Psychedelic Trials and Research

March 14, 2023

Written By: Alia Warner, PhD

What’s Up with All This Psychedelic Stuff?

While catching up over the holidays, my father asked me a timely and earnest question, “What’s up with all this psychedelic stuff?” The recent explosion of psychedelic research regarding treatment for mental illness may come as a surprise to many, especially adults that lived through the initial application of psychedelics to mental health treatment in the 1950s through the early 1970s. Despite the war on drugs in the 70s and 80s, psychedelics did not go out of style. In fact, a poll conducted in July of 2022 revealed 28% of Americans have tried psychedelics (Orth, 2022), though use remains largely recreational and outside of clinical practice.

What are psychedelics?

Psychedelics are a group of hallucinogenic drugs that cause psychological changes, temporary perceptual alterations, and alter consciousness. Several naturally occurring and synthetic psychedelic drugs are used culturally, recreationally, and medically, that vary drastically in their mechanisms of action and subjective effects. Lysergic acid diethylamide (LSD), psilocybin (magic mushrooms), and dimethyltryptamine (DMT) are fairly similar in their mechanisms of action, mediating serotonin 2A (5-HT2A) activity (Garcia-Romeu & Richards, 2018) though experiential differences have been reported across agents.

Brief historical context

Hallucinogens have been used since prehistoric times and played significant roles in ancient cultures. Today, some indigenous populations are afforded legal protections to use psychedelics, such as psilocybin, peyote (a cactus that contains mescaline), and ayahuasca (a tea made from plants that contains a form of DMT), as these substances play a central role in rituals for healing, spirituality, and religiosity.

The introduction of psychedelics into modern medicine began with the non-indigenous discovery of the psychoactive effects of LSD in the 1940s. Use of LSD and mescaline (isolated from peyote), were described by a German scientist as phantastica , “… giving rise to the human soul, as if by magic to apparitions whose brilliant, seductive, perpetually changing aspects produce a rapture …” (Lewin, 1931/1998, p. 80). These discoveries led to widespread scientific interest in the 1950s. LSD was used in scientific research with robust, positive clinical outcomes for existential anxiety, depression, and pain. It may come as a surprise that psychedelics were also used to treat substance use disorders like alcoholism and opioid dependence, with good success (Krebs & Johansen, 2012; Richards, Grof, Goodman, & Kurland, 1972), prior to the passage of the Controlled Substances Act in the US which ended most psychedelic research in 1971. Psychedelic substances were subsequently classified as schedule I substances, meaning they were thought to have no acceptable medical use and had a high potential for abuse.

Contemporary psychedelic research

Psychedelic research experienced a resurgence in the 1990s and continues today with gusto. A large proportion of contemporary serotonergic psychedelic research has focused on psilocybin. Following successful Phase 2 clinical trials, one mental health care company will soon enter Phase 3 to further investigate the use of psilocybin for treatment-resistant depression, the last phase of research required for FDA approval of pharmacological agents for medical use. Other psychedelic clinical research plans to or is already conducting trials on ayahuasca, LSD, and pure DMT, among others.

Unlike other pharmacological interventions (e.g., antidepressants), ongoing psychedelic research trials utilize distinct psychological and environmental features. Aesthetically pleasing environments and positive expectations when taking psychedelics strongly influence levels of anxiety and the overall experience (e.g., Hartogsohn, 2017; Studerus, Gamma, Kometer, & Vollenweider, 2012), illuminating a unique psychological component of therapeutic efficacy. Subsequently, psychedelics are typically administered within a psychotherapeutic context in clinical trials. Typically, participants engage in a series of psychologically-supported phases:

  1. Participant engages in preparation session(s) with a psychotherapist to prepare for the psychedelic experience.
  2. One or more psychotherapists support the participant throughout the hallucinatory experience in a curated environment. In several trials, the participant is encouraged to lie down with eyeshades and headphones with music. The number of psychedelic sessions, dose of the experimental drug, and length of psychedelic experience vary between type of drug and clinical trial.
  3. Finally, the participant attends integration session(s) to reflect on the psychedelic experience(s).

Mechanisms of action

Psilocybin significantly alters cerebral blood flow and functional connectivity, and psilocybin, LSD, and ayahuasca decrease integrity of the default mode network, which plays a role in self-perception and reflective awareness. It is hypothesized that these effects impact neuroplasticity, allowing a breakdown of dysfunctional beliefs and subsequent development of healthy beliefs that impact mood and behavior upon re-integration following drug administration (e.g., Carhart-Harris et al., 2017). In other words, if someone experiences depression, they may hold strong beliefs that they are unlovable and incompetent, and may believe the future is hopeless. While these beliefs are extreme, they can become deeply integrated into their worldview, despite counter-evidence. Hypothetically, the processes involved in psychedelic therapy allow the individual to break away from these unhelpful patterns and appraise themselves, others, and the world in novel ways that can facilitate learning of new perspectives that may have long-term benefits.

Research outcomes

Several large research trials across the world have examined the efficacy and safety of psilocybin treatment for depressive disorders. Overall, studies suggest the use of psilocybin is safe and relatively well-tolerated. Psilocybin-assisted treatment produced rapid, substantial antidepressant effects with significant durability (Carhart-Harris et al., 2018, 2021; Davis et al., 2021). A recent publication indicates the majority of participants experienced continued treatment response (≥ 50% reduction in depressive symptom severity) or remission 12 months following the last dosing session, with no serious adverse events (Gukasyan et al., 2022). Preliminary studies also provide support for use of psilocybin for existential anxiety among those with advanced cancer (Grob et al., 2011), obsessive compulsive disorder (Moreno, Wiegand, Taitano, & Delgado, 2006), smoking cessation (Johnson, Garcia-Romeu, & Griffiths, 2017), alcohol use disorder (Bogenschutz et al., 2015), among other forms of psychopathology. Ayahuasca may also have antidepressant effects (Sanches et al., 2016) and reduce substance abuse among drug or alcohol users (Grob et al., 1996; Halpern et al., 2008).

Even though several relatively effective treatments exist for various forms of psychopathology, we continue to evidence a high prevalence of mental illness that is often associated with subsequent disability and suicide completion. While the initial question my father posed is not yet answered, continued experimental psychedelic research that will pave the path to the answer is no less than exciting. While limitations of current research definitely exists, the studied and potentially undiscovered benefits will continue to unfold and inform the future of mental health treatment.

References

Bogenschutz, M. P., Forcehimes, A. A., Pommy, J. A., Wilcox, C. E., Barbosa, P. C., & Strassman, R. J. (2015). Psilocybin-assisted treatment for alcohol dependence: a proof-of-concept study. Journal of Psychopharmacology, 29, 289-299.

Carhart-Harris RL, Bolstridge M, Day C, et al. (2018) Psilocybin with psychological support for treatment-resistant depression: Six-month follow-up. Psychopharmacology 235: 399–408.

Carhart-Harris RL, Giribaldi B, Watts R, et al. (2021) Trial of psilocybin versus escitalopram for depression. New England Journal of Medicine 384(15): 1402–1141.

Carhart-Harris, R. L., Roseman, L., Bolstridge, M., Demetriou, L., Pannekoek, J. N., Wall, M. B., … Leech, R. (2017). Psilocybin for treatment-resistant depression: fMRI-measured brain mechanisms. Scientific Reports, 7(1), 13187.

Davis AK, Barrett FS, May DG, et al. (2021) Effects of psilocybin-assisted therapy on major depressive disorder: A randomized clinical trial. JAMA Psychiatry 78(5): 481–489.

Garcia-Romeu, A., & Richards, W. A. (2018). Current perspectives on psychedelic therapy: use of serotonergic hallucinogens in clinical interventions. International Review of Psychiatry, 30, 291-316.

Grob, C. S., Danforth, A. L., Chopra, G. S., Hagerty, M., McKay, C. R., Halberstadt,  A. L., & Greer,  G. R. (2011). Pilot study of psilocybin treatment for anxiety in patients with advanced-stage cancer. Archives of General Psychiatry, 68, 71-78.

Grob, C.S., McKenna, D.J., Callaway, J.C., Brito, G.S., Neves, E.S., Oberlaender, G., … & Boone, K. B. (1996). Human psychopharmacology of hoasca, a plant hallucinogen used in ritual context in brazil. Journal of Nervous and Mental Disease, 184(2), 86–94.

Gukasyan, N., Davis, A. K., Barrett, F. S., Cosimano, M. P., Sepeda, N. D., Johnson, M. W., & Griffiths, R. R. (2022). Efficacy and safety of psilocybin-assisted treatment for major depressive disorder: Prospective 12-month follow-up. Journal of Psychopharmacology. 36, 129-246.

Halpern, J. H., Sherwood, A. R., Passie, T., Blackwell, K. C., & Ruttenber, A. J. (2008). Evidence of health and safety in American members of a religion who use a hallucinogenic sacrament. Medical Science Monitor, 14(8), SR15-SR22.

Hartogsohn, I. (2017). Constructing drug effects: A history of set and setting. Drug Science, Policy and Law, 3, 1–17.

Johnson, M. W., Garcia-Romeu, A., & Griffiths, R. R. (2017). Long-term follow-up of psilocybin-facilitated smoking cessation. The American Journal of Drug and Alcohol Abuse. 43, 55-60

Krebs, T. S., & Johansen, P. Ø. (2012). Lysergic acid diethylamide (LSD) for alcoholism: Meta-analysis of randomized controlled trials. Journal of Psychopharmacology, 26(7), 994–1002.

Lewin, L. (1931/1998). Phantastica: A classic survey on the use and abuse of mind-altering plants. Rochester, VT: Park Street Press.

Moreno, F. A., Wiegand, C. B., Keolani Taitano, E., & Delgado, P. L. (2006). Safety, tolerability, and efficacy of psilocybin in 9 patients with obsessive-compulsive disorder. The Journal of Clinical Psychiatry, 67(11), 1735–1740.

Orth, T. (2022, July 28). One in four Americans say they’ve tried at least one psychedelic drug. YouGovAmerica. https://today.yougov.com/topics/society/articles-reports/2022/07/28/one-in-four-americans-have-tried-psychedelic-drugs

Richards, W. A., Grof, S., Goodman, L., & Kurland, A. (1972). LSD-assisted psychotherapy and the human encounter with death. Journal of Transpersonal Psychology, 4(2), 121–150.

Sanches, R. F., Osorio, L. F., Dos Santos, R. G., Macedo, L. R. H., Maia-de-Oliveira, J. P., Wichert-Ana, L., … & Hallak, J. E. C. (2016). Antidepressant effects of a single dose of ayahuasca in patients with recurrent depression: A SPECT study. Journal of clinical psychopharmacology, 36 (1), 77-81.

Studerus, E., Gamma, A., Kometer, M., & Vollenweider, F. X. (2012). Prediction of psilocybin response in healthy volunteers. PLoS One, 7(2), e30800.