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Improvements in mood and mental health after psilocybin microdosing

Research has demonstrated efficacy up to one month compared to non-microdosing controls.



Psilocybin microdosing regimen in rats to support research

Results from the largest longitudinal study investigating the practice of microdosing psilocybin for mental health, and one of the few to use a control group, have now been published.

Anecdotal evidence claims that microdosng psychedelic substances, such as psilocybin or LSD, could hold potential benefits for mental health. Whilst a few studies have investigated these claims, there is still much to be learned about the potential efficacy of microdosing.

Contributing to the growing literature on the practice, new research, published in Nature Portfolio, has demonstrated that microdosing psilocybin showed observed improvements in mood and mental health at one month, relative to non-microdosing controls.

See also  Does microdosing LSD work? 

The research has been carried out by Joseph M. Rootman, Maggie Kiraga, Pamela Kryskow, Kalin Harvey, Paul Stamets, Eesmyal Santos-Brault, Kim P. C. Kuypers and Zach Walsh, who highlight that “public uptake of microdosing has outpaced evidence, mandating further prospective research”.

Improvements in mental health

The study, which followed psilocybin microdosers and non-microdosing comparators for approximately 30 days, identified small- to medium-sized improvements in mood and mental health of participants.

The authors state the improvements were generally consistent across gender, age, presence of mental health concerns and psychomotor performance that were specific to older adults. 

In comparisons of microdosers to non-microdosers, the findings demonstrated greater improvements among microdosers across the depression anxiety stress scale (DASS) domains, and that the effect of microdosing over time was found to be moderated by gender in DASS depression.

See also  Microdosing: separating fact from fiction

The authors stated: “Specifically, microdose-related reductions in depression were stronger among females than among males.”

The paper highlights that among microdosers with mental health concerns, scores on depression changed from 18.85 (at baseline to 11.73 at month one; for anxiety, 11.04 at baseline to 7.46 at month one; and for stress, 19.93 at baseline to 13.91 at month one. 

Among respondents without a history of mental health concerns, the paper notes, scores on depression changed from 10.40 at baseline to 6.65 at month one; for anxiety, 6.53 at baseline to 4.81 at month one; and for stress, 13.96 at baseline to 9.78 at month one.

Regarding mood, the results showed that, relative to non-microdosers, microdosers exhibited greater increases in positive mood from baseline to month one.


The paper also highlights the practice of “stacking”, whereby microdoses of psilocybin are combined with the Hericium erinaceus fungus, also known as Lion’s mane, and sometimes with niacin (vitamin-B3).

The study highlights that this practice has been gaining increasing interest for its proposed treatment of depression and mild cognitive impairment, as well as preclinical evidence of facilitation of neurogenesis with implications for treating neurodegenerative disorders.

The authors state: “A cross-sectional survey of over 4000 microdosers, which used a sample that partially overlaps with that of the present study, found that over 50 per cent of psilocybin microdosers combined psilocybin with diverse substances, and that HE [Hericium erinaceus] was the most prevalent addition followed by a combination of niacin (vitamin-B3) and HE8. 

See also  Microdosing could be a tool for improving mental health, shows new study

“As this is the lone study to report on stacking, the generalizability of these results is unknown.”

And that: “Supplementary analyses indicated that combining psilocybin with HE and B3 did not impact changes in mood and mental health. However, among older microdosers combining psilocybin, HE and B3 was associated with psychomotor improvements relative to psilocybin alone and psilocybin and HE.”

The researchers highlight that these results are novel, and further research is needed in order to confirm and elucidate these effects.

Microdosing research

Poor mental health, such as depression and anxiety, affects nearly one billion people across the globe. This crisis has been compounded by the Covid-19 pandemic, which has seen many more people seeking treatment for mental health disorders.

Whilst current treatment regimens, such as SSRI’s and talking therapies, can be helpful for some, a large number people live with treatment-resistant depression, underlining the need for innovation in the field of mental health treatment. 

Research into psychedelic medicines is one area that many people believe could provide a new type of treatment across the fields of pharmacology and psychology – combining psychedelic treatments with psychotherapy, for example. 

Macrodoses of psychedelics, however, pose a number of challenges when it comes to incorporating them into mental health care – from scaling up, to having trained practitioners and therapists, to the length of time it takes to provide a therapy session, which can last between four and eight hours.

If efficacious, microdosing could provide a form of treatment that may be implemented into mental health care much more easily. 

The researchers highlight that more research is needed on the practice of microdosing, stating: “Considering the tremendous health costs and ubiquity of depression, as well as the sizable proportion of patients who do not respond to extant treatments, the potential for another approach to addressing this deadly disorder warrants substantial consideration. 

“The potential that psilocybin microdosing may provide a means to improve depression and anxiety clearly points to the need for further research to more firmly establish the nature of the relationship between microdosing, mood and mental health, and the extent to which these effects are directly attributable to psilocybin.

“A potential contribution of future research with placebo-controlled designs would be the capacity to disaggregate the contributions of positive expectancies and placebo effects.”

For this study, 80 per cent of participants reported prior experience using psychedelics, which the authors state, “makes it likely that scores on the expectancies measure were influenced by past experiences of direct drug effects.”

They also note a limitation of the study is that both micro and macrodosing participants were aware of their status from the onset of the study, “making it impossible to rule out the contributions of greater expectancies among the microdosing versus non-microdosing group.”

Further limitations include that the study was not a double-blind study, and the sample of microdosing participants was 953 compared to 180 non-macrodosing participants. 

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Psilocybin analogue shows positive results in Phase 2 depression study



Psilocybin analogue shows positive results in Phase 2 depression study

Cybin has announced positive Phase 2 topline safety and efficacy data for its proprietary deuterated psilocybin analogue – CYB003 – for the treatment of major depressive disorder (MDD).

Results from Cybin’s study have shown that 79% of patients were in remission from depression at six weeks after receiving two doses of CYB003.

CYB003 demonstrated a large improvement in symptoms after one dose and a total of 79% of patients were responsive to the treatment. The compound also demonstrated an excellent safety profile in doses tested, with all reported adverse events mild to moderate and self–limiting.

Additionally, Cybin has stated that the magnitude of improvement was superior compared to approved antidepressants and recently reported data with other psychedelics, stating that the effects translate into an unprecedented effect size.

The company has said that the results compare favorably to pooled data from 232 industry studies of current standard-of-care antidepressants, SSRIs, submitted to the FDA.

The announcement follows Phase 2 interim results in early November 2023, which demonstrated that CYB003 saw a “rapid, robust and statistically significant reduction in symptoms of depression three weeks following a single 12mg dose compared to placebo”.

Cybin CEO, Doug Drysdale, stated: “We are delighted to share that CYB003 achieved the primary efficacy endpoint in this study and showed rapid and statistically significant improvements in depression symptoms after a single dose, with a clear incremental benefit of a second dose, resulting in four out of five patients in remission from their depression at six weeks.

“This is an impressive finding and follows on from the unprecedented interim results we announced earlier this month.”

Drysdale emphasised that the strength of the data will support CYB003 into Phase 3 of the study.

Cybin CMO, Amir Inamdar, added: “The significant reduction in depression symptoms observed in our Phase 2 study is highly gratifying.

“At the three-week primary efficacy endpoint, a single 12mg dose of CYB003 showed a rapid, robust, and highly statistically significant improvement in depression symptoms compared to placebo, with a -14.08 point difference in change from baseline in MADRS. 

“This translated into a very large effect size. Similar significant and robust effects were also seen with a single 16mg dose, which resulted in an improvement in symptoms of depression as measured using the MADRS total score by about 13 points versus placebo. 

“These effects were evident on day one with the 16mg dose and were also highly statistically significant. When data from 12mg and 16mg are pooled, these robust effects are maintained. Further, with two doses, response and remission rates in excess of 75% were observed with CYB003 (12mg). 

“With these findings in hand, we are encouraged by the potential of CYB003 to help those with MDD and look forward to progressing to a multinational, multisite Phase 3 study early next year.”

Cybin is planning on submitting topline data to the FDA with an aim to hold a Phase 2 meeting in Q1 of 2024, with further 12-week durability data from Phase 2 CYB003 expected in Q1, and recruitment for the Phase 3 study anticipated to begin by the end of Q1 2024.

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Clerkenwell Health calls for volunteers to support groundbreaking psychedelic research



Clerkenwell Health calls for volunteers to support groundbreaking psychedelic research

Mental health research provider Clerkenwell Health is calling for volunteers to join its groundbreaking clinical trials that will research whether psychedelics can provide effective treatments for complex mental health conditions.

Clerkenwell is seeking a diverse group of volunteers from across the UK between 18 and 65 years old to take part in the trials if they suffer from a relevant condition. 

The trials, which will be conducted at Clerkenwell Health’s purpose-built facility near Harley Street in London, are being run in partnership with a number of world-leading drug developers to test whether psychedelic drugs – often combined with talking therapy – can offer a new approach to treating a variety of mental health illnesses.

See also  Clerkenwell Health is launching a free UK psychedelic therapist training programme

Clerkenwell Health is seeking volunteers for trials that look to find cures for a range of conditions, including PTSD, depression, alcohol use disorder and anorexia. 

Many of the conditions have few successful treatment options and Clerkenwell’s innovative methods of combining psychedelics with therapy aim to to treat these problems more holistically, providing long-term quality of life for patients.

Chief Scientific Officer at Clerkenwell Health, Dr Henry Fisher, said: “With the current system for treating mental health disorders simply not working, we’re calling for patients to help identify the next wave of treatments. 

“These have the potential to be groundbreaking for the millions of people across the UK who are affected by poor mental health.

“The status quo for mental health treatment has not only resulted in patients experiencing debilitating side-effects, huge waiting lists and high relapse rates, but is costly, complicated and broadly ineffective. 

“By participating in upcoming clinical trials, patients have an opportunity to make a valuable contribution to growing research which will support the development of the next generation treatments for mental health conditions.”

According to MIND, approximately 1 in 4 people in the UK will be affected by a mental health condition each year and with a significant rise in people contacting mental health services in recent years, there has never been a more desperate need to identify new and innovative treatments.

Given the challenges facing the country’s health service and with mental health challenges on the rise, the search for volunteers to test effective treatments has never been more pressing. 

Clerkenwell has stated, in this regard, that it has gone national with its search for volunteers in an effort to deliver medical breakthroughs in mental health akin to the Polio clinical trials in the 20th Century.

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Paper explores extended difficulties following psychedelic trips



Paper explores extended difficulties following psychedelic trips

A new paper has explored the extended difficulties experienced by some people following psychedelic drug use and discusses psychedelic harm reduction.

While multiple studies have shown that psychedelics can be safe when administered appropriately, some people experience difficulties following their use. These difficulties can last anywhere from a few days to years.

With a rise in clinical research surrounding these compounds, there is a drive to change drug policy and several places have already implemented progressive approaches to accessing these therapies such as decriminalisation or including them on authorised medical access schemes. 

In light of these developments, it is vital to understand the potential risks associated with psychedelic use and what actions can be taken to reduce these risks.

The paper has been published in Plos One and authored by a team of leading psychedelic scientists from the Universities of Exeter, Greenwich and Queen Mary, University College London and Royal Holloway, New York University and the Perception Restoration Foundation.

Extended difficulties following psychedelic use

The team of researchers has gathered data on the context of use, nature and duration of these difficulties and explored risk factors and perceived causes that may contribute to these experiences. 

The most common forms of extended difficulty that the team uncovered include symptoms such as anxiety/fear and existential struggle, as well as social disconnection, depersonalisation and derealisation.

“For approximately one-third of the participants, problems persisted for over a year, and for a sixth, they endured for more than three years,” the authors write.

The findings revealed that the length of time these experiences last following psychedelic use could be predicted by the participants’ knowledge of dose and drug type, and that the experiences were shorter if a participant had taken part in a guided psychedelic experience. 

Additionally, the most common length of time such difficulties lasted was between one and three years. When asked about mental illness onset following the psychedelic experience, 18.8% said they had gone on to be diagnosed with a mental illness, while 76.8% said they had not.

The authors write: “Our findings support the results of Simonsson et al., who found that anxiety was the most common enduring difficulty, based on quantitative questionnaire data and Bouso et al’s study of the Global Ayahuasca Survey, in which ‘feeling nervous, anxious or on edge’ was the second most common adverse mental health effect. Our findings also suggest that a Sense of disconnection from others was within the top five most prevalent themes, as did the studies by Simonsson et al. and Bouso et al. 

“Some extended adverse effects that were quite common in other studies weren’t so common in our data set–for example, feeling a harmful connection to the spirit world was reported by 14% of respondents to the Global Ayahuasca Survey but by less than 4% of our data set, which may suggest some forms of difficulty are particularly associated with certain psychedelic substances and/or their associated cultures.”

Reducing risk factors

The authors suggest a number of actions that could be taken to reduce these risks.

Highlighting that, as anxiety and fear are some of the most commonly reported difficulties, the authors suggest that all legal psychedelic experience providers give guidance on methods for “self-soothing and overcoming bouts of anxiety following the retreat, clinical trial or ceremony.”

Further suggestions include informing participants of potential harms and risks and advising participants that the integration process may take some time, and what practices can be done to help people cope with difficulties. The authors say these practices will be explored in an upcoming paper.

The team writes: “We envisage using the information in this study, and accompanying future papers that focus on social support and forms of coping used by those with enduring difficulties, to provide structured guidance and training to psychedelic retreats, therapists and clinical trial centers about the potential for adverse experiences, what the potential risk factors are and what can be done to help individuals who report such extended difficulties.”

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