The Psychedelic Aspect of Esketamine is an Opportunity, Not a Side Effect

Esketamine, the newly FDA-approved stereoisomer of ketamine, was widely touted this month at the American Psychiatric Association meeting in San Francisco. The excitement makes sense, as this compound represents the first drug approved by the FDA for the treatment of depression that does not work directly on monoamines, unlike the bulk of our antidepressant armamentarium.

I’m excited about the emergence of esketamine for different reasons. This FDA approval validates what has been demonstrated in multiple investigational studies and increasingly in clinical practice: that ketamine is an effective, relatively safe, and rapidly acting antidepressant. The cost of the stereoisomer concerns me, as it may prevent patients from being able to access this drug (it ranges from $595 to $885 per dose and must be given twice per week for the first month, then every 1 to 2 weeks following¹). The price tag on esketamine may provide an impetus to reconsider racemic ketamine as not only a viable treatment, but a more affordable one as well.

Setting aside issues of health care economics and FDA procedures, esketamine also represents the first psychedelic treatment approved by the FDA for a psychiatric condition. Psychedelic medications occasion nonordinary states of consciousness that are often highly internal, emotionally significant, and personally meaningful. The psychedelic state frequently creates a temporary window of psychological disarrangement, after which the person may reorganize with fewer symptoms of depression. (Other psychedelic medicines are being investigated for the treatment of PTSD, substance use disorder, and other conditions).

Psychedelic medicines have a storied history in psychiatry, and before the prohibition of LSD and MDMA in the 1970s and 1980s, respectively, both compounds and others were investigated and found to improve psychotherapeutic outcomes². The conflation of therapeutic drugs and substance abuse that kept research from progressing for 40 years is only just now being disentangled, and these drugs are regaining their rightful place in our pharmacopeia. While ketamine’s psychedelic mechanism of action (glutamate receptor antagonism) is different than the serotonin 2A receptor agonism of classic psychedelics such as psilocybin and LSD, it should be clear that this drug can be considered a psychedelic. When racemic ketamine, was used in procedural anesthesia, practitioners were warned to watch for “emergence delirium.” In other words, a psychedelic experience.

While the FDA may have approved a psychedelic medicine, they approved only the drug and the mechanism of how the drug is to be delivered (intranasally, followed by an observation period of 2 hours). The FDA did not require esketamine providers to help patients therapeutically navigate the psychedelic experience brought on by the drug (up to 75% of subjects reported these effects)³. This psychedelic experience is not an undesired side effect. Rather, it is likely central to the healing that occurs as a result of the drug experience. Repeatedly, studies with other psychedelic compounds such as psilocybin have revealed that not only was this intensely personal psychedelic experience critical to the therapeutic effect, but that the intensity and challenge of the experience is positively correlated with the degree of psychological improvement⁴.

In our biologically driven model of psychiatry, we frequently disassociate those of us who provide medications (often known by the unpoetically mechanistic title of “med providers”) from those of us who provide psychotherapy. This unnatural split, driven largely by health care economics and managed care organizations has not only generated a false narrative in our field (that therapy doesn’t change the brain and that medication prescribers don’t provide therapy), but has also fragmented the provision of care.

Psychedelic therapy challenges this artificial rift and invites its reconciliation if it is to work effectively. Psychedelic medicines should be given in a therapeutic environment by providers who have established trust and rapport, in a setting that is comfortable, nurturing, and safe. Without first building a strong therapeutic alliance, a person given a psychedelic medicine, be it ketamine, esketamine, psilocybin or MDMA, at best may not be optimally helped by the medicine, or at worst, could be emotionally harmed by the treatment experience without an appropriate holding environment. Similarly, the experiences and insights engendered by the psychedelic need careful holding and integration in the liminal time after the medication has worn off. To do less than this is to not only undercut the power of these medicines, but to also potentially cause harm to our patients.

My two loves in mental health have been psychopharmacology and psychotherapy. One of the things that drew me to psychedelic-assisted therapies was seeing how one could potentiate the other to improve the patient’s healing. It is imperative, as we now have an FDA-approved psychedelic at our disposal, to create psychotherapeutic containers for our patients to safely and effectively navigate this experience. If a clinician providing the esketamine does not feel personally comfortable doing this kind of therapy, they should partner with clinicians who have been trained in psychedelic-assisted therapy⁵ or at the very least, with clinicians who are comfortable working with patients in nonordinary states of consciousness that can arise out of meditation or somatic psychotherapy practices. Space should be provided for both preparation for the experience and also, integration of the experience after the drug has passed. If we can create this safe container, both before, during, and after the psychedelic medicine treatment, not only will we protect our patients from harm, we will also be able to harness these very powerful medicines for healing.

1. Hamilton J. National Public Radio. FDA Approves Esketamine Nasal Spray For Hard-To-Treat Depression. Published March 5, 2019. Accessed May 23, 2019.

2. Sessa B. The Psychedelic Renaissance: Reassessing the Role of Psychedelic Drugs in 21st Century Psychiatry and Society. London: Muswell Hill Press; 2012.

3. Spravato [package insert]. Titusville, NJ: Janssen Pharmaceuticals Inc; 2019.

4. Griffiths RR, Richards, WA, McCann U, Jesse R. Psilocybin can occasion mystical-type experiences having substantial and sustained personal meaning and spiritual significance. Psychopharmacology. 2006;187(3):268-283.

5. California Institute of Integral Studies. Center for Psychedelic Therapies and Research. https://www.ciis.edu/research-centers/center-for-psychedelic-therapies-and-research. Accessed May 22, 2019.