Age: 18+
Sex: Any
Travel: May Be Covered
Time Reimbursement: Varies
Trial Phase: Phase 2
Recruiting
Sponsor: Robin Carhart-Harris, PhD, MA
Must not be taking: SSRIs, MAO-Is, TCAs, lithium
Disqualifiers: Psychiatric disorders, Cardiovascular conditions, Drug use, others
Prior Safety Data
Approved in 2 jurisdictions
Trial Summary
What is the purpose of this trial?One hundred twenty healthy participants, ages 21 to 70, who experience moderate-to-lower-than-average mental well-being will be evenly randomized into four different study arms, using a 2x2 factorial design. Depending on the study arm, participants will either receive an inactive placebo or up to 25mg psilocybin (oral dose), in one of two set and setting conditions; drug administration contexts that are predicted to modulate drug effects.
The purpose of this study is to evaluate any interaction effects between an oral dose of psilocybin and the surrounding context (set and setting).
Do I have to stop taking my current medications to join the trial?
The trial requires participants to stop taking certain medications and substances, especially those with potential drug interactions like SSRIs, MAO-Is, TCAs, lithium, and serotonin-acting supplements such as St. John's wort. If you are currently taking any of these, you may need to stop before participating.
What evidence supports the effectiveness of the drug psilocybin for improving low mood?
Research shows that psilocybin can lead to significant and long-lasting improvements in mood for people with depression, even those who haven't responded to other treatments. It is generally well-tolerated with few side effects, making it a promising option for mood-related conditions.
12345Is psilocybin safe for humans?
Psilocybin has been studied in clinical trials, showing promise for treating depression and substance use disorders. In a study with healthy adults, escalating doses of psilocybin were tested, and the safety profile was described, indicating it can be safe under controlled conditions.
678910How is the drug psilocybin unique in treating low mood?
Psilocybin is unique because it works by activating serotonin receptors in the brain, particularly the 5-HT2A receptor, which can lead to psychedelic effects and potentially improve mood. Unlike traditional antidepressants, psilocybin's effects are rapid, occurring within an hour of ingestion, and it is derived from natural sources like 'magic mushrooms'.
68111213Eligibility Criteria
This trial is for healthy individuals aged 21 to 70 who feel their mental well-being is moderate to low. Participants must not have any serious health issues and should be interested in how different environments might influence the effects of psilocybin, a substance being studied for its potential to improve mood.Inclusion Criteria
Participants must agree to inform the investigators within 48 hours of any new or changed medical conditions
Participants must be fluent in speaking and reading English
Participants able to become pregnant must be non-lactating, have a negative pregnancy test at study entry and prior to each Experimental Session, and must agree to an adequate form of birth control over the course of the study
+7 more
Exclusion Criteria
Participants with a positive alcohol breathalyzer test result on any study visit
Breastfeeding participants or participants with a positive pregnancy test
I am not taking any supplements or drugs that could interfere with the trial.
+18 more
Trial Timeline
Screening
Participants are screened for eligibility to participate in the trial
2-4 weeks
1 visit (in-person)
Baseline Assessment
Baseline assessments including psychological well-being and brain imaging
1 week
1 visit (in-person)
Treatment
Participants receive a single dose of either psilocybin or placebo in a controlled context
1 day
1 visit (in-person)
Follow-up
Participants are monitored for changes in mental well-being and brain activity
4 weeks
Multiple visits (in-person and virtual)
Participant Groups
The study tests if the setting affects how psilocybin works on mood. One group gets a placebo (no active drug), while others get up to 25mg of psilocybin. They're placed in one of two different contexts designed to see if environment changes the drug's impact.
4Treatment groups
Experimental Treatment
Placebo Group
Group I: Psilocybin C2Experimental Treatment2 Interventions
Following screening and a baseline assessment visit, healthy volunteers will receive one dose of up to 25mg psilocybin in a context (Context 2) that is hypothesized to modulate acute and post-acute drug effects.
Group II: Psilocybin C1Experimental Treatment2 Interventions
Following screening and a baseline assessment visit, healthy volunteers will receive one dose of up to 25mg psilocybin in a context (Context 1) that is hypothesized to modulate acute and post-acute drug effects.
Group III: Placebo C1Placebo Group2 Interventions
Following screening and a baseline assessment visit, healthy volunteers will receive one dose of an inactive placebo in a context (Context 1) that is hypothesized to modulate acute and post-acute drug effects.
Group IV: Placebo C2Placebo Group2 Interventions
Following screening and a baseline assessment visit, healthy volunteers will receive one dose of an inactive placebo in a context (Context 2) that is hypothesized to modulate acute and post-acute drug effects.
Psilocybin is already approved in United States, European Union for the following indications:
🇺🇸 Approved in United States as Psilocybin for:
- Treatment-resistant depression (TRD) under Breakthrough Therapy designation
🇪🇺 Approved in European Union as Psilocybin for:
- Treatment-resistant depression (TRD) under PRIME designation
Find a Clinic Near You
Research Locations NearbySelect from list below to view details:
UCSF Mission BaySan Francisco, CA
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Who Is Running the Clinical Trial?
Robin Carhart-Harris, PhD, MALead Sponsor
References
Psilocybin in Palliative Care: An Update. [2023]This review article summarizes clinically and socially relevant developments over the past five years in the therapeutic use of the classical tryptamine psychedelic substance psilocybin, with respect to the common challenges faced by palliative care patients and their care teams. Psilocybin is available in whole fungal and isolated forms but is not yet approved for therapeutic use in the United States. Using targeted database and gray literature searches, and author recall, key sources were identified, reviewed, and synthesized as to the safety and efficacy of psilocybin in palliative care.
[Treatment with psilocybin: applications for patients with psychiatric disorders]. [2021]After a cessation of almost 40 years, there is renewed interest into therapeutic applicationsof the serotonergic psychedelic psilocybin for the treatment of patients with various psychiatric disorders. PubMed was searched for clinical trials into "psilocybin" between 2000 and 2020, complemented by handsearching. Articles were also screened for explanatory models and working mechanisms. Psilocybin has been studied in 9 clinical trials: for the treatment of substance use disorders, depression, end-of-life anxiety, demoralization, and obsessive-compulsive disorder. Results show that psilocybin is well tolerated, with only limited side-effects, while even patients with treatment-resistant disorders sometimes show marked, long-term improvements after one or a few sessions. Initial results are encouraging, but there are several limitations. More research is needed to determine which patient populations can benefit, what role setting and the placebo response play, and how these novel treatments can be optimized.
Metabolism of psilocybin and psilocin: clinical and forensic toxicological relevance. [2018]Psilocybin and psilocin are controlled substances in many countries. These are the two main hallucinogenic compounds of the "magic mushrooms" and both act as agonists or partial agonists at 5-hydroxytryptamine (5-HT)2A subtype receptors. During the last few years, psilocybin and psilocin have gained therapeutic relevance but considerable physiological variability between individuals that can influence dose-response and toxicological profile has been reported. This review aims to discuss metabolism of psilocybin and psilocin, by presenting all major and minor psychoactive metabolites. Psilocybin is primarily a pro-drug that is dephosphorylated by alkaline phosphatase to active metabolite psilocin. This last is then further metabolized, psilocin-O-glucuronide being the main urinary metabolite with clinical and forensic relevance in diagnosis.
Renal excretion profiles of psilocin following oral administration of psilocybin: a controlled study in man. [2019]In a clinical study eight volunteers received psilocybin (PY) in psychoactive oral doses of 212+/-25 microg/kg body weight. To investigate the elimination kinetics of psilocin (PI), the first metabolite of PY, urine was collected for 24 h and PI concentrations were determined by high-performance liquid chromatography with column switching and electrochemical detection (HPLC-ECD). Sample workup included protection of the unstable PI with ascorbic acid, freeze-drying, and extraction with methanol. Peak PI concentrations up to 870 microg/l were measured in urine samples from the 2-4 h collection interval. The PI excretion rate in this period was 55.5+/-33.8 microg/h. The limit of quantitation (10 microg/L) was usually reached 24 h after drug administration. Within 24 h, 3.4+/-0.9% of the applied dose of PY was excreted as free PI. Addition of beta-glucuronidase to urine samples and incubation for 5 h at 40 degrees C led to twofold higher PI concentrations, although 18+/-7% of the amount of unconjugated PI was decomposed during incubation. We conclude that in humans PI is partially excreted as PI-O-glucuronide and that enzymatic hydrolysis extends the time of detectability for PI in urine samples.
Efficacy and safety of psilocybin-assisted treatment for major depressive disorder: Prospective 12-month follow-up. [2022]Preliminary data suggest that psilocybin-assisted treatment produces substantial and rapid antidepressant effects in patients with major depressive disorder (MDD), but little is known about long-term outcomes.
[Hallucinogenic mushrooms]. [2018]The group of hallucinogenic mushrooms (species of the genera Conocybe, Gymnopilus, Panaeolus, Pluteus, Psilocybe, and Stropharia) is psilocybin-containing mushrooms. These "magic", psychoactive fungi have the serotonergic hallucinogen psilocybin. Toxicity of these mushrooms is substantial because of the popularity of hallucinogens. Psilocybin and its active metabolite psilocin are similar to lysergic acid diethylamide. These hallucinogens affect the central nervous system rapidly (within 0.5-1 hour after ingestion), producing ataxia, hyperkinesis, and hallucinations. In this review article there are discussed about history of use of hallucinogenic mushrooms and epidemiology; pharmacology, pharmacodynamics, somatic effects and pharmacokinetics of psilocybin, the clinical effects of psilocybin and psilocin, signs and symptoms of ingestion of hallucinogenic mushrooms, treatment and prognosis.
The pharmacology of psilocybin. [2016]Psilocybin (4-phosphoryloxy-N,N-dimethyltryptamine) is the major psychoactive alkaloid of some species of mushrooms distributed worldwide. These mushrooms represent a growing problem regarding hallucinogenic drug abuse. Despite its experimental medical use in the 1960s, only very few pharmacological data about psilocybin were known until recently. Because of its still growing capacity for abuse and the widely dispersed data this review presents all the available pharmacological data about psilocybin.
Liquid chromatography-mass spectrometric and liquid chromatography-tandem mass spectrometric determination of hallucinogenic indoles psilocin and psilocybin in "magic mushroom" samples. [2016]Accurate and sensitive analytical methods for psilocin (PC) and psilocybin (PB), tryptamine-type hallucinogens contained in "magic mushrooms," were investigated using liquid chromatography-mass spectrometry (LC-MS) and liquid chromatography-tandem mass spectrometry (LC-MS-MS). The chromatographic separation on an ODS column and mass spectral information gave complete discrimination between PC and PB without derivatization. The mass spectrometric detection had a high sensitivity, and the tandem mass spectrometric detection provided more specificity and accuracy, as well as high sensitivity. The detection limits ranged from 1 to 25 pg by LC-MS in the selected ion monitoring mode, and the intra- and inter-day coefficients of variation were estimated to be 4.21-5.93% by LC-MS-MS in the selected reaction monitoring mode. By applying the present LC-MS-MS technique to four real samples, the contents of PC and PB were found to vary over a wide range (0.60-1.4 and 0.18-3.8 mg/g dry wt. for PC and PB, respectively) between samples.
Pharmacokinetics of Escalating Doses of Oral Psilocybin in Healthy Adults. [2022]Psilocybin is a psychedelic tryptamine that has shown promise in recent clinical trials for the treatment of depression and substance use disorders. This open-label study of the pharmacokinetics of psilocybin was performed to describe the pharmacokinetics and safety profile of psilocybin in sequential, escalating oral doses of 0.3, 0.45, and 0.6 mg/kg in 12 healthy adults.
Intravenous mushroom poisoning. [2019]Mushrooms of the genus Psilocybe frequently are ingested by recreational drug users for their hallucinogenic effects. We present the case of a 30-year-old man who allegedly received an intravenous injection of an extract of Psilocybe mushrooms. His clinical course was characterized in part by vomiting, severe myalgias, hyperpyrexia, hypoxemia, and mild methemoglobinemia, and it was similar to two previously reported cases. The patient improved rapidly with supportive care.
Structure-Activity Relationships for Psilocybin, Baeocystin, Aeruginascin, and Related Analogues to Produce Pharmacological Effects in Mice. [2023]4-Phosphoryloxy-N,N-dimethyltryptamine (psilocybin) is a naturally occurring tertiary amine found in many mushroom species. Psilocybin is a prodrug for 4-hydroxy-N,N-dimethyltryptamine (psilocin), which induces psychedelic effects via agonist activity at the serotonin (5-HT) 2A receptor (5-HT2A). Several other 4-position ring-substituted tryptamines are present in psilocybin-containing mushrooms, including the secondary amine 4-phosphoryloxy-N-methyltryptamine (baeocystin) and the quaternary ammonium 4-phosphoryloxy-N,N,N-trimethyltryptamine (aeruginascin), but these compounds are not well studied. Here, we investigated the structure-activity relationships for psilocybin, baeocystin, and aeruginascin, as compared to their 4-acetoxy and 4-hydroxy analogues, using in vitro and in vivo methods. Broad receptor screening using radioligand binding assays in transfected cells revealed that secondary and tertiary tryptamines with either 4-acetoxy or 4-hydroxy substitutions display nanomolar affinity for most human 5-HT receptor subtypes tested, including the 5-HT2A and the serotonin 1A receptor (5-HT1A). The same compounds displayed affinity for 5-HT2A and 5-HT1A in mouse brain tissue in vitro and exhibited agonist efficacy in assays examining 5-HT2A-mediated calcium mobilization and β-arrestin 2 recruitment. In mouse experiments, only the tertiary amines psilocin, psilocybin, and 4-acetoxy-N,N-dimethyltryptamine (psilacetin) induced head twitch responses (ED50 0.11-0.29 mg/kg) indicative of psychedelic-like activity. Head twitches were blocked by 5-HT2A antagonist pretreatment, supporting 5-HT2A involvement. Both secondary and tertiary amines decreased body temperature and locomotor activity at higher doses, the effects of which were blocked by 5-HT1A antagonist pretreatment. Across all assays, the pharmacological effects of 4-acetoxy and 4-hydroxy compounds were similar, and these compounds were more potent than their 4-phosphoryloxy counterparts. Importantly, psilacetin appears to be a prodrug for psilocin that displays substantial serotonin receptor activities of its own.
Magic truffles or Philosopher's stones: a legal way to sell psilocybin? [2019]"Magic mushrooms" is the most common name given to hallucinogenic fungi containing the psychoactive alkaloids psilocybin and psilocin. In recent years, fungis' sclerotia, commonly called "magic truffles" have become a form of supply of psychoactive Psilocybe alkaloids since Psilocybe sclerotia are not specifically included in the laws banning the sale, the purchase and the use of such substances and mushrooms containing them. A liquid chromatography -tandem mass spectrometry (LC-MS/MS) method was developed for the rapid determination of psilocybin and psilocin in Psilocybe sclerotia. Following a simple step extraction with methanol, the alkaloids were separated on a reversed-phase column using a gradient of 0.1% formic acid - acetonitrile s a mobile phase at a flow rate of 0.2 mL/min.. Separated analytes were detected by electrospray ionization tandem mass spectrometry in the positive ion mode using multiple reaction monitoring. The developed method was linear over the calibration range for all two substances under investigation, with a r(2) > 0.99. The detection and quantification limits were 0.3 µg and 1 µg per 100 mg truffles, for both psilocin and psilocybin and the intra- and inter-day coefficients of variation were always better than 15%. Using this method, the presence of only psilocybin was demonstrated in examined Psilocybe sclerotia. The content of psilocybin was found to vary over a concentration range of 59.3 to 167.8 µg per 100 mg of fresh sclerotia.
Ethnomycology, biochemistry, and cultivation of Psilocybe samuiensis Guzmán, Bandala and Allen, a new psychoactive fungus from Koh Samui, Thailand. [2019]Several specimens of Psilocybe and Copelandia species in Koh Samui, Thailand were recently collected for herbarium deposit and scientific study. This paper presents an ethnomycological and biochemical study of one of the species; P. samuiensis Guzmán, Bandala and Allen, a new psychoactive gill fungus reported from Thailand. Mycelium for the cultivation of P. samuiensis was obtained on 6% malt agar from the spores of a dried specimen. The growth of P. samuiensis was similar to that of P. tampanensis Guzmán and Pollock, but more rapid than the mycelium of P. semilanceata (Fr.:Sacc.) Kumm. Laboratory analyses indicates that the alkaloid content in cultured fruit bodies of P. samuiensis is of the same order of magnitude as that found in naturally occurring mushrooms of this species. HPLC analyses of both naturally occurring and in vitro cultivated fruit bodies of P. samuiensis revealed high concentrations of psilocybin and psilocin. Small amounts of baeocystin were also detected. Psilocybin levels varied from 0.23% up to 0.90%. The psilocybin content was highest in the caps. Psilocybin was also found in the cultured non-bluing mycelia of P. samuiensis and varied from 0.24% to 0.32% dry weight. The relative alkaloidal content of psilocybin, psilocin, and baeocystin found in P. samuiensis was similar to that measured in many other psychoactive fungi species, but completely different from that found in P. semilanceata.