While Psychedelic Therapies Show Promise, More Research is Needed

Nora D. Volkow, MD

In a viewpoint published in JAMA Psychiatry, the director of the National Institute on Drug Abuse (NIDA) at the National Institutes of Health (NIH) Nora D. Volkow, MD, and a team of investigators discussed the potential of psychedelic drugs, such as psilocybin, LSD, and DMT, as a new approach to treating mental illnesses like depression and substance use disorders.¹

These conditions pose significant challenges and often remain unresponsive to existing pharmacologic treatments like antidepressants and medications for opioid use disorder (OUD). Research has suggested that classic psychedelics interact with the serotonin signaling system, promoting neuroplasticity and dendritic growth, which are associated with therapeutic benefits.

However, the investigators’ letter stated the evidence for psychedelic therapeutic use remains limited, with the strongest support found for psilocybin as a fast-acting antidepressant for severe depression. Some trials have also shown beneficial effects of psilocybin for alcohol and nicotine use disorders.

Despite these promising results, caution was advised as adverse events, though rare, have been reported in psilocybin trials which can be as severe as suicidal behavior.

“As of this writing, the science policy office of the National Institute on Drug Abuse tallies the current active projects on therapeutic use of psychedelics funded by the National Institutes of Health at more than 70,” investigators wrote.

Many aspects of how psychedelics work, their safety, and patient suitability for treatment are still unknown, which investigators said requires further research.

Suggested Research Questions:

1. Are the subjective experiences associated with psychedelic drugs intrinsic to or separable from their therapeutic effects?
2. Can the desired neuroplastic effects of psychedelic drugs be decoupled from the cognitive and sensory distortions that raise safety concerns?
3. How do contextual factors, such as mindset and setting, influence the individual's experience and therapeutic outcomes during psychedelic treatment?
4. What is the role of the clinician's time and attention in producing the therapeutic effects of psychedelics, and how can this be rigorously tested?
5. How can clinical trials on psychedelics be conducted despite challenges related to their Schedule I status and the lack of indistinguishable placebos?
6. What are the long-term outcomes and potential risks associated with psychedelic-assisted therapies, and how can they be better understood through longer follow-up studies?
7. What risk evaluation and mitigation strategies are needed to gain FDA approval for psychedelic-assisted therapies?
8. How can access to future FDA-approved and reimbursed psychedelic therapies be facilitated through evidence-based drug approval and reimbursement determinations?
9. How can researchers build trust with study participants and encourage participation, particularly among racial and ethnic minoritized groups?
10. How can psychedelic-assisted treatments be made affordable and accessible to everyone, considering potential challenges such as time intensity and transportation issues?
11. How can research on psychedelic use for therapeutic and recreational purposes inform public health policies?
12. How can understanding the mechanisms by which psychedelics increase resilience contribute to the development of alternative treatment modalities for mental health conditions?

Challenges faced in conducting clinical trials on psychedelics as stated in the letter consisted of administrative hurdles due to their Schedule I status, lack of indistinguishable placebos, and the need for long-term follow-up studies. Additionally, past ethical transgressions in psychedelic research highlight the importance of transparency, trust-building with study participants, and inclusivity of diverse populations.

The team emphasized the need for affordable and accessible psychedelic-assisted treatments, designed with the eventual FDA approval² scaling-up, and reimbursement in mind. Investigation of benefits and risks will be necessary to guide public health policies regarding psychedelic use.¹

"Challenges notwithstanding, the promise of psychedelics research goes beyond the promise of new pharmacotherapies. Declining life expectancy among US residents in recent years has been tied to despair—overdoses, suicides, and diseases attributable to alcohol misuse all reflect large swaths of society feeling increased pain and loss of connection," the team wrote.

"We know a great deal about what goes awry in the brains of people with mental illnesses including substance use disorders, but we know less about what goes right in the brains of people whose lives are full of meaning and connection and who may be more resilient to the development of psychiatric conditions."

References:

1. Volkow ND, Gordon JA, Wargo EM. Psychedelics as Therapeutics—Potential and Challenges. JAMA Psychiatry. Published online July 26, 2023. doi:10.1001/jamapsychiatry.2023.1968
2. Walter K. FDA Drafts First Guidance on Psychedelic Drug Trials. HCPLive. June 23, 2023. https://www.hcplive.com/view/fda-drafts-first-guidance-psychedelic-drug-trials