Psychedelic Drugs: Lessons From Ketamine and Psilocybin

Psychedelic drugs like LSD could be used to treat depression, study suggests
Psychedelic drugs like LSD could be used to treat depression, study suggests
After a decades-long global stop of research on psychedelic drugs, investigation of psychedelics in the context of psychiatric disorders is yielding some positive results.

Psychedelics are making their way out of the counterculture and back into the mainstream, with research and media interest in the mind-altering substances growing substantially. Some have even called psychedelics “psychiatry’s brave new world.”1

The revitalization of psychedelics has occurred alongside a shift away from the research and development of traditional psychiatric medications by leading pharmaceutical companies.1 Research on psychedelics, however, remains difficult given serious legal and regulatory barriers to studying these substances in laboratory settings. The history of psychedelics in the counterculture of the 1960s and in traditional indigenous medicine, as well as controversies surrounding their study and recreational use, have continued to make psychedelics somewhat taboo.1,2

Innovative research centers at top institutions, such as Johns Hopkins and Imperial College, as well as the Multidisciplinary Association for Psychedelic Studies (MAPS), have rigorously pursued the study of potential psychedelic treatments for psychiatric disorders in recent years.3 In addition, private enterprises like Compass Pathways, which became the first psychedelics company to go public in September 2020, and nonprofit organizations like Usona Institute are investing heavily in the future of psychedelics.4

These research efforts have brought together an unusual array of psychotherapists, alternative medicine advocates, private investors, philanthropists, neuroscientists, and even journalists and nutrition advocates like Michael Pollan, bestselling author of How to Change Your Mind: What the New Science of Psychedelics Teaches Us About Consciousness, Dying, Addiction, Depression, and Transcendence.

While concerns about adverse effects, feasibility, and cost remain, psychedelic treatments may offer relief to patients who have not experienced improvements with traditional psychiatric medications or may allow patients to engage in a small number of psychedelic interventions rather than taking medications daily. In some cases, psychedelics may disrupt the conventional division between psychopharmacological approaches and psychotherapy.1-2

Ketamine: A Model for Other Psychedelics?

On March 5, 2019, esketamine nasal spray became the first Food and Drug Administration (FDA) approved psychedelic treatment for a psychiatric disorder. The approval of intranasal esketamine has been widely heralded as one of the most exciting developments in psychiatry, opening up a new potential treatment for patients with refractory depression.5 In August 2020, the FDA extended its approval for esketamine to adults with major depressive disorder with acute suicidal ideation or behavior.6

Offered by prescription in the form of Spravato and classified as a Schedule III substance, esketamine must be taken under supervision due to the risk of serious adverse outcomes related to dissociation and sedation. In addition, patients must take an oral antidepressant alongside esketamine.5 Enrollment in concurrent therapy sessions may also play a role in facilitating positive outcomes.5-7

Although esketamine produces psychedelic effects through glutamate receptor antagonism, the drug’s psychedelic properties have not been a focal point for many advocates.8 Notably, the FDA approval stresses the involvement of providers during esketamine administration mainly for the safety of the patient, and not for therapeutic purposes.5,8 However, some researchers are investigating potential applications of ketamine-assisted psychotherapy.9

The initial trials of esketamine demonstrate that the new drug may help reduce depressive symptoms when taken alongside an antidepressant.10-11 A randomized double-blind active-controlled study of 223 patients with treatment-resistant depression found a significantly greater decrease in Montgomery-Asberg Depression Rating Scale scores for adjunctive esketamine vs placebo after 28 days.10

A double-blind randomized study of patients with active suicidal ideation with intent found that patients treated with esketamine vs placebo had significantly lower depressive symptoms after 4 hours. However, there were not any significant differences in improvements related to severity of suicidality.11

The approval of esketamine may offer a template for future psychedelic products looking to enter the mainstream, which could entail downplaying hallucinogenic effects and highlighting its novel neurobiological mechanism. The controversial approval process for esketimine may also offer some possible warning signs for psychedelic research and development.

Several experts have raised concerns about the FDA’s approval process for esketamine, including mixed evidence about the drug’s rapid effect, which helped manufacturer Janssen Pharmaceuticals, Inc. receive a Breakthrough Therapy Designation, and the loosening of criteria for treatment-resistant depression.12-14

In a commentary in The American Journal of Psychiatry, Alan F. Schatzberg, MD, of Stanford University School of Medicine in Stanford, California, argued that esketamine may carry a risk of abuse related to its “opioid properties” and questioned the efficacy of the new drug due to relatively small effect sizes.13 Similarly, in The British Journal of Psychiatry, Mark A. Horowitz, MBBS, PhD, of the Division of Psychiatry, University College London, United Kingdom, criticized Janssen’s reliance on a single positive efficacy trial and a discontinuation trial.14  

Dr Horowitz stated in an interview, “What they’ve demonstrated very clearly in the trials that they’ve done is that ketamine gets you a bit high for a few hours and has little effect on depression scores at 4 weeks.” He argued, “Looking at it objectively, it’s a very ineffective medication. On top of that, it’s also a reasonably dangerous medication.”

The adverse effects of esketamine may be downplayed amid widespread excitement over a novel treatment for depression, noted Dr Horowitz. A recent paper analyzing reports submitted to the FDA Adverse Event Reporting System database identified serious concerns about esketamine’s real world safety profile, including dissociation, sedation, and suicidal ideation.14

Although esketamine has been approved in the United States, where it remains fairly expensive nonetheless, the National Institute for Health and Care Excellence (NICE) in the United Kingdom did not recommend the provision of esketamine in the National Health Service given a lack of clinical evidence and cost-effectiveness.14

Psilocybin and Psychedelic-Assisted Psychotherapy

Psychedelic treatments may offer treatment benefits beyond their direct neurobiological effects.1,16-17 The psychedelic experience itself may allow providers an opportunity to work through therapeutical issues with patients, which is the case for psilocybin, the active ingredient of “magic mushrooms” and a 5-hydroxytryptamine 2A receptor agonist.1,17

In contrast to esketamine, researchers promote the psychedelic properties of psilocybin as a means of engaging with patients therapeutically.16 As Nutt, et al noted in their paper published in Cell, “psychedelic therapy harnesses a therapeutic window opened up by the brain via the effects of the drugs to facilitate insight and emotional release.”1

Currently, there is promising evidence for psilocybin-assisted psychotherapy. A Phase 2 study (N=80; NCT03866174), conducted by the Usona Institute and granted a Breakthrough Therapy Designation last year, is investigating supervised single-dose psilocybin administration as a treatment for patients with MDD.18

In a promising open label feasibility study (N=12) published in The Lancet Psychiatry, Robin L. Carhart-Harris, PhD, who directs the Centre of Psychedelic Research, Imperial College London in the United Kingdom, and colleagues found that depressive symptoms were reduced at 1 week and 3 months in patients with treatment-resistant depression who received 2 oral doses of psilocybin in a therapeutic setting.19 The investigators also noted that psilocybin was generally well-tolerated.

Furthermore, psilocybin has reduced anxiety and depressive symptoms in patients with cancer, demonstrating sustained improvements at 6-month follow-up for nearly 80% of patients.20-21

Natalie Gukasyan, MD, a psychiatrist and postdoctoral research fellow at Johns Hopkins University, Baltimore, Maryland, studies psilocybin-assisted psychotherapy at the Center for Psychedelic & Consciousness Research.3,22 In an interview, she noted that the approach is quite resource-intensive. Study participants receive 8 hours total of face-to-face time beforehand to develop rapport and trust with 2 facilitators, who are then present for the full therapeutic session and follow-up.

Performing a life review and getting to know the patient’s history is critically important before administering psilocybin. On the day of administration, therapeutic approaches differ depending on the needs of the patient and may involve cognitive behavioral therapy, motivational interviewing, mindfulness, or reflective activities.

“Interestingly, many people we see have never tried psychedelics before. They aren’t really experienced psychonauts,” Dr Gukasyan stated. Paranoia, dysphoria, and anxiety can make for a “bad trip,” but therapists can deploy mitigating techniques, such as touch cues or breathing exercises. On rare occasions, risperidone or benzodiazepines are on hand. “During preparation, we warn people that 20-30% of patients have what they describe as a challenging experience,” she noted.

Challenging experiences do not necessarily imply bad outcomes, and overcoming these experiences can offer a therapeutic opportunity. “People who have challenging experiences often go on to do very well,” Dr Gukasyan said. “Challenging experiences in the lab are often different from challenging experiences in the real world,” she added, “In the lab, it’s much lower. There’s something very important about doing this in a setting where you can be supported.”

Dr Gukasyan noted that several challenges lay ahead for psilocybin despite promising findings thus far. “Psychiatrists will be critical in a lot of aspects of treatment, but getting insurance companies to pay for that will be a challenge,” she stated. This barrier may preclude psychiatrists from being fully present supervisors for this therapy.

In addition, there are important challenges for psilocybin research, which may have ramifications of psychedelic research more broadly. According to Dr Gukasyan, the trials in many ways “cherry-pick” subjects since participants seek out the studies, and as a result they tend to have a high positive expectation effect. As she explored in a recent paper, placebo effects and expectancy can play a critical role.22 Furthermore, patients and providers can be un-blinded given the obvious hallucinogenic effects of psilocybin, and it may be difficult to standardize the psychotherapeutic approach in studies.

“We need to wait and see what the phase 3 studies bear out before we get excited,” Dr Gukasyan concluded, emphasizing the need to explore long-term results and interactions with other medications. Ongoing studies at Johns Hopkins will examine possible applications for psilocybin in anorexia nervosa and substance use disorders, as well as broader safety concerns and patient experiences.3,23

Psychedelics: Are We Ready for Psychiatry’s Brave New World?

The examples of esketamine and psilocybin demonstrate that treatments with psychedelic effects differ greatly in terms of their mechanisms of action and therapeutic applications, despite falling under the “psychedelic” umbrella.1,16,24 Psilocybin shares many serotonergic properties with ayahuasca, LSD, mescaline, and DMT, and these compounds may suit the psychedelic-assisted psychotherapy approach offered at Johns Hopkins.1,16  In contrast, techniques like microdosing, or isolating nonhallucinogenic components of psychedelics such as cannabis-derived cannabidiol (CBD), may help provide unique psychopharmacologic benefits without the risks of getting high.1-2,24-25

Given the preliminary evidence for MDMA-based treatments for posttraumatic stress disorder, which has received a Breakthrough Therapy Designation and expanded access program from the FDA, MDMA has also received renewed interest as a psychiatric treatment.26-27 These efforts range from Phase 3 trials sponsored by MAPS to a highly experimental Phase 1 trial of combined LSD-MDMA in healthy subjects led by the pharmaceutical company MindMed.27-28  

Patience, hesitancy, and openness with patients and other researchers will go a long way in ensuring that psychedelics are implemented in a safe and effective manner. Like existing psychiatric medications, psychedelics will inevitably carry certain risks and fail some patients. Being realistic and avoiding hopes of a magic bullet, as well as building up a solid evidence base, could make psychedelics an excellent treatment opportunity for patients with psychiatric disorders.


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