocybin therapy in a safe and legal manner.

The US Food and Drug Administration (FDA) has also shown interest in prioritizing the approval of certain psychedelic drugs. Both psilocybin- assisted psychotherapy for major depressive disorder (MDD) and treatment-resistant depression,2,3 as well as MDMA-assisted psychotherapy for posttraumatic stress disorder (PTSD),4 have received the breakthrough therapy designation from the FDA to fast-track the approval process because of the growing clinical evidence demonstrating substantial improvement over currently available therapies.

Safety Issues and Scaling Up

The growing research results continue to confirm that psychedelic medicines are not only safe, but well tolerated by the majority of recipients. A psilocybin study found that cases of mental health complications following a psychedelic are rare (<0.1%) even in vulnerable populations (<0.2%), and rarer still with proper screening.5 Another study examined the classical psychedelics, LSD, psilocybin, and mescaline. It found no evidence of increased rates of mental health problems; in fact, it demonstrated psychedelic use was associated with reduced psychological distress and suicidality.6 Additionally, results of studies examining psychedelic substance use patterns in humans as well as self-administration in animals suggest that classic psychedelics possess little or no abuse liability and may even be antiaddictive.7

Results of other studies suggest psychedelics may have protective effects when it comes to mental illness in general. Pooling more than 190,000 adults, researchers evaluated the relationship of classic psychedelic use and psychological distress and suicidality. They found that lifetime psychedelic use was associated with significantly reduced odds of past-month psychological distress, past-year suicidal thinking, past-year suicidal planning, and past-year suicide attempt.8 This offers new insight into the potential promise of psychedelics in helping to prevent suicide.

More research is still needed to fully understand safety, especially in the context of at-risk conditions and mechanisms of action. However, the favorable safety profiles are opening doors for deeper exploration of these medicines.

MDMA

MDMA-assisted psychotherapy, the psychedelic treatment closest to receiving FDA approval, is currently undergoing phase 3 clinical trials in patients with PTSD.9 The study included 90 patients with severe, chronic PTSD from a variety of different causes (eg, abuse, combat, sexual trauma). It is worth mentioning that this was a treatment-resistant group, meaning patients had suffered with PTSD for an average of 14 years without relief. All participants completed a 12-week treatment program composed of 3 full-day sessions, during which they received either MDMA or a placebo, plus weekly nondrug psychotherapy sessions. No serious adverse effects were detected beyond transient, mild symptoms during drug treatment such as nausea or sweating. No increases in suicide risk or potential for abuse were noted in the MDMA group relative to placebo. Two months after treatment, 67% of the MDMA cohort no longer qualified for PTSD diagnosis, compared with 32% of the placebo group. In addition, 88% of those in the MDMA group experienced a clinically significant reduction in symptoms (Figure 1).9

MDMA is unique in its ability to promote acceptance of and empathy for self and others. In addition to elevating oxytocin levels, MDMA stimulates the release of the monoamines serotonin, norepinephrine, and dopamine, resulting in improved mood and increased sociability.10 Brain imaging after administration of MDMA shows there is decreased amygdala activation and reduced fear response,11,12 allowing the patient to emotionally engage in therapy without becoming overwhelmed by anxiety or difficult emotions. The combination of medication plus psychotherapy represents a new frontier for the FDA, with unique challenges to be addressed such as therapeutic approaches and therapist training.

Psilocybin

Psilocybin, the main psychoactive component of magic mushrooms, is currently in phase 2 clinical trials for MDD. As a classic psychedelic, it is an agonist of serotonergic 5-HT2A receptors in the brain,13 which are particularly abundant in the cortex and regions associated with cognitive functions and social interactions.14 Stimulation of this receptor has been directly linked to cognitive flexibility, enhanced imagination, and creative thinking.15

In pivotal study results, 71% of individuals with MDD who received 2 doses of psilocybin were treatment responders, and half of the participants entered remission (Figure 2).16 Some follow-up studies after therapy, although small, have shown lasting benefits.17,18

Concluding Thoughts

Psychedelic medicine is forging ahead as a promising new treatment paradigm, in which psychedelics, paired with psychotherapy, have the potential to treat various mental health conditions. Preliminary findings show successful results for these treatments, with significant clinical improvements and fewif anyserious adverse effects. The emerging results likely have implications for future psychiatric research, education, and policyand most importantly, they are poised to offer new therapeutic options and improve the lives of those we serve.

Dr Robison is a board-certified psychiatrist and Chief Medical Officer of Novamind. He is the co-founder of Cedar Psychiatry and serves as the Medical Director for the Center for Change, a leading eating disorders center. Dr Robison previously served as a coordinating investigator for the MAPS-sponsored MDMA-assisted psychotherapy study of eating disorders.

References

1. Oregon psilocybin services. Oregon Health Authority. Accessed December 5, 2021. https://www.oregon.gov/oha/PH/PREVENTIONWELLNESS/Pages/Oregon-Psilocybin-Services.aspx

2. COMPASS Pathways receives FDA breakthrough therapy designation for psilocybin therapy for treatment-resistant depression. News release. COMPASS Pathways; October 23, 2018. Accessed December 5, 2021. https://compasspathways.com/compass-pathways-receives-fda-breakthrough-therapy-designation-for-psilocybin-therapy-for-treatment-resistant-depression

3. Brooks M. FDA grants psilocybin second breakthrough therapy designation. News release. Medscape Medical News; November 25, 2019. Accessed December 5, 2021. https://www.medscape.com/viewarticle/921789

4. FDA grants Breakthrough Therapy designation for MDMA-assisted psychotherapy for PTSD, agrees on special protocol assessment for phase 3 Trials. News release. Multidisciplinary Association for Psychedelic Studies; August 26, 2017. Accessed December 5, 2021. https://maps.org/news/media/6786-press-release-fda-grants-breakthrough-therapy-designation-for-mdma-assisted-psychotherapy-for-ptsd,-agrees-on-special-protocol-assessment-for-phase-3-trials

5. Studerus E, Kometer M, Hasler F, Vollenweider FX. Acute, subacute and long-term subjective effects of psilocybin in healthy humans: a pooled analysis of experimental studies. J Psychopharmacol. 2011;25(11):1434-1452.

6. Krebs TS, Johansen P. Psychedelics and mental health: a population study.PLoS One. 2013;8(8):e63972.

7. Heal DJ, Gosden J, Smith SL. Evaluating the abuse potential of psychedelic drugs as part of the safety pharmacology assessment for medical use in humans.Neuropharmacology. 2018;142:89-115.

8. Hendricks PS, Thorne CB, Clark CB, et al. Classic psychedelic use is associated with reduced psychological distress and suicidality in the United States adult population.J Psychopharmacol. 2015;29(3):280-288.

9. Mitchell JM, Bogenschutz M, Lilienstein A, et al. MDMA-assisted therapy for severe PTSD: a randomized, double-blind, placebo-controlled phase 3 study.Nat Med. 2021;27(6):1025-1033.

10. Hysek CM, Schmid Y, Simmler LD, et al. MDMA enhances emotional empathy and prosocial behavior.Soc Cogn Affect Neurosci. 2014;9(11):1645-1652.

11. Bedi G, Phan KL, Angstadt M, de Wit H. Effects of MDMA on sociability and neural response to social threat and social reward.Psychopharmacology (Berl). 2009;207(1):73-83.

12. Hake HS, Davis JKP, Wood RR, et al. 3,4-methylenedioxymethamphetamine (MDMA) impairs the extinction and reconsolidation of fear memory in rats.Physiol Behav. 2019;199:343-350.

13. Tyl F, Plenek T, Horek J. Psilocybinsummary of knowledge and new perspectives.Eur Neuropsychopharmacol. 2014;24(3):342-356.

14. Celada P, Puig M, Amargs-Bosch M, et al. The therapeutic role of 5-HT1A and 5-HT2A receptors in depression.J Psychiatry Neurosci. 2004;29(4):252-265.

15. Vollenweider FX, Preller KH. Psychedelic drugs: neurobiology and potential for treatment of psychiatric disorders.Nat Rev Neurosci. 2020;21(11):611-624.

16. 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 appears in JAMA Psychiatry. 2021;78(5):569.

17. 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.

18. Agin-Liebes GI, Malone T, Yalch MM, et al. Long-term follow-up of psilocybin-assisted psychotherapy for psychiatric and existential distress in patients with life-threatening cancer.J Psychopharmacol. 2020;34(2):155-166.

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Psychedelics and the Future of Psychiatry