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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.



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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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Is connection key? How clinicians impact patient outcomes in psychedelic therapy



A wealth of research is showing how psychedelic-assisted therapy holds promise for the treatment of mental health conditions such as depression, but what role does the therapist play in a patient’s outcome? A new study has suggested it may be a big one.

Psychedelics have piqued huge interest due to their effects on the brain. Research points to their ability to induce neuroplasticity in the brain as one of the key reasons they may help with conditions such as depression and anxiety.

However, set – the individual’s (or patient’s) mental state – and setting – the individual’s environment during a psychedelic experience – are hugely impactful on the outcome of these experiences.

In the traditional use of psychedelic medicines, shamans help to guide set and setting throughout the experience with singing, drumming and ritual. Today, in scientific research, trials, and in clinics, the clinician is essentially playing this role.

Senior author of a new study, Alan Davis, associate professor and director of the Center for Psychedelic Drug Research and Education in The Ohio State University College of Social Work, has highlighted that the impact of clinicians on patient outcomes is not new, with research consistently showing that a trusting relationship between patients and clinicians has been key to better outcomes. This concept is known as a “therapeutic alliance”.

Understanding the therapeutic alliance

To find out more about the impact of this therapeutic alliance in psychedelic therapy, researchers from Ohio State University College of Medicine analysed data from a clinical trial that investigated psilocybin-assisted psychotherapy for the treatment of major depressive disorder (MDD).

In the trial, participants received two doses of psilocybin and 11 hours of psychotherapy, completing a therapeutic alliance questionnaire afterward, which assessed the strength of the therapist-participant relationship.

Participants also completed questionnaires about any mystical and psychologically insightful experiences they had during the drug treatment sessions. In psychedelic research, the mystical experience has often been shown to be related to the continuing positive effects of this therapy.

The Ohio team looked at the depression outcomes alongside patient reports about their experiences with the medicines as well as their connection with their therapists.

They found that a stronger relationship between patient and clinician led to a better clinical outcome for the patient – with improved depression scores up to 12 months following the experience.

Lead author Adam Levin, a psychiatry and behavioral health resident at Ohio State University College of Medicine, stated: “What persisted the most was the connection between the therapeutic alliance and long-term outcomes, which indicates the importance of a strong relationship.”

Analysis results revealed that over time, the alliance score increased, and in fact demonstrated more acute mystical experiences for the patient. The team also found that acute effects were linked to lower depression four weeks following treatment, but were not associated with better depression outcomes a year after the trial.

“The mystical experience, which is something that is most often reported as related to outcome, was not related to the depression scores at 12 months,” Davis stated.

“We’re not saying this means acute effects aren’t important – psychological insight was still predictive of improvement in the long term. But this does start to situate the importance and meaning of the therapeutic alliance alongside these more well-established effects that people talk about.”

According to the team, the analysis showed that a stronger relationship during the final therapy preparation session predicted a more mystical and psychologically insightful experience – which in turn was linked to further strengthening the therapeutic alliance.

“That’s why I think the relationship has been shown to be impactful in this analysis – because, really, the whole intervention is designed for us to establish the trust and rapport that’s needed for someone to go into an alternative consciousness safely,” Davis stated.

“This isn’t a case where we should try to fit psychedelics into the existing psychiatric paradigm – I think the paradigm should expand to include what we’re learning from psychedelics,” Levin added.

“Our concern is that any effort to minimise therapeutic support could lead to safety concerns or adverse events. And what we showed in this study is evidence for the importance of the alliance in not just preventing those types of events, but also in optimizing therapeutic outcomes.”

The authors emphasised that efforts to minimise negative experiences in future studies of psychedelics is vital, and that therapy is critical to creating a supportive environment for patients.

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Phase 2a trial to investigate 5-MeO-DMT candidate for alcohol use disorder



Beckley Psytech and Clerkenwell Health are collaborating on a Phase 2a trial investigating Beckley’s synthetic 5-MeO-DMT candidate combined with psychological support as a treatment for alcohol use disorder (AUD).

AUD is estimated to affect around 237 million people across the globe and over 7.5 million people in the UK.

Treatment options for the harmful use of alcohol are not always effective – there are high relapse rates and there are around three million deaths each year attributed to the substance’s misuse.

Increasing research is showing that psychedelics may hold promise as innovative treatments for addiction, including substances such as ketamine and psilocybin.

See also  How psychedelics could help those living with alcohol use disorders

BPL-003 is Beckley Psytech’s short-duration and fast-acting synthetic formulation of 5-MeO-DMT – a psychedelic found in several plant species and the glands of at least one toad species – which is administered intranasally via an FDA-approved delivery device.

The compound has shown in Phase I data to be well-tolerated with a reproducible and dose-linear pharmacokinetic profile.

The Phase 2a trial

Beckley and Clerkenwell have confirmed that the collaborative Phase 2a open-label trial will evaluate the safety, tolerability and pharmacodynamic effects of a single dose of Beckley BPL-003 combined with abstinence-oriented psychological support in participants with AUD.

Currently taking place at King’s College London, Clerkenwell Health’s clinic near Harley Street, London, will provide an additional trial site.

According to Beckley, BPL-003 has been successful in eliciting psychedelic experiences of “similar intensity but shorter duration than psilocybin”.

Dr Henry Fisher, Chief Scientific Officer at Clerkenwell Health, stated: “An estimated 600,000 people are dependent on alcohol in England. This, coupled with an alarming increase in alcohol-related deaths of 89% over the past 20 years, shows the status quo isn’t working.

“Conventional treatments for alcohol dependency aren’t producing meaningful improvements and new avenues must be explored. This trial will assess whether psychedelic-assisted treatment can be an effective therapy for alcohol use disorder, with the hope of rolling out the treatment widely.

“Health professionals and policymakers should seriously consider such treatments, which could be genuinely ground-breaking for the NHS and for the hundreds of thousands of people being treated for alcohol use disorder in the UK.”

Beckley Psytech and Clerkenwell have emphasised that the results of the trial may be used to provide support for further study of psychedelic-assisted treatment for alcohol dependency.

Dr Rob Conley, Chief Medical and Scientific Officer at Beckley Psytech, added: “We’re committed to developing a transformative and effective treatment option for individuals struggling with alcohol use disorder.

“Based on our preclinical and Phase I data, we are optimistic about the potential therapeutic benefits of BPL-003 for substance use disorders and we are excited to evaluate the compound further in this clinical trial.

“I want to extend my thanks to the team at Clerkenwell Health and King’s, as well as to the patients who have joined, and will join, this study. Their participation, support and collaboration are absolutely critical to furthering research into this area of huge unmet need.”

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The Entourage Effect in Mushrooms: Natural psilocybin may outperform synthetic



The Entourage Effect in Mushrooms: Natural psilocybin may outperform synthetic

A new study from the Hebrew University-Hadassah Medical Center has indicated that natural psilocybin extracts may demonstrate superior efficacy to synthetic psilocybin extracts.

Recent years have seen a boom in research into psilocybin for the treatment of mental health conditions such as anxiety and depression.

Many of the clinical trials investigating psilocybin use synthetic extracts rather than natural ones. This is because synthetic extracts will contain psilocybin alone, whereas natural psilocybe mushroom extracts will contain several different compounds such as psilocybin, psilocin, baeocystin and norbaeocystin.

Having multiple compounds can pose a challenge when running clinical trials as identifying which compounds are active and what their impact is becomes difficult to measure, and the concentrations of these compounds can vary depending on factors such as growth conditions and processing techniques.

This makes the standardisation of multi-compound medicines a huge challenge, as medicine consistency, reproducibility and dosing become difficult. However, these are essential factors when it comes to conducting clinical trials and receiving approval for medicines from regulators.

The Entourage Effect

In 2011 Dr Ethan Russo put forward the theory of the Entourage Effect in cannabis. 

The cannabis plant contains over 400 different cannabinoids that have so far been identified, such as THC, CBD, CBN and CBG.

Russo hypothesised that these different cannabinoid compounds work synergistically to create a therapeutic effect, as opposed to compounds such as THC or CBD working in isolation.

This hypothesis has been touched on only a few times in the scientific literature in relation to psychedelic mushrooms.

For example, in Dr Jochen Gartz’s 1989 paper ‘Biotransformation of tryptamine derivatives in mycelial cultures of Psilocybe’ which proposed a synergistic relationship between compounds in the mushrooms, and a 2015 paper by Zhuck et al, ‘Research on Acute Toxicity and the Behavioral Effects of Methanolic Extract from Psilocybin Mushrooms and Psilocin in Mice’, which observed that the effect of psychedelic mushroom extracts on mice was much stronger than pure psilocybin.

There has been very limited research on this hypothesis in mushrooms since. 

A new study: Natural may outperform synthetic

Now, a research team from Hebrew University-Hadassah Medical Center BrainLabs Center for the Psychedelic Research have compared a natural psilocybin extract to a chemically synthesised version.

Published in Molecular Psychiatry, results from the study indicate that the natural extract increased the levels of synaptic proteins associated with neuroplasticity in key brain regions, including the frontal cortex, hippocampus, amygdala, and striatum.

The ability of psilocybin to induce neuralplasticity has been indicated as one of the key features that contribute to its therapeutic effects.

The researchers suggest that these new study results indicate that nautral psilocybin extracts may offer unique therapeutic effects that may not be not achievable with synthesised, single-compound psilocybin alone. 

Metabolomic analyses also revealed that the natural extract exhibited a distinct metabolic profile associated with oxidative stress and energy production pathways.

The researchers write: “In Western medicine, there has historically been a preference for isolating active compounds rather than utilising extracts, primarily for the sake of gaining better control over dosages and anticipating known effects during treatment. The challenge with working with extracts lay in the inability, in the past, to consistently produce the exact product with a consistent compound profile. 

“Contrastingly, ancient medicinal practices, particularly those attributing therapeutic benefits to psychedelic medicine, embraced the use of extracts or entire products, such as consuming the entire mushroom. Although Western medicine has long recognised the “entourage” effect associated with whole extracts, the significance of this approach has gained recent prominence.”

However, compared to cannabis, the researchers suggest that mushroom extracts present a unique case, as they are highly influenced by their growing environment such as substrate, light exposure temperature and more.

“Despite these influences, controlled cultivation allows for the taming of mushrooms, enabling the production of a replicable extract,” the team writes.

The researchers emphasise that this research underscores the superiority of extracts with diverse compounds, and also highlights the feasibility of incorporating them into Western medicine due to the controlled nature of mushroom cultivation.

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Psychedelic Health is a journalist-led news site. Any views expressed by interviewees or commentators do not reflect our own. We do not provide medical advice or promote the personal use of psychedelic compounds. Please seek professional medical advice if you are concerned about any of the issues raised.

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