Psychotherapy with Psilocybin and MDMA in the treatment of depression

It is a "free grace," which is neither necessary nor sufficient for salvation, but which, if used properly, can be of great help to those who have received it. (Aldous Huxley)

Given that, according to projections by the World Health Organization, mental health will be one of the most critical areas of this century, it is urgent to develop new psychiatric treatments. Recent advances with psilocybin in the treatment of major depression and 3,4-methylenedioxymethamphetamine (MDMA) in the treatment of post-traumatic stress disorder (PTSD) have led to the granting of "breakthrough therapy status" by the U.S. Food and Drug Administration. ¹ In this edition, we report the successful results of MDMA-assisted psychotherapy for Brazilian patients with severe PTSD (summarized in...). Figure 1 ). ² This approach deserves the attention of mental health professionals across the country, since the prevalence of this disorder, which is already high, will likely increase as COVID-19 infections and deaths rise in Brazil. ³

The history of psychiatry and these drugs began around 1953, when psychiatrist Humphry Osmond gave Aldous Huxley a glass of water containing 400 mg of mescaline, fearing it might drive the famous writer insane. In 1956, his ongoing intellectual exchange led Osmond to coin the neologism 'psychedelic' (from the Greek for "mind manifesting itself"), arguing that: "The name must have a clear meaning, be reasonably easy to spell and pronounce, and not be too similar to some other name. [...] Psychedelic seems unambiguous, not burdened with old associations, and clear." At that time, both men had also experimented with LSD, which was invented in 1938 by Albert Hofmann, who discovered its psychoactivity in 1943. ^4 , 5 These occurrences predate the discovery of serotonin in the mammalian brain, as well as the use of chlorpromazine, iproniazid, and lithium, commonly considered the first modern psychiatric medications. However, LSD was tested for various conditions, primarily alcoholism, in the 1950s and played a significant role in the widespread acceptance of chemical neurotransmission due to its remarkable long-lasting effects in small quantities (tens to hundreds of micrograms). ^4 , 5

In the 1980s, LSD was used in studies that established the existence of different serotonin, 5HT-1, and 5HT-2 receptors, demonstrating that the psychoactivity of these drugs was not due to toxic effects on the brain, as previously speculated, but rather to the precise activation of proteins that occur naturally in neuronal membranes. ^{1 , 5 , 6} Four decades later, non-invasive and minimally invasive neuroimaging technology, such as M/EEG, fMRI, and PET, has made it possible to decode human brain activity during the acute action of psychedelics. The results showed, for example, that psilocybin binds to 5HT-2A receptors, which are more densely expressed in the apical dendrites of pyramidal neurons in layer V of the human neocortex, and increases their firing rates. This reaction spreads through the cortex, inducing temporary desynchronization of brain rhythms, the subjective effects of which correlate statistically with receptor occupancy and spectral changes in specific networks. ^{1 , 5 , 6}

This refined neurophysiological understanding of their acute pharmacological mechanisms of action, from the cellular to the systemic level, is remarkable because, unlike most psychiatric drugs, psychedelics are not intended for chronic use. Instead, psilocybin and MDMA, which increase serotonin, norepinephrine, and dopamine levels, have demonstrated exceptional rapid-acting therapeutic potential when administered on very few occasions in conjunction with psychotherapy. ^{1 , 5 , 6} Both drugs are currently being tested for addiction problems, and published studies show promising results for end-of-life anxiety in cancer patients, smoking cessation interventions, social anxiety in autistic adults, and, most importantly, depression and PTSD. ^{1 , 5 , 6} The acute neuroimaging of the action of these drugs, which are used clinically in only one to three sessions per patient, has enormous translational value for future psychiatric clinical practice, since psychedelic-assisted psychotherapy is conceptually different from current drug-only treatments. ^1. Non-daily administration may reduce adverse effects, including withdrawal symptoms, which increase with prolonged daily use of psychiatric drugs. Administering psychedelics under medical and/or psychological supervision also limits or completely eliminates the risk of drug deviation and abuse, not to mention the risk of dependence, which is very low for psychedelic substances, especially when administered on a few occasions under medical supervision. ^{1 , 5 , 6}

During our MDMA study in 2018, the Brazilian authority responsible for all activities involving controlled substances, the National Health Surveillance Agency (ANVISA), also granted us authorization (AEP 012/2018) to use psilocybin in a study to treat severe depression, which is also very prevalent in the country. However, the research protocol was rejected twice by an ethics committee, which incorrectly stated that these substances could not be used in scientific research. Since ANVISA has clear rules regarding this research ( Ordinance 344), ^7. An administrative action was filed and ethical approval was obtained, but with a delay of more than a year. ANVISA also recognized the importance of facilitating research with controlled substances, proposing new regulations in December 2018 ( Public Consultation 587) ⁸ and approving a resolution in April 2020 ( Resolution of the Board of Directors 367) ⁹ to keep this research unimpeded. Such measures could facilitate the approval of treatments involving psychedelics in Brazil. The safety and efficacy of MDMA are being tested in an ongoing international Phase 3, randomized, multicenter, double-blind study. ⁵

Given the rise in depression and PTSD, which are expected to cause serious economic and mental health problems, these advances could be a welcome innovation for Brazilian psychiatry. Therefore, it is time for mental health professionals to seriously consider whether psychedelics, while not yet sufficient, may become necessary.

Disclosure

The author reports no conflicts of interest.

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