Neurobehavioral Disorders

Hallucinogens in Mental Health Treatment: Drug Pipeline Updates

Jennifer Leavitt, MS
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Publish Date
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Hallucinogens are being evaluated in Phase 2 and Phase 3 clinical trials for their therapeutic potential to treat a wide variety of mental health disorders.

Recent breakthroughs in research have demonstrated the utility of hallucinogens in mental health treatment.1 Once stigmatized, substances like ketamine and psilocybin are now being explored in the drug pipeline due to their significant therapeutic potential for treatment-resistant mental health disorders. In this update, Psychiatry Advisor provides the latest status of clinical trials investigating hallucinogenic therapies for mental health.

The Evolution of Psychedelic Research

Although hallucinogens in mental health have gained increasing popularity in recent years,research into the therapeutic effects of psychedelics is not new. The exploration of psychedelics for treatment purposes began in the mid-20th century, when researchers discovered the profound psychological effects of substances like lysergic acid diethylamide (LSD) and psilocybin.2 However, recreational use of hallucinogens became much more widespread during the 1960s and these substances were subsequently criminalized – significantly slowing scientific research.3

A few decades later at the start of the 21st century, interest in psychedelic research was revived – spurred by a new wave of studies demonstrating the safety and efficacy of these compounds in controlled settings.3 Advocacy groups like the Multidisciplinary Association for Psychedelic Studies (MAPS) championed the therapeutic potential of psychedelics and breakthroughs in psychopharmacology brought hallucinogens to the forefront of mental health treatment.4 This resurgence paved the way for modern clinical trials and the potential integration of psychedelics into mainstream mental health treatment.

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As hallucinogens progress through the drug pipeline, their potential to transform mental health treatment becomes increasingly apparent and could offer new hope for patients with treatment-resistant conditions.

Hallucinogens in the Drug Pipeline

In a Johns Hopkins School of Medicine Congressional briefing Associate Professor Frederick Barrett, PhD, commented that recent studies at his institution and others in the US are demonstrating “the potential safety and potential efficacy of psychedelic therapies for the treatment of mood disorders, substance abuse disorders, and a growing number of indications.”5

To provide a comprehensive update on hallucinogens for mental health in the drug pipeline, Psychiatry Advisor conducted a review of ClinicalTrials.gov to identify 1) completed phase 2 trials and 2) phase 3 trials that are completed, active, and/or currently recruiting patients.

Ketamine


Ketamine was the first psychedelic to be legalized for medical use in the United States as an anesthetic.6 After being granted the Fast Track and Breakthrough Therapy designation, the Food and Drug Administration (FDA) approved a nasal spray containing esketamine (the S+ enantiomer of ketamine) in 2019 to be used in conjunction with an oral antidepressant for 1) treatment-resistant depression (TRD) and 2) patients with major depressive disorder (MDD) presenting with acute suicidal ideation or behavior.7 However, unlike esketamine, ketamine is not FDA-approved for the treatment of any psychiatric disorder.

A total of 54 phase 2 trials have been completed to date. Of these clinical trials, 39 studies evaluated ketamine and/or esketamine for the treatment of depressive disorders, 9 for substance use, 6 for suicidality, 5 for post-traumatic stress disorder (PTSD), 4 for obsessive-compulsive disorder (OCD), 3 for bipolar disorder, and 1 for postpartum depression.

For phase 3 trials of ketamine for mental health, 24 trials have been completed, 9 are currently recruiting patients, and 1 trial is active and not recruiting participants. Of these 34 phase 3 trials, indications for ketamine include depressive disorders (n=23), suicidality (n=8), substance use (n=3), PTSD (n=2), and postpartum depression (n=1).

Ketamine, particularly in intravenous (IV) form, continues to display rapid antidepressant effects across several studies and is being evaluated among both adults8 and adolescents.9 Ketamine has also demonstrated noninferiority to other treatment approaches for TRD.

In a clinical trial that compared the efficacy of IV ketamine vs electroconvulsive therapy (ECT) for TRD, 403 patients were randomly assigned in a 1:1 ratio to receive either ECT sessions (3 per week) or 2 ketamine treatments (2 per week) over 3 weeks.10 Researchers then followed patients for 6 months post-treatment and measured long-term clinical outcomes, including depressive symptoms, cognition, and quality of life. The researchers found that ketamine demonstrated noninferiority to ECT for improving depressive symptoms in TRD. Ketamine was also associated with improved quality of life scores.

Preliminary findings also indicate that ketamine has yielded significant improvements in PTSD symptom severity when used in conjunction with prolonged exposure therapy11 and even after a single IV infusion.12 To further understand potential mechanisms underlying ketamine’s efficacy, researchers at Yale University are currently recruiting participants for a phase 2 imaging study that will analyze cerebral alterations in functional connectivity following an intensive 7-day treatment of ketamine and exposure therapy for PTSD.13

Overall, phase 2 and phase 3 trials have yielded promising results for the utility of ketamine for the treatment of psychiatric disorders – especially depressive disorders. However, ongoing research is needed to replicate and confirm these preliminary results.

MDMA

In a recent analysis of ClinicalTrials.gov, there were 12 completed phase 2 trials and 6 phase 3 trials (completed: n=3; active: n=1; recruiting: n=2) of 3,4-methylenedioxy-methamphetamine (MDMA) for mental health. The therapeutic use of MDMA has primarily been evaluated for the treatment of PTSD (n=16), but has also been explored for anxiety disorders (n=2).

Thus far, MDMA has shown significant efficacy in treating PTSD. Researchers posit that the improved mood and feelings of well-being associated with MDMA help reduce the emotional distress of trauma, enabling patients to process and integrate their experiences more effectively.

In a phase 3 trial of MDMA for the treatment of PTSD, 90 patients received either MDMA or a placebo alongside psychotherapy.14 After 3 treatment sessions, 67% of individuals who received MDMA with therapy no longer met the criteria for a PTSD diagnosis, compared with 32% of those who received therapy and a placebo. These findings were confirmed in a subsequent phase 3 trial, in which 71% of people who received a combination MDMA and therapy no longer qualified for a PTSD diagnosis compared with 48% of those who received placebo and therapy.15 The drug appeared equally efficacious in individuals who had comorbid depression, longer-term PTSD, and other mental illnesses. Additionally, results were consistent across racial and ethnic groups.

Although only 2 phase 2 trials have evaluated MDMA for the treatment of anxiety, results have been promising. In a study of MDMA-assisted psychotherapy for anxiety and psychological distress related to life-threatening illnesses, the MDMA group had a greater reduction in anxiety scores 1 month after treatment, compared with placebo.16 A combination of MDMA and psychotherapy was also efficacious in reducing social anxiety among adults with autism spectrum disorder.17

Psilocybin

Psilocybin has been evaluated for mental health treatment in 12 completed phase 2 trials Additionally, 5 phase 3 trials are currently recruiting patients. In completed trials, psilocybin was investigated as a therapy for depressive disorders (n=9), anxiety (n=2), anorexia (n=1), and body dysmorphia (n=1).

The therapeutic potential of psilocybin has been most extensively studied for the treatment of depressive disorders. Following Breakthrough Therapy designation for synthetic psilocybin,18 an exploratory phase 2 clinical trial explored the safety and efficacy of a single 25 mg dose of psilocybin, administered in conjunction with psychological support and selective serotonin reuptake inhibitors (SSRIs), in a cohort of 19 patients with TRD.19 After 3 weeks, investigators observed that 42% of patients had a clinically significant response to psilocybin.

These outcomes were parallel to a phase 2b study that assessed psilocybin in a larger cohort of 233 participants with TRD who were not receiving other antidepressants.20 Psilocybin at a single dose of 25 mg was associated with significantly lower depression scores over 3 weeks (P <.001), relative to a 1 mg dose.

Furthermore, the FDA granted Breakthrough Therapy designation to CYB003, a proprietary psilocybin analog for the adjunctive treatment of MDD.21 The designation was based on phase 2 data which demonstrated that 2 doses of CYB003 (12 mg or 16 mg) were associated with robust and sustained improvements in depressive symptoms up to 4 months following treatment.22

LSD

There are 5 completed phase 2 studies on ClinicalTrials.gov that investigated the use of LSD for anxiety (n=3), attention-deficit/hyperactivity disorder (n=1), and depression (n=1).

The FDA recently granted Breakthrough Therapy designation to a tartrate salt form of LSD – MM120 – for the treatment of generalized anxiety disorder (GAD).23 The designation followed results from a phase 2 study that assessed anxiety symptoms in 194 patients with GAD.24 Participants were randomly assigned to receive a single dose of 25µg, 50µg, 100µg or 200µg of MM120 or placebo. At a dose of 100 µg, individuals who received MM120 had a significant improvement in anxiety symptoms (P <.003), relative to placebo. This dose achieved a 65% clinical response rate and a 48% clinical remission rate sustained through 12 weeks.

Phase 2 trials of LSD for the treatment of attention-deficit/hyperactivity disorder and depression have been completed, but results are not yet publicly available.

The Future of Hallucinogens in Mental Health

A growing body of evidence supports the therapeutic application of psychedelics for several mental health disorders – especially depressive disorders and PTSD. As hallucinogens progress through the drug pipeline, their potential to transform mental health treatment becomes increasingly apparent and could offer new hope for patients with treatment-resistant conditions. Continued research and clinical trials will be crucial in understanding the full scope of their benefits and risks, ultimately guiding their use in clinical practice.

This article originally appeared on Psychiatry Advisor

References:
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