John Krystal, MD: Exploring the Future of Ketamine and Psychedelic Treatment

CLINICAL CONVERSATIONS

It has been a roller coaster year for psychedelics in psychiatry. On the one hand, there have been safety and efficacy studies promising a brave new world of psychopharmacological options for patients with major depressive disorder, posttraumatic stress disorder (PTSD), generalized anxiety disorder, and psychiatric disorders. On the other, this summer the US Food and Drug Administration delivered a disappointing response in the quest for 3,4-methylenedioxymethamphetamine (MDMA)-assisted therapy as a treatment option for PTSD, despite pleas from veteran organizations, government officials, and psychiatric experts.

So what does the future hold for psychedelics in general and ketamine in particular? Psychiatric Times sat down with John Krystal, MD, Robert L. McNeil, Jr. Professor of Translational Research and Professor of Psychiatry, of Neuroscience, and of Psychology at Yale University to discuss his work and what next steps might look like. Krystal is also Co-Director of the Yale Center for Clinical Investigation; Chair of Psychiatry; Physician-in-Chief of Psychiatry at Yale New Haven Hospital; Director of the National Institute on Alcohol Abuse and Alcoholism Center for the Translational Neuroscience of Alcoholism; and Director of the Clinical Neuroscience Division at the VA National Center for PTSD.

Psychiatric Times: What drew you to study psychedelics as potential treatment for psychiatric disorders?

John Krystal, MD: Most of my work has been with ketamine rather than classical psychedelic drugs.1-4 I was drawn to study ketamine because I thought it might provide a path for studying the impact of deficits in N-methyl-D-aspartate [NMDA] glutamate receptor signaling on psychosis and cognitive impairments. In using ketamine in this way in patients with depression, we found the antidepressant effects of ketamine.

Psychiatric Times: Can you share more about the work you are undertaking to better understand the potential of ketamine and other psychedelics in the treatment of psychiatric disorders?

John Krystal, MD: I co-founded Freedom Biosciences, which is using drug combinations to try to overcome some of the limitations of ketamine and psychedelic treatments. In particular, Freedom is testing a drug combination that may extend the duration of efficacy of ketamine, so that it can be administered less frequently in standard treatment. Freedom is also developing combination treatments that may provide the effectiveness of psychedelic drugs but with limited effects on perception.

There are a number of companies that are following different scientific paths to generating short-acting psychedelics, similar to DMT [N,N-Dimethyltryptamine] and 5-MeO-DMT [5-methoxy-N,N-dimethyltryptamine], or non-hallucinatory psychedelics. If these companies are successful, it might lead to psychedelic treatments that can be made more widely accessible.

Psychiatric Times: How has our understanding of treatment-resistant depression (TRD) evolved over the last 10 to 15 years? How has this understanding impacted treatment choices and strategies as well as research into new strategies?

John Krystal, MD: I think that the treatment of TRD has already changed dramatically, in large part due to the emergence of esketamine (Spravato) by Janssen. Prior to esketamine, patients with TRD who failed to respond to standard approaches (ie, combining antidepressants, adding lithium, adding an antipsychotic medication, etc) were decreasingly likely to get access to more definitive treatments, like electroconvulsive therapy (ECT). In fact, despite the efficacy of ECT, a declining number of sites in the US were offering it as a treatment. Psychiatry seemed to be backing away from the most effective treatments for the most severely refractory patients.

However, with esketamine, there has been widespread and growing investment in building “Interventional Psychiatry,” ie, the infrastructure and expertise needed to deliver esketamine, TMS, and ECT. In parallel, the rate of esketamine prescriptions has grown substantially, and access challenges for esketamine seem to be declining. Psilocybin and MDMA are not yet approved by the FDA for the treatment of psychiatric disorders. However, the research studies are also very promising.

Psychiatric Times: Are there other areas in psychiatry that the use of psychedelics might be warranted?

John Krystal, MD: Psilocybin is likely to be approved initially for major depression. MDMA in combination with psychotherapy for PTSD was not approved by the FDA, but it is likely that additional studies will be conducted to enable its ultimate approval. Psychedelics are also being studied for the treatment of PTSD, migraine, and substance use disorders.

Psychiatric Times: What are you most excited about regarding the use of psychedelics in psychiatry in general as well as specifically in depression and TRD?

My goal in treating patients is simply to see them get better. We know that depression is an extremely heterogeneous condition and that esketamine and ECT will not work for everyone. Therefore, having more rapidly effective and highly effective treatment options is likely to open doors to recovery for many patients.

Psychedelics are serious psychotropic medications and treatment may stir up distressing memories and feelings, including suicidal ideation. However, some patients describe exposure to psychedelic drugs as among the most important experiences of their lives. We have much to learn about the basis for this experience.

Psychiatric Times: How has the FDA’s review of MDMA-assisted psychotherapy impacted research into the usefulness of psychedelics?

John Krystal, MD: First, it is important to remember that MDMA is not a classical psychedelic drug. It is called an empathogen because it stimulates feelings of empathy and connections to other people.

Classical psychedelics, like psilocybin, produce hallucinatory and other experiences by stimulating the serotonin-2A receptor. MDMA is an amphetamine derivative that we believe works primarily—like other amphetamine molecules—by causing the release of monoamine neurotransmitters.

I know that many people were discouraged by the ICER [Institute for Clinical and Economic Review] report, which raised many questions about the MDMA trials prior to the FDA Advisory Panel Review. Many of the issues raised in this report came up again in the FDA Advisory Panel discussion. The bottom line is that we need more data to be confident about the balance of risks and benefits offered by MDMA in combination with the therapy. This was clearly a setback for Lykos and for advocates for MDMA, but having more data will teach us more about MDMA. And this may be a good thing in the long run.

References

1. Moujaes F, Ji JL, Rahmati M, et al. Ketamine induces multiple individually distinct whole-brain functional connectivity signatures. Elife. 2024;13:e84173.

2. Krystal JH, Kaye AP, Jefferson S, et al. Ketamine and the neurobiology of depression: Toward next-generation rapid-acting antidepressant treatments. Proc Natl Acad Sci U S A. 2023;120(49):e2305772120.

3. Krystal JH, Preller KH, Corlett PR, et al. Psychedelics and the Neurobiology of Meaningfulness. Biol Psychiatry Cogn Neurosci Neuroimaging. 2024;9(5):462-463.

4. Nikayin S, Murphy E, Krystal JH, Wilkinson ST. Long-term safety of ketamine and esketamine in treatment of depression. Expert Opin Drug Saf. 2022;21(6):777-787