Updated: Aug 8
In mid-2022 a letter from Substance Abuse and Mental Health Services Administration (SAMHSA) disclosed the anticipated FDA approval of psilocybin for depression and MDMA for PTSD within 24 months.
Both chemicals are DEA Schedule I (illegal) currently. In mid-2022 a bipartisan bill was introduced, with psilocybin in mind, to force the DEA to stop barring terminally ill patients from trying controlled drugs which have passed early trials, as a clarification of 2018 "Right to Try" legislation.
Here is the psilocybin monograph for Cafer's Psychopharmacology 2nd Edition, also anticipated within 24 months.
Pronounced: sil uh SY bin
Mascot: “Silo” magic mushrooms
Mechanism: 5-HT2A agonist
Psilocybin (4-phosphoryloxy-N,N-dimethyltryptamine) is a naturally occurring psychedelic prodrug produced by "magic mushrooms". Structurally, psilocybin is a (tryptamine) and has "trip" in its name. The body converts psilocybin into psilocin, the active hallucinogen. In the early 1960s psilocybin was used legally along with supportive psychotherapy, until outlawed in 1968.
Psilocin is a 5-HT2A serotonin receptor agonist, which is the opposite mechanism of action of second generation antipsychotics, which are 5-HT2A antagonists. Psilocin also enhances synaptic plasticity, possibly by altering brain glutamate levels.
The psychological effects of psilocybin are highly variable and depend on dose, setting and mindset of the user. Group size (smaller is better) was found to be an important determinant of the drug response (Leary, 1960s).
The FDA has granted psilocybin breakthrough status and fast-tracked research to explore its use for treatment-resistant depression (TRD).
In a phase 2b trial, a single dose of synthetic psilocybin 25 mg (in combination with psychotherapy) was given to patients with TRD. Results were impressive—three weeks later 29% of participants were in remission and 37% had at least a 50% decrease in depression scores. At the 3-month mark, only 20% reported significant improvement (Goodwin et al, 2022). 10 mg was not found superior to 1 mg, which served as the placebo.
A psilocybin-assisted therapy trial At Johns Hopkins (Davis AK et al, 2021) administered the drug in two sessions separated by one week. The first session used 20 mg of psilocybin (moderately high dose) and the second at 30 mg (high dose) per 70 kg in the context of supportive psychotherapy. Each session lasted approximately 11 hours and was preceded by several preparatory meetings. 13 of 14 patients who participated in session one continued to session two, the dropout due to difficulty sleeping. Results were rapid with effect size 4 times greater than expected with traditional antidepressants. At 4 weeks, 71% of participants continued to show at least 50% reduction in depressive symptoms.
The mind-altering effects of psilocybin typically last from two to six hours, although to individuals under the influence of psilocybin, the effects may seem to last much longer, since the drug can distort the perception of time.
84% of participants receiving the 25 mg dose reported adverse events, which only occurred on the day of administration: headache, nausea, dizziness, fatigue.
Panic attacks as part of dysphoric “bad trips” may occur with psilocybin, although this risk can be minimized with proper environmental conditions. On the day of psilocybin administration the participants listened to a tailored music playlist and wore eye shades while reclining in a comfortable chair to direct attention inwardly. The John Hopkins psilocybin playlist is available on Spotify, comprised of mostly classical music and songs like “Here Comes the Sun” by the Beatles.
Patients receiving psilocybin (compared to an SSRI) reported greater perceived improvements “in the ability to cry and feel compassion, intense emotions, and pleasure” (Carhart-Harris et al, 2021).
Compared to ketamine, the antidepressant effect of psilocybin is sustained for weeks rather than days. Psilocybin has lower addiction liability and fewer toxic effects than ketamine (Johnson MW et al, 2018). Psilocybin is generally not associated with long-term perceptual disturbances (“flashbacks”) as reported with LSD (Studerus et al, 2011).
Pronounced adverse effects, occurring in up to 13% of those who consume hallucinogenic mushrooms (Schwartz & Smith, 1988), are less likely with pure psilocybin. Mushrooms contain varying amounts of phenylethylamine (PEA), which has sympathomimetic effects. Tachycardia is a common finding in mushroom intoxication (Olof Beck et al, 1998) but not with pure psilocybin.
Subjects with history of bipolar disorder or psychosis were excluded from clinical trials.
Psilocybin poses a risk of serotonin syndrome if coadministered with antidepressants. In controlled trials, participants had been tapered off of traditional antidepressants.
I found no information regarding the potential of psilocybin to inDuce or inHibit CYP450 enzymes. Interactions will be described in the package insert if psilocybin is approved.