Psilocybin for Prolonged Grief Disorder

Overseen By Tamika Braveheart, Registered Nurse

Age: 18+

Sex: Any

Trial Phase: Phase < 1

Sponsor: University of Virginia

Must be taking: Antidepressants

Must not be taking: Benzodiazepines, Opioids, MAOIs, others

Disqualifiers: Cardiovascular conditions, Type 1 diabetes, Severe psychiatric disorder, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

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

Compensation: Varies

Number of Visits: 7

Duration: 1 day

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores how psilocybin, a compound in certain mushrooms, might assist individuals with prolonged grief disorder, where intense mourning persists longer than usual. The study aims to determine if psilocybin is a practical treatment option for this condition. Participants will receive a single dose of psilocybin and must adhere to specific guidelines, such as avoiding certain medications and substances. This trial may suit those who have been grieving for an extended period and have remained stable on antidepressants for at least two months. As an Early Phase 1 trial, this research focuses on understanding psilocybin's effects in people, offering participants the opportunity to be among the first to explore its potential benefits for prolonged grief disorder.

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

You may need to stop taking certain medications for this trial. Participants must refrain from taking nonprescription medications, nutritional supplements, or herbal supplements for one week before each drug session, unless approved by the study investigators. Additionally, you cannot take muscle relaxers, antihistamines, or medications that cause lethargy or impair cognitive ability within one day prior to the psilocybin session.

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

Research has shown that psilocybin is usually safe and well-tolerated in clinical settings. Reviews of multiple studies have found that most clinical trials report benefits and safety with psilocybin-assisted therapy. For example, one study found that a single 25 mg dose of psilocybin significantly improved symptoms in people with treatment-resistant depression, with no major safety concerns.

Prospective trial participants should know that psilocybin has been widely studied. Although this trial is in its early stages, past research has not shown significant safety issues with similar doses. Participants in previous studies have generally handled the treatment well, with few side effects. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising?

Most treatments for Prolonged Grief Disorder rely on talk therapy or antidepressants, which can take weeks or even months to show effectiveness. But psilocybin works differently, targeting the brain's serotonin receptors to potentially provide relief more quickly. Researchers are excited about psilocybin because it is derived from a compound found in certain mushrooms, offering a new mechanism of action that might help rewire the brain's response to grief. This unique approach could lead to rapid improvements in emotional well-being, making it a promising alternative for those who haven't found success with traditional therapies.

What evidence suggests that psilocybin might be an effective treatment for prolonged grief disorder?

Research has shown that psilocybin, a substance found in certain mushrooms, might help people with prolonged grief disorder (PGD). Early studies suggest that psilocybin can alter emotional processing, potentially reducing grief symptoms. It may ease the handling and progression through difficult emotions. Although not yet proven for PGD, psilocybin has shown promise in addressing other mental health issues, offering hope for its potential here. Initial results are promising, but further research is needed to confirm its benefits for prolonged grief. Participants in this trial will receive a 25 mg dose of psilocybin in an open-label, single-arm study to further investigate its effects on PGD. ^{2 6 7 8 9}

Who Is on the Research Team?

Jennifer K Penberthy, PhD

Principal Investigator

University of Virginia

Are You a Good Fit for This Trial?

Adults aged 21-65 with Prolonged Grief Disorder, who speak English, can avoid psychoactive drugs and caffeine before sessions, use effective birth control if applicable, have low suicide risk, are stable on certain antidepressants for two months prior to the trial, and have limited hallucinogen use. Excludes pregnant or nursing individuals, those with significant medical conditions or psychiatric disorders like schizophrenia or bipolar I disorder.

Inclusion Criteria

I am between 21 and 65 years old.

Participant must agree to taper or not consume caffeine on the day of intervention

Fluent in English

Exclusion Criteria

Person who is pregnant, nursing, or planning to get pregnant determined at screening and before drug session by urine test or self-report

BMI <18

Clinically significant transaminitis (AST or ALT greater than two times normal value)

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Preparation

Participants undergo a preparation session before receiving psilocybin

1 week

Treatment

Participants receive a single dose of 25 mg psilocybin

1 day

1 visit (in-person)

Integration

Two semi-structured integration sessions to process the psilocybin experience

2 weeks

2 visits (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment

6 months

4 visits (in-person)

What Are the Treatments Tested in This Trial?

Interventions

• Psilocybin

Trial Overview The study is testing a single dose of Psilocybin (25 mg) to see if it's feasible as a treatment for Prolonged Grief Disorder. Participants will be observed in a controlled setting during the drug session which lasts up to 10 hours.

How Is the Trial Designed?

Group I: Open-label, single arm trial Experimental Treatment 1 Intervention

25 mg psilocybin administered to each participant

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?

University of Virginia

Lead Sponsor

Trials

802

Recruited

1,342,000+

Published Research Related to This Trial

This study found that the binding of serotonin 2A receptors (5-HT2AR) in the brain can predict how long the peak effects of psilocybin last and how quickly individuals return to normal consciousness after its effects wear off.

Higher levels of 5-HT2AR binding were associated with lower scores on the Mystical Experience Questionnaire, suggesting that individual differences in receptor availability may influence the subjective experience of psilocybin, which could have implications for its therapeutic use.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Brain serotonin 2A receptor binding predicts subjective temporal and mystical effects of psilocybin in healthy humans. Stenbæk, DS., Madsen, MK., Ozenne, B., et al.[2022]

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]

This study identified phenylethylamine in Psilocybe semilanceata mushrooms, which may contribute to adverse reactions during psilocybin intoxication, as evidenced by a case involving three young men who experienced severe symptoms.

The levels of phenylethylamine in these mushrooms can vary significantly, with the highest concentration found in the case of hospitalization, suggesting that this compound could play a role in the tachycardia and other symptoms not directly linked to psilocybin.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Presence of phenylethylamine in hallucinogenic Psilocybe mushroom: possible role in adverse reactions. Beck, O., Helander, A., Karlson-Stiber, C., et al.[2019]

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]

A meta-analysis of psilocybin studies found that higher doses of psilocybin are associated with stronger subjective experiences, particularly in areas like perceptual alterations and ego dissolution, based on data from standardized questionnaires.

Challenging experiences were less affected by dose, suggesting that individual and environmental factors also play a significant role in the psilocybin experience, indicating that these findings are most relevant in controlled settings rather than recreational use.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Dose-response relationships of psilocybin-induced subjective experiences in humans. Hirschfeld, T., Schmidt, TT.[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]

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]

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]

The study developed highly sensitive and accurate methods using liquid chromatography-mass spectrometry (LC-MS) and tandem mass spectrometry (LC-MS-MS) to effectively distinguish between psilocin and psilocybin, two active compounds in magic mushrooms.

Detection limits for these compounds were extremely low, ranging from 1 to 25 picograms, and the methods demonstrated high precision with low variability, making them suitable for analyzing psilocin and psilocybin content in various samples.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Liquid chromatography-mass spectrometric and liquid chromatography-tandem mass spectrometric determination of hallucinogenic indoles psilocin and psilocybin in "magic mushroom" samples. Kamata, T., Nishikawa, M., Katagi, M., et al.[2016]

Citations

1. clinicaltrials.gov clinicaltrials.gov/study/NCT06724289

NCT06724289 | Psilocybin for Prolonged Grief Disorder The study aims to investigate whether a single dose of 25 mg psilocybin can reduce the symptoms of grief and trauma associated with PGD.

2. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC12004488/

Psilocybin-Assisted suppoRtive psychoTherapy IN the ... The first study to consider psilocybin-assisted psychotherapy as a potential treatment for prolonged grief.

3. newsroom.uvahealth.com newsroom.uvahealth.com/2025/07/25/psilocybin-prolonged-grief-clinical-trial/

Can Psilocybin Help People With Prolonged Grief? “Psilocybin might be able to facilitate meaningful shifts in perception, emotional processing and cognitive flexibility, factors that may help ...

4. clinicaltrials.eu clinicaltrials.eu/trial/study-on-the-effects-of-pex010-psilocybin-capsules-for-patients-with-prolonged-grief-disorder/

Study on the Effects of PEX010 Psilocybin Capsules for ... The purpose of the study is to see if taking the PEX010 Psilocybin Capsules can help reduce the symptoms of prolonged grief disorder.

5. news.med.virginia.edu news.med.virginia.edu/research/can-psilocybin-help-people-with-prolonged-grief/

Can Psilocybin Help People With Prolonged Grief? - Research “Psilocybin might be able to facilitate meaningful shifts in perception, emotional processing and cognitive flexibility, factors that may help ...

6. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC10106897/

Psilocybin in Palliative Care: An Update - PMC Meta-analyses and systematic reviews reveal that the majority of clinical trials show benefit and safety with psilocybin-assisted therapy in the ...

7. researchgate.net researchgate.net/publication/368255068_Single-dose_psilocybin_for_a_treatment-resistant_episode_of_major_depression_Impact_on_patient-reported_depression_severity_anxiety_function_and_quality_of_life

Single-dose psilocybin for a treatment-resistant episode of ... Results: At Week 3, psilocybin 25 mg, compared with 1 mg, was associated with greater improvements from Baseline total scores in all measures.

8. anzctr.org.au anzctr.org.au/Trial/Registration/TrialReview.aspx?id=385797&isReview=true

actrn12623000827639 PARTING: Assessing the feasibility, acceptability and safety of Psilocybin-Assisted suppoRtive psychoTherapy IN the treatment of prolonged Grief in bereaved ...

9. cen.acs.org cen.acs.org/biological-chemistry/magic-mushrooms-psilocybin/103/web/2025/10

Is there more to magic mushrooms than psilocybin? - C&EN Clinical trials with its psilocybin drug are ongoing to test its effectiveness in conditions like major depressive disorder and prolonged grief.