Weak Evidence for Psychedelic Drugs as Potential Treatments for Depression and Other Mental Illnesses
Health Letter, July 2023
By Michael T. Abrams, M.P.H., Ph.D.
Psychiatric illnesses, such as depression, anxiety, obsessive-compulsive disorder, mania, post-traumatic stress disorder and schizophrenia, are often very difficult to treat. In recent years, psychedelic substances — including lysergic acid diethylamide (“‘LSD,” “acid”), psilocybin (“‘magic mushrooms”) and 3,4-methyenedioxymethamphetamine (MDMA, “ecstasy” or “Molly”) — have reemerged as one approach to treating psychiatric illnesses.[1] Evidence supporting the therapeutic value of psychedelics for psychiatric disorders is limited, however.[2] At present, esketamine (SPRAVATO) is the only such medication that has been approved by the Food and Drug Administration (FDA).[3] The prescribing information for esketamine includes a black-box safety warning for sedation and dissociation, abuse and misuse, and suicidal thoughts and behaviors. Dissociation is a serious collection of symptoms characterized by disruption in consciousness, identity, memory, perception, emotion, motor control and other behaviors.
Although some psychedelics may have a role in treating certain psychiatric disorders, these substances are different than other therapies at the leading edge of neuroscience-based drug development. A 2023 review article in Nature Medicine explained:
…the rise of psychedelics clashes with the goal of circuit-targeted precision and rational treatment design. These plant-based compounds, in use for thousands of years, affect the brain globally. Yet, the renewed excitement regarding their use may in part be due to the rise of circuit-based understanding of psychiatric disease and the role of neuroplasticity in reshaping circuitry.[4]
Psychedelics refer to a broad cluster of naturally occurring (for example, psilocybin) or synthetic (for example, MDMA) chemicals “defined by their ability to induce altered states of consciousness, including changes in perceptions, thinking and feelings.”[5] One theory regarding the efficacy of psychedelics as treatments for mental disorders is that they function as a “belief relaxer,” such that strongly held and maladaptive behaviors can be more easily overcome via psychedelic use.[6] Other theories are biochemically based, including that psychedelics engage specific brain-based molecules, especially those related to the neurotransmitter serotonin, which in turn influence brain-cell spiking (neuron firing), structural plasticity (remodeling) and interactions (interconnectivity).[7]
The use of psychedelics as medicine has a rich and evolving history. From 1950 to 1970, psychedelic drugs were given to thousands of patients in the United States to treat a variety of conditions such as substance-use disorders, depression and end-of-life distress.[8] In 1970, however, these drugs were classified as Schedule I, the most restrictive designation under the newly enacted federal Controlled Substances Act. As a result, legal use of these substances largely stopped.
In 2000, the Department of Psychiatry and Behavioral Sciences at Johns Hopkins University obtained regulatory approval to resume research with psychedelics in healthy volunteers. In 2019, that same institution secured $17 million in private funds to start the Center for Psychedelic and Consciousness Research.
In 2023, Oregon became the first state to allow the use of psilocybin, but only in adults and only at licensed service centers.[9] Patients with or without a mental health diagnosis are expected to be treated, with intensive oversight by trained “guides” or “facilitators,” many of whom have mental health credentials.
Use of psilocybin may expand beyond Oregon because other states and municipalities (for example, Colorado, California and Seattle) have begun to decriminalize the drug.[10] If the FDA were to approve facilitated psylocibin and MDMA therapies for the treatment of depressive and post-traumatic stress disorders, then use would expand further.[11]
The structures of ketamine, a general anesthetic delivered using an intravenous or intramuscular injection, and esketamine are nearly identical, varying only by their three-dimensional orientations. Technically, these substances are distinct from classic psychedelics because they do not act directly on the serotonin system; instead, they act on other brain molecules (N-methyl-D-aspartate [NMDA] receptors).[12] Ketamines, however, are psychedelic-like in the sense that they are powerful drugs that alter consciousness and perception. In 1970, the FDA approved ketamine for medical use.
Esketamine was developed as a nasal spray for treatment-resistant depression and for depressive symptoms in adults with major depressive disorder with suicidal thoughts or actions.[13] Despite opposition from Public Citizen’s Health Research Group and others, the FDA approved esketamine in 2019. Although the FDA has not approved the use of ketamine for psychiatric illness, it is used off-label. Clinics where ketamine or esketamine is administered to treat illnesses such as treatment-resistant depression and post-traumatic stress disorder have become an investment target of venture capital firms.[14] Recently, some of these clinics have closed in part because these therapies are expensive to deliver (requiring hours of mental health clinician oversight), and because insurance companies resist covering off-label use for ketamine or the relatively high drug cost for esketamine.
Effectiveness data for esketamine are limited, and the drug has many adverse effects. All the pivotal trials that led to the FDA approval have weaknesses: Two trials did not demonstrate that esketamine was effective for treatment-resistant depression. Another trial purporting to show effectiveness was biased because the subjects were all given the medication and unblinded (meaning it was a noncontrolled, open-label study).
The one trial (known as Study 3002) providing evidence for the effectiveness of esketamine was a randomized comparison of intranasal esketamine with intranasal placebo, with a total of 223 subjects. Both Study 3002 groups also received oral antidepressant medications. Subjects were evaluated at 28 days using change from baseline on a depression rating scale composed of 10 items: sadness, apparent sadness, inner tension, reduced sleep, reduced appetite, concentration difficulties, lassitude (tiredness), inability to feel, pessimistic thoughts and suicidal thoughts. At 28 days, the esketamine group showed lower (better) depression scores by 4 points, a significant but small effect relative to the maximal possible score of 60 points.
Among the adverse effects of esketamine are an increased risk of suicidal thoughts and behaviors, potential for abuse and misuse, sedation, and dissociation. The sedative and dissociation effects of esketamine do not dissipate with time, as they do with more commonly used antidepressants.
A post-market pharmacovigilance study published in 2021 confirmed the safety concerns for esketamine. The study reviewed the FDA Adverse Event Report System (FAERS) data for esketamine and compared these reports to those for all other medications in the database. From March 2019 to March 2020 (the first year esketamine was marketed), there were 2,274 reports to FAERS (covering 962 patients), including 22 deaths. During that same period, over 4 million total reports were submitted to FAERS. The Table shows the most frequently reported adverse events. The right-hand column of the Table shows that these adverse events were more common for esketamine than for all of other medications. As reports to the FAERS database are voluntary, the number of reports and the reporting odds ratios should be interpreted with this limitation in mind. The reporting for both esketamine and other medications is incomplete.
Table. Post-market Adverse Events During the First Year of Esketamine’s Approval
| Adverse Event | Number of Reports* | Reporting Odds Ratio** |
| Dissociation | 212 | 1,613 |
| Sedation | 173 | 239 |
| Feeling drunk | 20 | 96 |
| Euphoric mood (intense happiness) | 16 | 46 |
| Suicidal ideation (thoughts) | 64 | 24 |
| Oral hypoesthesia (numbness) | 10 | 22 |
| Dysgeusia (taste disorder) | 20 | 14 |
| Panic attack | 16 | 14 |
| Blood pressure increase | 62 | 10 |
|
*This table only includes events found in at least 10 separate FDA adverse event reports during the study period. **Reporting odds ratio reflects how frequently the stated adverse event was reported with esketamine as compared to all other drugs in the FAERS database. |
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In sum, there are important concerns about the safety and effectiveness of esketamine, as well as other psychedelics under development for mental health disorders. Caution and skepticism about the use of psychedelic medications as treatments for depression and other mental illnesses is warranted.
References
[1] Scangos KW, State MW, Miller AH, et al. New and emerging approaches to treat psychiatric disorders. Nat Med. 2023;29(2):317-333.
[2] Feduccia A, Agin-Liebes G, Price CM, et al. The need for establishing best practices and gold standards in psychedelic medicine. J Affect Disord. 2023;332:47-54.
[3] Ibid.
[4] Scangos KW, State MW, Miller AH, et al. New and emerging approaches to treat psychiatric disorders. Nat Med. 2023;29(2):317-333.
[5] Barber GS, Aaronson ST. The Emerging Field of Psychedelic Psychotherapy. Curr Psychiatry Rep. 2022;24(10):583-590.
[6] Ibid.
[7] Kwan AC, Olson DE, Preller KH, et al. The neural basis of psychedelic action. Nat Neurosci. 2022;25(11):1407-1419.
[8] Barber GS, Aaronson ST. The Emerging Field of Psychedelic Psychotherapy. Curr Psychiatry Rep. 2022;24(10):583-590.
[9] Jacobs A. Legal use of hallucinogenic mushrooms begins in Oregon. The New York Times. January 3, 2023.
[10] Sheets C. L.A. Dispensaries openly sell ‘magic mushrooms’ as state weighs decriminalization. Los Angeles Times. May 16, 2023.
[11] Feduccia A, Agin-Liebes G, Price CM, et al. The need for establishing best practices and gold standards in psychedelic medicine. J Affect Disord. 2023;332:47-54.
[12] Kamal S, Jha MK, Radhakrishnan R. Role of Psychedelics in Treatment-Resistant Depression. Psychiatr Clin North Am. 2023;46(2):291-305.
[13] Janssen Pharmaceuticals. Label: esketamine (SPRAVATO). July 2020. https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/211243s004lbl.pdf. Accessed June 23, 2023.
[14] Cueto I, Goldhill O. Ketamine clinics’ bust serves as warning of business challenge facing psychedelic therapy. STAT+. May 16, 2023.