Psilocybin

Structure

Psilocybin (N-phosphoryloxy-N,N-dimethyltryptamine), a simple tryptamine, is dephosphorylated to psilocin (4-hydroxy-N,N-dimethyltryptamine) by alkaline phosphatase in the gastrointestinal tract and kidneys during first-pass metabolism. Psilocin, the pharmacologically active compound, is an indole derivative with structural similarities to serotonin. Psilocybin is detectable by high performance liquid chromatography, but this is not available in most clinical settings.

Action

Psilocin is a high-affinity agonist at serotonin 5HT _2A receptors, which are especially prominent in the prefrontal cortex. The net result of 5HT _2A agonism is increased cortical activity secondary to down-stream postsynaptic glutamate effects. Psilocin is also active at 5HT _1A , 5HT _1D , and 5HT _2C receptors, although these are thought to play a lesser role in its effects.

Additional evidence about the mechanism of action comes from studies of receptor antagonists. In the presence of the 5HT _2A antagonist ketanserin, the mental status changes typical of psilocybin do not occur, supporting the notion that primary effects are due to action at presynaptic 5HT _2A receptors [ ]. Although psilocybin has no affinity for dopamine D ₂ receptors, a PET study using the dopamine D ₂ receptor ligand raclopride showed that psilocybin increases dopamine transmission in the striatum, probably through secondary increases in dopamine [ , ]. Some psilocybin-containing mushrooms contain phenylethylamine, which may contribute to sympathomimetic effects.

Psilocybin like other serotonergic hallucinogens, such as lysergic acid diethylamide (LSD) and N,N-dimethyltryptamine (DMT), alters mood, perception, and cognition.

In healthy volunteers, changes in emotion, consciousness, perception and thought begin within 20–30 minutes of ingestion and peak in 30–50 minutes. Peak effects persist for 2 hours, with resolution of effect within 6 hours. Lower doses may produce shorter lasting effects of 1–2 hours. Moderate oral doses (12–30 mg) alter consciousness, increase introspection, and induce derealization, dream-like states, illusions, complex hallucinations, synesthesia, and altered perceptions of time and space. Muscle relaxation is also experienced with intoxication. Disruptions in attention, such as difficulty in disengaging from prior stimuli and impairment in monitoring several simultaneous visual stimuli, have been described [ ]. Euphoria, grandiosity, and other amplifications of affective experience are common. The majority of psilocybin users experience a pleasant alteration in mood, but some experience panic or dysphoria. A user’s expectations and environment very strongly influence the hallucinogenic effects. Settings with more interpersonal support reduce panic and paranoia and increase positive experiences [ ].

Psilocybin and psilocin are renally excreted, and about 2/3 of excretion occurs in the first 3 hours. The half-life is about 50 minutes [ ]. After 24 hours, the compound is undetectable in the urine [ ].

Uses

Psilocybin has been used in obsessive–compulsive disorder (OCD) and some studies support its efficacy in this disorder. In a double-blind study, nine subjects received four doses, low (100 micrograms/kg), medium (200 micrograms/kg), and high (300 micrograms/kg), in a series of 8-hour sessions with a very low dose (25 micrograms/kg) inserted randomly in a double-blind manner. All the subjects had a reduction in their symptoms (measured by the Yale-Brown Obsessive Compulsive Scale) during at least one of the sessions, and improvement lasted at least 24 hours. No dose effect was noted, probably because of the small number of subjects studied and large interindividual variability. With the exception of one subject who had transient hypertension, psilocybin was well tolerated and without adverse reactions [ , ].

Synthetic psilocybin (Indocybin) was used for investigational and psychotherapeutic purposes in the 1960s. The serotonin hypothesis of schizophrenia grew in part from the psychotomimetic effects of psilocybin seen in these investigations, as well as similar observations in studies of LSD. Psilocybin impairs thalamic sensory gating, resulting in an inability to screen out extraneous stimuli and difficulties attending to appropriate stimuli, which overwhelms frontal organizational capacities and is thought to result in the observed psychotomimetic effects [ , ].

Cardiovascular

An 18-year-old man developed Wolff–Parkinson–White syndrome and had a myocardial infarction during psilocybin intoxication [ ]. The mechanism for myocardial infarction is not known, although it is theorized that serotonin-induced changes in platelet aggregation and sympathetically-induced vasospasm may play a role [ ].

In a study of the dose-dependent effects of psilocybin 45–315 micrograms/kg in eight subjects, there was no effect on the electrocardiogram or heart rate [ ]. At the highest doses, mean arterial blood pressure rose significantly in the 60 minutes after psilocybin ingestion, leading the authors to recommend that those with untreated hypertension should abstain from psilocybin.

An acute coronary syndrome with ST-segment elevation has been reported in the absence of coronary artery disease after abuse of psychoactive fungi (“magic mushrooms”) [ ].

• A 17-year-old boy developed chest pain and dyspnea at rest after consuming Psilocybe semilanceata . His blood pressure was 120/60 mmHg and his heart rate 93/minute. In a 12-lead electrocardiogram there were right bundle branch block and ST-segment elevation in leads I, II, aVL, aVF, and V3–V6. Serum troponin T concentration and creatine kinase (CK) activity were raised, as was the CK-MB fraction. Drug screening excluded other substances. He had no cardiovascular risk factors. Coronary angiography showed normal coronary arteries, but left ventriculography showed a regional wall motion abnormality in the apical segment and a reduced ejection fraction. Cardiovascular MRI scanning confirmed the contractile pattern. There was a pericardial effusion. Left ventricular function normalized after 6 days and the pericardial effusion resolved with anti-inflammatory drug therapy.

The authors attributed this presentation to takotsubo cardiomyopathy (left ventricular ballooning syndrome) due to psilocybin, probably resulting from its catecholamine-like action.