Psilocybin Microdosing for Depression

Overseen By Rotem Petranker

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: Rotem Petranker

Must not be taking: Antidepressants, Opioids, MAO inhibitors, others

Disqualifiers: Cardiovascular conditions, Epilepsy, Cancer, others

Prior Safety Data This treatment has passed at least one previous human trial

Approved in 2 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: 8

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial investigates whether small doses of psilocybin, a compound in certain mushrooms, can safely and effectively aid individuals with Major Depressive Disorder (MDD). Participants will receive either psilocybin or a placebo (a substance with no therapeutic effect) once a week for four weeks, without knowing which they are taking. The trial aims to determine if these small, non-hallucinogenic doses can improve depression symptoms. Individuals with an existing MDD diagnosis who are not currently experiencing a depressive episode may be suitable for this trial. As a Phase 2 trial, the research measures the treatment's effectiveness in an initial, smaller group of people.

Do I have to stop taking my current medications for the trial?

Yes, you may need to stop taking certain medications. Participants cannot take psychotropic medications, antidepressants, or medications affecting serotonin neurons. If you were on antidepressants, a washout period of five half-lives plus seven days is required. You must also refrain from starting new medications and using certain metabolic inducers or inhibitors. Consult the research team for specific guidance.

Do I need to stop taking my current medications for the trial?

Yes, you will need to stop taking certain medications. Participants must not be on any regular psychotropic medications, including antidepressants, and must refrain from using certain other drugs. If you were previously on antidepressants, a specific period must pass before starting the trial.

Is there any evidence suggesting that this treatment is likely to be safe for humans?

Research has shown that psilocybin, the substance tested in this trial, has been studied for safety in humans. In earlier studies, small doses of psilocybin were generally well-tolerated, with participants experiencing mild side effects like headaches and slight nausea, which usually resolved on their own.

While higher doses of psilocybin can cause hallucinations, the small dose in this trial is not expected to do so. The trial uses a 2mg dose, which is too low to cause hallucinations.

Although specific data on this exact dose is unavailable, the study's Phase 2 status indicates that earlier trials have already demonstrated some safety in humans. This phase typically focuses on better understanding the treatment's effects and safety in a larger group. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising for depression?

Most treatments for depression, like SSRIs and SNRIs, focus on altering neurotransmitter levels over several weeks. But psilocybin offers a different approach, acting on serotonin receptors in the brain to potentially reset neural pathways. Unlike traditional antidepressants, psilocybin might offer rapid, lasting effects after just a few doses, reducing the need for daily medication. Researchers are excited because this psychedelic compound could revolutionize how we approach mental health, offering new hope for those who haven’t found relief with existing options.

What evidence suggests that psilocybin might be an effective treatment for depression?

Research shows that psilocybin, a substance found in certain mushrooms, may help treat depression. Earlier studies found that psilocybin can greatly improve mood and emotional well-being in people with depression. Participants noticed a reduction in their depressive symptoms after taking psilocybin, with positive effects lasting several weeks. Psilocybin influences serotonin receptors in the brain, which regulate mood. While more research is needed, these early findings suggest that psilocybin could be a promising treatment for major depressive disorder. In this trial, participants will be assigned to different groups: one receiving psilocybin without knowing, another receiving a placebo without knowing, and a third group openly receiving psilocybin. ^{1 2 3 4 5}

Are You a Good Fit for This Trial?

Adults aged 18-65 with Major Depressive Disorder can join this trial. They must speak and read English well, have a high school education, not use psychoactive drugs or alcohol before sessions, and women must test negative for pregnancy and use birth control. Excluded are those with certain medical conditions like uncontrolled blood pressure, seizures, cancer history; those on specific medications; smokers; substance abuse disorders within the last 5 years; unstable health conditions.

Inclusion Criteria

You have given informed consent.

I have been diagnosed with persistent depressive disorder, dysthymic subtype.

If of childbearing potential, must have a negative pregnancy test at study entry and must agree to use adequate birth control through 10 days after the last Experimental Session (refer to section 9.4.2 for contraceptive guidelines).

Exclusion Criteria

I have had a stroke, mini-stroke, brain aneurysm, or a blood vessel malformation.

I will not start any new medications during the trial.

The subject has blood pressure exceeding screening criteria

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Blinded Treatment

Participants receive either placebo or psilocybin once weekly for 4 weeks without knowing which they are receiving

4 weeks

4 visits (in-person)

Open Label Treatment

Participants receive psilocybin once weekly for 4 weeks and are informed they are receiving psilocybin

4 weeks

4 visits (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment

up to 2 years

What Are the Treatments Tested in This Trial?

Interventions

• Psilocybin

Trial Overview The trial is testing if small doses of psilocybin (2mg) can safely improve mood in people with depression without causing hallucinations. Participants will receive either psilocybin or a placebo first to compare effects.

How Is the Trial Designed?

Group I: Open Label Experimental Treatment 2 Interventions

In this condition participants will receive psilocybin once weekly for 4 weeks, and will be told that they are receiving psilocybin.

Group II: Blinded Psilocybin Experimental Treatment 1 Intervention

In this condition participants will receive psilocybin once weekly for 4 weeks, but they will not know whether they receive placebo or psilocybin.

Group III: Blinded Placebo Placebo Group 1 Intervention

In this condition participants will receive an inert placebo once weekly for 4 weeks, but they will not know whether they receive placebo or psilocybin.

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

Who Is Running the Clinical Trial?

Rotem Petranker

Lead Sponsor

Trials

1

Recruited

50+

Nikean Foundation

Collaborator

Trials

2

Recruited

70+

Published Research Related to This Trial

Psilocybin, derived from Psilocybe cubensis mushrooms, is being investigated as a novel treatment for major depression, with a focus on its safety and efficacy compared to traditional antidepressants.

The proposed study will include both preclinical toxicity evaluations in mice and a clinical trial assessing the safety and pharmacokinetics of psilocybin in healthy adults, followed by an open trial in patients with major depressive disorder, aiming to provide comprehensive data on its therapeutic potential.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A Proposal to Study the Safety and Efficacy of Psilocybe cubensis in Preclinical and Clinical Studies as a Therapeutic Alternative for Major Depressive Disorder. Escamilla, R., González-Trujano, ME., González Mariscal, JM., et al.[2023]

Psilocybin has shown promise in clinical trials for reducing symptoms of depression, indicating its potential as a novel treatment option.

Patients with treatment-resistant depression (TRD) may benefit the most from psilocybin therapy, although the risks associated with its use are still not fully understood.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Assessing potential of psilocybin for depressive disorders. Kozak, Z., Johnson, MW., Aaronson, ST.[2023]

A single, moderate dose of psilocybin significantly reduced depressive symptoms in 52 participants with major depressive disorder, showing a decrease of 13.0 points on the MADRS scale compared to baseline, which was significantly greater than the placebo group.

54% of participants in the psilocybin group met the criteria for remission of depression 14 days after treatment, and no serious adverse events were reported, indicating a favorable safety profile for this novel treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Single-dose psilocybin-assisted therapy in major depressive disorder: A placebo-controlled, double-blind, randomised clinical trial. von Rotz, R., Schindowski, EM., Jungwirth, J., et al.[2023]

Mycelial cultures of Psilocybe cubensis can effectively convert synthetic N,N-diethyl-tryptamine into 4-hydroxy-N,N-diethyltryptamine, demonstrating a unique ability for hydroxylation at the 4-position, with yields of up to 3.3%.

This study marks the first instance of fungi being used for directed biosynthesis of tryptamine compounds, highlighting the potential for using fungal cultures in the production of psychoactive substances like psilocybin.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Biotransformation of tryptamine derivatives in mycelial cultures of Psilocybe. Gartz, J.[2019]

Psilocybin shows promising effects in alleviating anxiety, depression, and emotional distress in palliative care patients, with a favorable safety profile, based on recent studies and reports.

Despite its potential benefits, psilocybin is not yet approved for therapeutic use in the U.S., and significant barriers exist for access, particularly for vulnerable populations like the elderly and those in palliative care.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Psilocybin in Palliative Care: An Update. Whinkin, E., Opalka, M., Watters, C., et al.[2023]

Psilocybin, a serotonergic psychedelic, has shown promise in treating various psychiatric disorders, including depression and substance use disorders, with 9 clinical trials conducted between 2000 and 2020.

The treatment is generally well tolerated with limited side effects, and some patients with treatment-resistant conditions have experienced significant long-term improvements after just a few sessions, indicating its potential efficacy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Treatment with psilocybin: applications for patients with psychiatric disorders]. Breeksema, JJ., Koolen, MHB., Somers, M., et al.[2021]

In a placebo-controlled study involving individuals with moderate to severe major depressive disorder, psilocybin (0.3 mg/kg) showed larger antidepressant effect sizes compared to placebo, with 66.7% of participants responding and 46.7% achieving remission after treatment.

The antidepressant effects of psilocybin persisted for an average of 2 months, indicating its potential as a long-lasting treatment option for depression, although the strength of the mystical experience during dosing did not correlate with these effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Psilocybin-assisted therapy for major depressive disorder: An exploratory placebo-controlled, fixed-order trial. Sloshower, J., Skosnik, PD., Safi-Aghdam, H., et al.[2023]

Psilocybin, a hallucinogenic compound found in certain mushrooms, has been associated with increasing rates of drug abuse, highlighting the need for comprehensive pharmacological understanding.

Despite its historical use in the 1960s for experimental medical purposes, recent research has only begun to uncover the pharmacological properties of psilocybin, indicating a gap in knowledge that needs to be addressed.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The pharmacology of psilocybin. Passie, T., Seifert, J., Schneider, U., et al.[2016]

In a study involving 12 healthy adults, escalating doses of psilocybin (0.3, 0.45, and 0.6 mg/kg) were administered safely, with no serious adverse events reported, indicating a favorable safety profile for this psychedelic compound.

The pharmacokinetics of psilocin, the active metabolite of psilocybin, were linear across the tested doses, with an elimination half-life of about 3 hours, suggesting that no dose adjustments are necessary for individuals with mild to moderate renal impairment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pharmacokinetics of Escalating Doses of Oral Psilocybin in Healthy Adults. Brown, RT., Nicholas, CR., Cozzi, NV., et al.[2022]

Psilocybin, a prodrug for psilocin, shows strong agonist activity at the serotonin 5-HT2A receptor, which is responsible for its psychedelic effects, and has been shown to have nanomolar affinity for various serotonin receptor subtypes in both in vitro and in vivo studies.

In mouse experiments, psilocybin and related compounds induced head twitch responses, a sign of psychedelic activity, which were blocked by a 5-HT2A antagonist, confirming the involvement of this receptor in their effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Structure-Activity Relationships for Psilocybin, Baeocystin, Aeruginascin, and Related Analogues to Produce Pharmacological Effects in Mice. Glatfelter, GC., Pottie, E., Partilla, JS., et al.[2023]

Psilocybin-containing mushrooms, commonly known as hallucinogenic or 'magic' mushrooms, rapidly affect the central nervous system within 0.5-1 hour of ingestion, leading to effects such as ataxia, hyperkinesis, and hallucinations.

The review discusses the significant toxicity associated with these mushrooms, highlighting the need for awareness and understanding of their pharmacology, clinical effects, and potential treatment for adverse reactions.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Hallucinogenic mushrooms]. Reingardiene, D., Vilcinskaite, J., Lazauskas, R.[2018]

Psilocybin, a compound found in 'magic mushrooms', has shown potential in recent studies for treating various mental health conditions, including obsessive-compulsive disorder, alcohol and tobacco addiction, and major depressive disorder, particularly in terminally ill cancer patients.

Despite its classification as a Schedule I drug in 1970, which halted much research, there is a renewed interest in psilocybin's therapeutic effects, highlighting its importance in both historical and contemporary neuroscience.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

DARK Classics in Chemical Neuroscience: Psilocybin. Geiger, HA., Wurst, MG., Daniels, RN.[2019]

A 30-year-old man experienced severe symptoms, including vomiting and muscle pain, after receiving an intravenous injection of Psilocybe mushroom extract, highlighting the potential dangers of using hallucinogenic substances in non-traditional ways.

The patient showed rapid improvement with supportive care, suggesting that while the effects of Psilocybe mushrooms can be serious, timely medical intervention can effectively manage the symptoms.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Intravenous mushroom poisoning. Curry, SC., Rose, MC.[2019]

Citations

1. en.wikipedia.org en.wikipedia.org/wiki/Psilocybin

Psilocybin Psilocybin, also known as 4-phosphoryloxy-N,N-dimethyltryptamine (4-PO-DMT), is a naturally occurring tryptamine alkaloid and investigational drug found in ...

2. pubchem.ncbi.nlm.nih.gov pubchem.ncbi.nlm.nih.gov/compound/Psilocybin

Psilocybin | C12H17N2O4P | CID 10624 - PubChem - NIH Psilocybin is a tryptamine alkaloid that is N,N-dimethyltryptamine carrying an additional phosphoryloxy substituent at position 4. The major hallucinogenic ...

3. en.wikipedia.org en.wikipedia.org/wiki/Psilocin

Psilocin Psilocin, also known as 4-hydroxy-N,N-dimethyltryptamine (4-HO-DMT), is a substituted tryptamine alkaloid and a serotonergic psychedelic.

4. webbook.nist.gov webbook.nist.gov/cgi/cbook.cgi?ID=520-52-5

Psilocybine - the NIST WebBook Formula · C12H17N2O4P ; Molecular weight · 284.2481 ; Permanent link for this species. Use this link for bookmarking this species for future reference.

5. zfin.org zfin.org/CHEBI:8614

ZFIN ChEBI: psilocybin A tryptamine alkaloid that is N,N-dimethyltryptamine carrying an additional phosphoryloxy substituent at position 4. The major hallucinogenic alkaloid isolated ...