The potential use of psychedelics in the treatment of various mental health conditions has made these drugs a hot area of scientific research, as well as growing public interest. A variant of ketamine called esketamine is already FDA approved and utilized for treatment-resistant depression, and the FDA has designated formulations of psilocybin and MDMA for the treatment of depression and PTSD, respectively, as “breakthrough therapies,” a process designed to expedite their development and review. NIDA is actively funding research on these compounds—NIDA and the National Institute on Mental Health are the largest funders of psychedelic research at NIH—as they represent a potential paradigm shift in the way we address substance use disorders too. Yet there is much we still do not know about these drugs, the way they work, and how to administer them, and there is danger of the hype getting out ahead of the science.
The promise of psychedelic compounds likely centers on their ability to promote rapid neural rewiring.1 Recent preclinical studies have suggested that the “neuroplastogen” properties of psilocybin, for example, may have to do with its ability to bind to 5HT2A (serotonin) receptors inside neurons, something that serotonin itself cannot do.2 That rewiring may explain these compounds’ relatively long-lasting effects, even with just one or a few administrations. Some trials have found effects lasting weeks3, but smaller studies (and anecdotes) are suggestive of much longer durations. What is needed is sound scientific research including clinical trials that can substantiate therapeutic efficacy, duration, and safety in large numbers of participants.
As part of a research study, psychedelics are administered by clinicians within highly controlled settings. This is important not only for safety reasons but because contextual factors and expectations play a crucial role in their effectiveness.4 Whether a patient has a positive or negative experience depends to a significant extent upon their mindset going into the experience and whether the setting is one in which they feel secure. This raises an important question—the extent (if any) to which the clinician’s time and attention and/or therapeutic approach play a role in psychedelics’ therapeutic efficacy—where much more research is needed. The extent to which psychotherapy is necessary in conjunction with psychedelics and which methods work best is an open question.
The potential use of psychedelics in treating addiction goes back several decades. In the late 1950s, Bill Wilson, the founder of Alcoholics Anonymous, participated in LSD experiments and encouraged further research on whether psychedelics could be useful in helping people recover from alcohol addiction. Since then, there have been many anecdotal reports of people beating substance use disorders using psychedelics, and experimental studies are lending some support to those claims, especially for alcohol use disorder.5 Currently NIDA is funding clinical trials on psilocybin for smoking cessation, ketamine for stimulant use disorder, and psilocybin and ketamine as adjuncts to medications for opioid use disorder (MOUDs). Unlike existing medication treatments, for instance MOUD, psilocybin and related 5HT2A agonists do not interact with the receptors for addictive substances (e.g., opioid receptors, cannabinoid receptors, nicotinic receptors). Those drugs are not themselves thought to be addictive, although ketamine and MDMA, which increase dopamine in brain reward regions, have addiction liability. Indeed ketamine misuse (use other than as prescribed for a medical purpose) has grown in prevalence globally and it is increasingly involved in overdose deaths in the United States.6
Wilson specifically believed that, by inducing spiritual experiences, psychedelics would help with Step 12 of his system, the acknowledgment of a higher power. One of the most interesting questions around psychedelics is whether the commonly reported spiritual experiences and other subjective effects sought by some users are essential to their purported therapeutic effects, or whether they are side effects that could potentially be decoupled to make a safer and easier-to-administer pharmacologic compound.7,8 There are contrasting schools of thought on this question, and thus far the evidence remains inconclusive.9
However, there are many challenges to studying psychedelics in clinical trials. One is the lack of placebos that are indistinguishable enough from the drug to make trial participants unsure which they have received. Low doses of the psychedelic, given as placebo, are one potential solution used in a growing number of trials. There are also administrative challenges for researchers of some psychedelics like psilocybin resulting from their Schedule I status. Patients taking psychedelics in clinical trials are in a highly vulnerable state, and the current lack of widely accepted therapeutic protocols to ensure their safety is another impediment that must be addressed.10 We also need to learn how to address the challenges of conducting research with groups like veterans with PTSD, who might benefit the most from treatment with psychedelics but for whom the potential risks are also high. If psychedelic-based therapies were to gain FDA approval, protocols to train clinicians will be needed for these therapies to enter mainstream psychiatric treatment, as well as questions answered about credentialing (i.e., what kinds of training, education, and experience qualify someone to deliver psychedelic-based therapy?). And given that with adjunctive psychotherapy these treatments will be expensive, there must be a model for reimbursing providers to facilitate equitable access.
Harnessing the brain’s natural plasticity in effecting therapeutic gains is an intuitively obvious avenue for drug development including the development of psychedelics as therapeutics, which requires a mechanistic understanding to optimally harness their benefits. The potential value of such research goes well beyond the prospect of new treatments. The profoundly meaningful experiences some people report following use of psychedelics could give neuroscientists valuable insights into meaning-making and the ability of the brain to change in a healthy direction after addiction or trauma. As former NIMH Director Joshua A. Gordon and I argued in JAMA Psychiatry, we know a lot about what goes wrong in the brains of people with addiction and other mental illnesses, but we know less about what goes right in people who do not need psychiatric care.11 Research on psychedelics could provide insights into wellness that could augment psychiatry’s historic focus on illness and disorder.
- References
- Ly C, Greb AC, Cameron LP, et al. Psychedelics Promote Structural and Functional Neural Plasticity. Cell Rep. 2018;23(11):3170-3182. doi:10.1016/j.celrep.2018.05.022
- Vargas MV, Dunlap LE, Dong C, et al. Psychedelics promote neuroplasticity through the activation of intracellular 5-HT2A receptors. Science. 2023;379(6633):700-706. doi:10.1126/science.adf0435
- Goodwin GM, Aaronson ST, Alvarez O, et al. Single-Dose Psilocybin for a Treatment-Resistant Episode of Major Depression. N Engl J Med. 2022;387(18):1637-1648. doi:10.1056/NEJMoa2206443
- Hartogsohn I. Modalities of the psychedelic experience: Microclimates of set and setting in hallucinogen research and culture. Transcult Psychiatry. 2022;59(5):579-591. doi:10.1177/13634615221100385
- Bogenschutz MP, Ross S, Bhatt S, et al. Percentage of Heavy Drinking Days Following Psilocybin-Assisted Psychotherapy vs Placebo in the Treatment of Adult Patients With Alcohol Use Disorder: A Randomized Clinical Trial. JAMA Psychiatry. 2022;79(10):953-962. doi:10.1001/jamapsychiatry.2022.2096
- Vivolo-Kantor AM, Mattson CL, Zlotorzynska M. Notes from the Field: Ketamine Detection and Involvement in Drug Overdose Deaths - United States, July 2019-June 2023. MMWR Morb Mortal Wkly Rep. 2024;73(44):1010-1012. Published 2024 Nov 7. doi:10.15585/mmwr.mm7344a4
- Yu Z, Burback L, Winkler O, et al. Alterations in brain network connectivity and subjective experience induced by psychedelics: a scoping review. Front Psychiatry. 2024;15:1386321. Published 2024 May 14. doi:10.3389/fpsyt.2024.1386321
- Hesselgrave N, Troppoli TA, Wulff AB, Cole AB, Thompson SM. Harnessing psilocybin: antidepressant-like behavioral and synaptic actions of psilocybin are independent of 5-HT2R activation in mice. Proc Natl Acad Sci U S A. 2021;118(17):e2022489118. doi:10.1073/pnas.2022489118
- Dahan JDC, Dadiomov D, Bostoen T et al. Meta-Correlation of the Effect of Ketamine and Psilocybin Induced Subjective Effects on Therapeutic Outcome. npj Mental Health Res. 2024;3:45. https://doi.org/10.1038/s44184-024-00091-w
- Anderson BT, Danforth AL, Grob CS. Psychedelic medicine: safety and ethical concerns. Lancet Psychiatry. 2020;7(10):829-830. doi:10.1016/S2215-0366(20)30146-2
- Volkow ND, Gordon JA, Wargo EM. Psychedelics as Therapeutics-Potential and Challenges. JAMA Psychiatry. 2023;80(10):979-980. doi:10.1001/jamapsychiatry.2023.1968
Dr. Nora Volkow, Director
Here I highlight important work being done at NIDA and other news related to the science of drug use and addiction.
