Although many are skeptical, the use of illegal recreational drugs in a clinical setting has become more and more commonplace for the treatment of brain illness. Over the last 20 years, cannabis, psilocybin, MDMA and ketamine have been investigated for efficacy in treating a variety of brain illnesses. In humans, a majority of these studies are labeled, “safety and feasibility” studies, as they are often have small sample sizes, meaning only that the results are not nearly as generalizable as results would be from studies with a large sample. As they are the least widely accepted, I will discuss the recent developments in the clinical use of psilocybin, MDMA and ketamine in treating brain illnesses which have limited effective treatment options.
Since the 1990’s, there has been a surge of neuroimaging and psychopharmacology studies with psychedelics. Three studies have investigated the impact of a single dose of psilocybin on depressive symptoms in patients with life-threatening cancer, all finding that post psilocybin there were rapid and enduring anti-anxiety and anti-depressant effects. An open-label trial for treatment-resistant depression in which patients received two doses, 7 days apart, supported these findings. In both cases, psilocybin is being used to fulfill unmet therapeutic roles, in cancer patients and those with treatment-resistant depression. Psilocybin increases the activity of a particular serotonin receptor (2A). The typical pharmacological treatment of depression involves SSRIs (selective serotonin re-uptake inhibitors), both treatments aim to increase the amount of available serotonin in the synapse, but do so using a different mechanism. One key difference is that the chronic use of SSRIs induces emotional blunting, while the mechanism of psilocybin administration results in emotional release. Psilocybin has also been demonstrated to improve obsessive compulsive disorder symptoms. It is important to note that any use of psilocybin in a therapeutic setting would be in conjunction with therapy, whether this be cognitive behavioral therapy (CBT), or in the case of OCD, exposure and response prevention (ERP) therapy.1
Another illegal drug now being investigated for its anti-depressant action is ketamine. Like psilocybin, ketamine is currently being assessed for its effectiveness in patients with treatment-resistant depression. Ketamine is a glutamate NMDA receptor antagonist, meaning that it inhibits glutamate from activating these receptors. After one dose of ketamine (0.5 mg/kg), patients with treatment resistant depression had significantly greater improvements in their MADRS score (assessing depressive symptoms) 24 hours post treatment when compared to patients who had received midazolam, a short-acting benzodiazepine and anesthetic.2
A 2016 study looks at HNK, a metabolite, or metabolic product, of ketamine which is implicated by the researchers as the primary mechanism for ketamine’s antidepressant action. Using EEG and analyses of biological signaling, the researchers concluded that AMPA receptors, another glutamatergic receptor, is activated by HNK and that the functional changes in the hippocampus and pre-frontal cortex are equivalent whether ketamine or HNK is administered. Not only does this study provide a possible alternative to ketamine that comes without the potential sensory-dissociation properties associated with ketamine use. These findings might also illustrate a new mechanism, involving AMPA receptors, by which ketamine is actually producing anti-depressant effects.3
Finally, MDMA, commonly referred to as ecstasy, has been the object of a number of studies particularly investigating the effect of this on PTSD symptoms, social anxiety in patients with ASD as well as in treatment-resistant depression. A double-blind clinical trial was conducted in 2018 assessing the effect of MDMA-assisted psychotherapy. The researchers found that after two 8-hr sessions of MDMA administration and psychotherapy, those patients who received 75 mg and 125 mg doses had significantly reduced PTSD symptom severity compared to the patients receiving 30 mg (an inactive dose) a month following treatment. Those who received 125 mg of MDMA also had significantly reduced depressive symptoms a month post-treatment. Both the 75 and 125 mg treatment groups had improved sleep quality at the same time point compared to the 30 mg group.4 MDMA-assisted therapy is also being investigated for its implications for adults with autism. A proposed model poses MDMA administration at two points during a consistent psychotherapy regimen. The author of review and study proposal is hopeful that MDMA could facilitate improved sociality and reduced social anxiety in ASD patients.5
The idea of drugs coming off of the street and being reintegrated into society to serve a medical purpose fills many with angst, and it should. However, once these substances make it through clinical trials, if they do, they will be far more regulated by the FDA than any street version that is available today. The road for these banned substances becoming approved for medical use is tumultuous and might appear never-ending, but it is important that researchers continue to investigate their clinical effectiveness. Examples like the study in which HNK, a metabolite of ketamine that does not have the same worrying side-effects in illustrative of the importance of this research. There is a lot to learn from some banned substances, I mean, they’re sought after for a reason.
 Carhart-Harris, RL & Goodwin, GM, The therapeutic potential of psychedelic drugs: Past, present, and future, Neuropsych. (2017) 2105-2113.
 Murrough, JW, Iosifescu, DV, Chang, LC, Al Jurdi, RK, Green, CE, Perez, AM, Iqbal, S, et al., Antidepressant efficacy of ketamine in treatment-resistant major depression: A two-sit randomized controlled trial, Am. J. Psychiat. (2013) 1134-1142.
 Zanos, P, Moaddel, R, Morris, PJ, Georgiou, P, Fischell, J, Elmer, GI, Alkondon, M, et al., NMDAR inhibition-independent antidepressant actions of ketamine metabolites, Nature (2016) 481-486.
 Mithoefer, MC, Mithoefer, AT, Feduccia, AA, Jerome, L, Wagner, M, Wymer, J, Holland, J, Hamilton, S, Yazar-Klosinski, B, Emerson, A, Doblin, R, 3,4-methylenedioxymethamphetamine (MDMA)-assisted psychotherapty for post-traumatic stress disorder in military veterans, firefighters, and police officers: A randomized, double-blind, dose-response, phase 2 clinical trial, Lancet Psychiatry (2018) 1-12.
 Danforth, AL, Struble, CM, Yazar-Klosinski, B & Grob, CS, MDMA-assisted therapy: A new treatment model for social anxiety in autistic adults, Prog. Neuropsychopharmacol. Biol. Psychiatry (2016) 237-249.