Acute effects of psilocybin after escitalopram or placebo pretreatment in a randomized, double-blind, placebo-controlled, cross-over study in healthy subjects

In this double-blind, cross-over, the effects of psilocybin (25mg) were assessed in healthy volunteers (n=23) who had been taking the antidepressant escitalopram (10-20mg, 14 days) or placebo before psilocybin treatment. Pretreatment with escitalopram had no relevant effect on positive mood but significantly reduced bad drug effects and adverse cardiovascular effects.

Abstract

“The psychedelic psilocybin is being investigated for the treatment of depression and anxiety. Unclear is whether antidepressant treatments interact with psilocybin. The present study used a double-blind, placebo-controlled, cross-over design with two experimental test sessions to investigate the response to psilocybin (25 mg) in healthy subjects after pretreatment with escitalopram or placebo. The treatment order was random and counterbalanced. Pretreatment consisted of 10 mg escitalopram daily for 7 days, followed by 20 mg daily for 7 days, including the day of psilocybin administration, or 14 days of placebo pretreatment before psilocybin administration. Psilocybin treatments were separated by at least 16 days. The outcome measures included self-rating scales that evaluated subjective effects, autonomic effects, adverse effects, plasma brain-derived neurotrophic factor (BDNF) levels, electrocardiogram QTc time, whole-blood HTR2A and SCL6A4 gene expression, and pharmacokinetics. Escitalopram pretreatment had no relevant effect on positive mood effects of psilocybin but significantly reduced bad drug effects, anxiety, adverse cardiovascular effects, and other adverse effects of psilocybin compared with placebo pretreatment. Escitalopram did not alter the pharmacokinetics of psilocin. The half-life of psychoactive free (unconjugated) psilocin was 1.8 h (range 1.1-2.2 h), consistent with the short duration of action of psilocybin. Escitalopram did not alter HTR2A or SCL6A4 gene expression before psilocybin administration, QTc intervals, or circulating BDNF levels before or after psilocybin administration. Further studies are needed with a longer antidepressant pretreatment time and patients with psychiatric disorders to further define interactions between antidepressants and psilocybin.”

Authors: Anna M. Becker, Friederike Holze, Tanja Grandinetti, Aaron Klaiber, Vanja E. Toedtli, Karolina E. Kolaczynska, Urs Duthaler, Nimmy Varghese, Anne Eckert, Edna Grünblatt & Matthias E Liechti

Summary

WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE?

This study gives a first indication that psilocybin is safe to take during escitalopram treatment, and that it has no relevant effects on the positive drug effects of psilocybin.

Psilocybin, the active metabolite of the prodrug psilocybin, produces an altered state of mind through serotonin 5- hydroxytryptamine- 2A (5- HT2A) receptor activation. These effects have been shown to be associated with positive long- term effects on depression, anxiety, and addiction.

Psychedelics are typically investigated and intended for use in patients with psychiatric disorders who may already be treated with antidepressant medications, typically serotonin transporter inhibitors. However, antidepressant treatment can also be problematic for some patients who require antidepressant treatment or suffer from withdrawal when stopping it.

Escitalopram pretreatment significantly reduced the 5 Dimensions of Altered States of Consciousness (5D- ASC) total scores compared with placebo pretreatment in a randomized, double- blind, placebo- controlled, crossover study in healthy subjects.

MATERIALS AND METHODS Study design

The study used a double-blind, placebo-controlled, crossover design with two experimental test sessions to investigate the response to psilocybin after pretreatment with escitalopram or placebo. Escitalopram was administered 2 hours before psilocybin to enhance compliance with daily pretreatment administration. Escitalopram concentrations were measured before the final dose of escitalopram was administered under supervision at the study site.

Participants

Twenty- seven healthy participants were recruited by word of mouth or an advertisement that was posted on the web market platform of the University of Basel. Twenty- three subjects completed the study (12 men and 11 women; 34 -10 years old).

The participants were screened for psychotic disorders, medications that may interfere with the study medications, chronic or acute physical illness, tobacco smoking > 10 cigarettes/day, lifetime prevalence of illicit drug use > 10 times, illicit drug use within the last 2 months, and illicit drug use during the study.

Study drugs

Psilocybin was synthesized by ReseaChem GmbH, Burgdorf, Switzerland, and administered as 5 mg capsules with an exact analytically confirmed actual psilocybin content of 4.61 0:09 mg. Escitalopram was obtained as the marketed drug Escitalopram- Mepha Lactab (10 mg), and encapsulated to ensure blinding.

Study procedures

The study included a screening visit, two 10-hour test sessions, and an end-of- study visit. The subjects were never alone during the test sessions, and were sent home at 5:30 pm with a partner or friend.

A 5D- ASC scale was administered 7 hours after psilocybin administration to retrospectively rate peak drug effects. 24 Mystical experiences were assessed using the States of Consciousness Questionnaire (SOCQ )24, 31 and the Adjective Mood Rating Scale (A MR S)35.

Autonomic and adverse effects

Adverse effects were assessed 1 hour before and 7 hours after psilocybin administration using the List of Complaints, and electrocardiograms were recorded 1 hour before and 2.5 hours after psilocybin administration.

Plasma BDNF levels

Plasma BDNF levels were measured at baseline and 4 and 7 hours after psilocybin administration. The variability was 3.3 and 2.3.

Gene expression

Blood samples were collected before psilocybin administration and analyzed using the PA Xgene Blood R NA System. PCR was performed on the HTR2A and SCL6A4 genes and four additional reference genes, and melting point analysis was performed on the PCR products.

Plasma psilocin concentrations

Blood was collected into lithium heparin tubes, plasma was stored at 80°C until analysis, and psilocin and escitalopram concentrations were determined using liquid chromatography tandem mass spectrometry. Pharmacokinetic parameters were estimated using noncompartmental methods in Phoenix WinNonlin 8.3 (Certara, Princeton, NJ, USA).

Data analysis

Peak effect and minimum effect values were determined for repeated measures and analyzed using paired two-sided t- tests. No correction for multiple testing was applied.

Subjective drug effects

Escitalopram had no effect on 3D- OAV total scores, but significantly reduced psilocybin-induced anxiety and “Anxious Ego- Dissolution” but not “Oceanic Boundlessness”.

Escitalopram reduced psilocybin-induced increases in VAS ratings of “any drug effects”, “bad drug effects”, “fear”, “talkative” and “open” and attenuated reductions of ratings of “happy” and “concentration”. Escitalopram did not significantly alter overall mystical experiences that were induced by psilocybin, measured by MEQ30 total score.

Autonomic and adverse effects

Escitalopram significantly reduced psilocybin-induced elevations of peak VAS scores for “any drug effect”, “bad drug effect” and “fear” but had no effect on “good drug effect”, “drug liking”, “drug high” or “feeling stimulated”.

Escitalopram reduced acute adverse effects associated with psilocybin administration compared with placebo, but did not alter QTc times. The longest QTc intervals observed in any subject were 489 and 422 ms after escitalopram and placebo, respectively, 1 hour before and 2.5 hours after psilocybin administration, respectively.

Pharmacokinetics of psilocin and its metabolites

Psilocin was metabolized to an approximately similar extent to inactive 4- HIAA and psilocin glucuronide during the first 7 hours after drug administration. Psilocin glucuronide concentrations remained higher beyond 7 hours, and the elimination half- life was 4.5 and 5.2 hours, respectively.

Adverse effects of escitalopram and gene expression

There was one nontreatment related severe adverse event, and escitalopram had no effect on the pharmacokinetics of psilocybin or its metabolites compared with placebo.

One subject dropped out of the study because of a vertebral disc hernia, but other subjects experienced nausea, headache, tiredness, lower libido, feeling depressed, loss of appetite, diarrhea, restless legs, increased appetite, bruxism, insomnia, anorgasmia, dizziness, difficulty concentrating, and visual disturbance.

Fourteen participants correctly identified the pretreatment sequence, and nine incorrectly identified the sequence during the end-of-study visit. Escitalopram concentrations were high in all subjects.

DISCUSSION

We did not confirm our primary hypothesis that treatment with a serotonin transporter inhibitor would attenuate the mind-altering effects of psilocybin. Escitalopram reduced untoward acute effects of psilocybin, including subjective bad drug effects, anxious-ego dissolution, anxiety, and nadir effects, compared with placebo pretreatment.

There are no previous studies on the interaction of antidepressants with psilocybin comparable to the present work. Escitalopram had no effect on the acute response to psilocybin in the present study, and stopping escitalopram treatment before psilocybin administration may not be warranted.

The present study tested escitalopram, which may not necessarily apply to other antidepressants, and included healthy subjects and no therapeutic setting. Escitalopram pretreatment resulted in relatively high plasma escitalopram concentrations and increased adverse events, although complaints on the List of Complaints did not differ.

The present study used a powerful within- subject design, made comparisons with placebo under double- blind conditions in a controlled laboratory setting, and used internationally established standardized and validated psychometric outcome measures.

Psilocybin slightly increased plasma BDNF levels, but had no significant effect on QTc time. Psilocybin may prolong QTc time in susceptible persons during the peak effects of the drug.

The present study measured the pharmacokinetics of psilocybin at a fixed dose of 25 mg psilocybin and found that the maximal plasma concentration of unconjugated psilocin was reached 2 hours after drug administration. The terminal half- life of unconjugated psilocin was 1.8 hours, consistent with the short duration of action of psilocybin. The total psilocin concentration is determined after deglucuronidation and represents psilocin glucuronide. Psilocybin glucuronide is the best analyte to document recent exposure to psilocybin. Previous studies used weight- adjusted doses of psilocybin, but subjective effects have not been associated with body weight or sex. Fixed doses have thus been recommended and are increasingly used.

CONCLUSION

Escitalopram pretreatment for 2 weeks reduced adverse effects of psilocybin compared with placebo pretreatment. Further studies are needed to clarify the interactive effects on therapeutic outcomes.

FUNDING

This work was supported by the University Hospital Basel and Mind Medicine, Inc. Mind Medicine, Inc. had no role in planning the present study.

AUTHOR CONTRIBUTIONS

Psilocybin has been shown to have beneficial effects in several studies, including a randomized double- blind trial for depression, an open- label feasibility study for treatment- resistant depression, and a randomized double- blind trial for anxiety and depression in patients with life- threatening cancer.

4-hydroxyindole-3-acetic acid, in human plasma, is a novel psychoactive tryptamine that is similar to classic hallucinogens. It interacts with serotonin 2A receptor occupancy and plasma psilocin levels, and may be used to treat depression. Acute subjective effects in LSD- and MDMA- assisted psychotherapy, safety and efficacy of lysergic acid diethylamide-assisted psychotherapy for anxiety associated with life-threatening diseases, and a prospective study on predicting responses to psychedelics are discussed. Psilocybin has been shown to have an acute, subacute and long-term subjective effect in healthy humans. The pharmacokinetics of escalating doses of oral psilocybin in healthy adults have also been studied. Optimal dosing for psilocybin pharmacotherapy is based on weight-adjusted and fixed dosing approaches.

Psilocybin, MDMA, and D-amphetamine can occasion mystical- type experiences having substantial and sustained personal meaning and spiritual significance, and lysergic acid diethylamide can cause acute effects in healthy subjects. A novel oral LSD formulation in healthy subjects shows promising pharmacokinetics and subjective effects, but is associated with altered response to tricyclic antidepressants, monoamine oxidase inhibitors or lithium.

MDMA- assisted psychotherapy for severe PTSD: a randomized, double- blind, placebo- controlled phase 3 study. Genetics, epigenetics and gene expression markers of major depressive disorder and antidepressant response. Escitalopram plasma levels and antidepressant response, ayahuasca modulation of serum brain-derived neurotrophic factor, psilocybin concentration- QTc relationship, and Griffiths, R.R., Johnson, M.W., Richards, W.A., Richards, B.D., McCann, U. & Jesse, R., have been studied.