The Promise and Perils of Psychedelic Therapy for Psychosis

This post was written as part of my studies in Psychedelics, Altered States, and Transpersonal Psychology at the Alef Trust

When it comes to the idea of using psychedelics for the treatment of psychosis, I err on the side of cautious optimism.

The cautious part of me results from recent revelations in The New York Times about an unreported suicide in a seminal psychedelic study (Borell, 2024) and reported cases of adverse effects of psychedelics on mental wellbeing (e.g. Barber et al, 2022). I’m concerned about the potential for harm associated with the disappointment that a person with treatment-resistant mental health issues (e.g. bipolar disorder, schizophrenia, depression) might feel if they were placed in a control/placebo group or if the psychedelic treatment (with or without accompanying therapy) in a clinical study failed to have positive outcomes.

While this potential always exists in a clinical trial with an experimental treatment for any condition, it seems of particular concern when working with disorders already characterized by extreme highs and lows, with high suicide rates, and/or other serious mental health issues that could worsen responses to disappointment or unrealistic expectations. I’m also slightly concerned about the tendency of some psychedelic research/ers to evangelize, to mix science with a spiritual mission, and play “fast and loose” with ethical considerations; these are but some of the pitfalls of using the scientific method and infrastructure to study the ineffable mysteries.

In addition, Bennett and Bravo (2022) note that “ketamine treatment occasionally increases suicidal ideation in a small fraction of severely depressed individuals (unipolar or bipolar), and this observation has been corroborated by a recent study of ketamine treatment in “real world” clinical treatment” (p. 6). Also, a “manic episode can occur when individuals take a psychedelic substance, perhaps especially when one is predisposed to bipolar disorder” (Gard et al 2021, p. 5), and though Simonsson et al (2024) “find that naturalistic use of psychedelic may be associated with lower rates of psychotic symptoms among adolescents. At the same time, the association between psychedelic use and manic symptoms seems to be associated with genetic vulnerability to schizophrenia or bipolar I disorder” (p.1). The combination of potential for manic or psychotic episodes, along with potential for suicide ideation or realization, gives cause for concern and extreme caution. In fact, “administration of psychedelic doses of psychedelic drugs to patients with schizophrenia would clearly be a hazardous undertaking and is not recommended” (Wolf et al 2023, p.52).

My optimism, on the other hand, results from expert opinion suggesting that a supportive, therapeutic context and follow up might create a setting conducive to therapeutic indications of psychedelics for treatment of psychotic disorders; for example,

[t]he experts agree that psychedelic use may not be contraindicated for psychotic disorders and symptoms alone; rather, a number of supports, precautions, and specific conditions are needed to safely and effectively provide psychedelic-assisted psychotherapy to people with symptoms of psychosis. (LaTorre et al, 2021)

In any clinical trial or treatment context, the usual safety protocols would need to be strictly adhered to and possibly strengthened when working with populations who have or are at risk for psychotic disorders. In particular, the experts interviewed in LaTorre et al’s (2021) study suggested that “a strong support system would be particularly important, as well as the ability to build rapport with the therapist since psychedelic-assisted psychotherapy is highly relational” and that “therapists must be prepared for when someone moves into a psychotic state and that they must be ready to protect and nourish them in a variety of ways for a couple of months”.  Similarly, Bennett and Bravo (2022),  suggest that “the beneficial [sic] of ketamine treatment can be extended in some patients by combining conventional pharmacotherapy, ketamine, and psychotherapy (p. 7).

Therefore, psychotherapeutic support before, during, and after psychedelic interventions should be implemented and maintained in order to increase safety and likelihood of positive outcomes, especially when working with a population with a history of or potential for psychosis.

The consideration of excluding “hallucinogenic” effects from psychedelic substances to treat disorders such as schizophrenia, either through managing dosing or using non-hallucinogenic versions of psychedelics that still retain the effect of neuroplasticity, as suggested by Wolf et al (2023) is an interesting route of exploration, though of course there is a correlation between “mystical experience” and positive outcomes in psychedelic therapy, as recent reviews of the literature posit (e.g. Ko, 2022; Kangslampi, 2023). Without the mystical experience, is psychedelic therapy effective? Is it even “psychedelic”? Though if psychedelic substances without hallucinogenic effects can increase neuroplasticity - otherwise known as reopening critical learning periods - (e.g. Nardou et al, 2023; Calder and Hasler, 2023), then perhaps there is an opportunity to “rewire” the brain to reduce negative symptoms of disorders such as bipolar and schizophrenia, without the need for a mystical experience.

In summary, I think that Gard et al’s (2021) and Arnovitz et al’s (2022) calls for more clinical, ethical, and careful study of the safety and efficacy of using psychedelics to treat psychosis disorders such as bipolar and schizophrenia are warranted. Clinical studies should pay careful attention to ethics and safety, including potentially including ongoing psychotherapeutic support, which could make future studies considerably expensive. For now, I look forward to learning the outcomes of recent clinical trials (e.g. https://www.clinicaltrials.gov/study/NCT05065294 that ended in January and for which I assume publications are forthcoming).

References

Arnovitz, M. D., Spitzberg, A. J., Davani, A. J., Vadhan, N. P., Holland, J., Kane, J. M., & Michaels, T. I. (2022). MDMA for the treatment of negative symptoms in schizophrenia. Journal of Clinical Medicine, 11(8), 3255. https://doi.org/10.3390/jcm11083255

Barber G, Nemeroff CB, Siegel S. (2022) A Case of Prolonged Mania, Psychosis, and Severe Depression After Psilocybin Use: Implications of Increased Psychedelic Drug Availability. American Journal of Psychiatry, 1;179(12):892-896. doi: 10.1176/appi.ajp.22010073. PMID: 36453037

Bennett, R., Yavorsky, C., & Bravo, G. (2022). Ketamine for bipolar depression: Biochemical, psychotherapeutic, and psychedelic approaches. Frontiers in Psychiatry, 13, 867484. https://doi.org/10.3389/fpsyt.2022.867484

Borell, B. (2024, March 21). The psychedelic evangelist. The New York Times. https://www.nytimes.com/2024/03/21/health/psychedelics-roland-griffiths-johns-hopkins.html. Accessed March 24, 2024.

Calder, A. E., & Hasler, G. (2023). Towards an understanding of psychedelic-induced neuroplasticity. Neuropsychopharmacology, 48, 104–112. https://doi.org/10.1038/s41386-022-01389-z

Gard, D. E., Pleet, M. M., Bradley, E. R., Penn, A. D., Gallenstein, M. L., Riley, L. S., DellaCrosse, M., Garfinkle, E. M., Michalak, E. E., & Woolley, J. D. (2021). Evaluating the risk of psilocybin for the treatment of bipolar depression: A review of the research literature and published case studies. Journal of Affective Disorders Reports, 6(2021), 100240. https://doi.org/10.1016/j.jadr.2021.100240

Kangslampi, Samuli.  (2023) Association between mystical-type experiences under psychedelics and improvements in well-being or mental health – A comprehensive review of the evidence. Journal of Psychedelic Studies, 7 (2023) 1, 18–28.

Ko K, Knight G, Rucker JJ and Cleare AJ (2022) Psychedelics, Mystical Experience, and Therapeutic Efficacy: A Systematic Review. Front. Psychiatry 13:917199. doi: 10.3389/fpsyt.2022.917199.

La Torre, J. T., Mahammadli, M., Faber, S. C., et al. (2023). Expert opinion on psychedelic-assisted psychotherapy for people with psychopathological psychotic experiences and psychotic disorders. International Journal of Mental Health and Addiction. Advance online publication. https://doi.org/10.1007/s11469-023-01149-0

Nardou R., Sawyer E, Song YJ, Wilkinson M, Padovan-Hernandez Y, de Deus JL, Wright N, Lama C, Faltin S, Goff LA, Stein-O'Brien GL, Dölen G. (2023)Psychedelics reopen the social reward learning critical period. Nature, 618(7966):790-798. doi: 10.1038/s41586-023-06204-3. Epub 2023 Jun 14. PMID: 37316665; PMCID: PMC10284704.

Simonsson, O., Mosing, M. A., Osika, W., Ullén, F., Larsson, H., Lu, Y., & Wesseldijk, L. W. (2024). Adolescent Psychedelic Use and Psychotic or Manic Symptoms. JAMA Psychiatry. Advance online publication. https://doi.org/10.1001/jamapsychiatry.2024.0047

Wolf, G., Singh, S., Blakolmer, K., & et al. (2023). Could psychedelic drugs have a role in the treatment of schizophrenia? Rationale and strategy for safe implementation. Molecular Psychiatry, 28, 44–58. https://doi.org/10.1038/s41380-022-01832-z