This research briefing is co-published with the excellent Report on Psychedelics.

January 10th, 2022

In the Research Briefing

• Psilocybin can be administered safely for up to six people simultaneously
• An Open Science approach toward MDMA synthesis
• Nitrous Oxide could be the next antidepressant

The largest peer-reviewed study with psilocybin to date

Ensuring drugs are safe for human consumption is one of the most critical parts of drug development. Alongside proving their effectiveness in treating their target disorder, researchers must prove that their new drugs do not threaten human health. To do so, new drug candidates must undergo rigorous testing in what is known as the clinical trial process. This process consists of various phases, with each phase having different requirements the drug under study must meet. Randomised-controlled trials (RCTs) have become the gold standard of this process. These trials tend to consist of large sample sizes to enhance the statistical significance and generalizability of trial results.

In the realm of psychedelic research, the criterion set out by the gold standard RCTs is proving challenging to meet. Firstly, sample sizes in trials tend to be low given that psychedelics remain as Schedule I substances, making them difficult and expensive to procure. Blinding and randomisation are also tricky, given the potency and effects psychedelics have once consumed. Despite these difficulties, as psychedelic research progresses, it slowly becomes more compliant with these gold-standard RCTs favoured by regulatory agencies like the FDA and EMA.

The present study is the most extensive study with psilocybin published in a peer-reviewed journal to date. As one of the many trials sponsored by Compass Pathways, the overall aim of this study was to assess the safety and feasibility of the simultaneous administration of single doses of either 10 or 25 mg doses of psilocybin compared with placebo in healthy participants. The study also assessed the effects of psilocybin on some key aspects of cognitive function. This Phase I study saw 89 healthy participants administered either 10mg or 25mg of psilocybin or a placebo simultaneously in groups of up to six people. Dosing took place in a controlled environment, and each participant had one-to-one psychological support.

The main findings:

• 10mg and 25mg of doses of psilocybin were generally well tolerated by trial participants, given their willingness to undergo simultaneous administration and group preparation sessions.
• 511 treatment-emergent adverse events (TEAEs) were reported during the 12 week study period: 217 in the 25mg psilocybin arm, 203 in the 10mg psilocybin arm and 91 in the placebo arm. 67% of TEAEs were resolved on the administration day, while no serious TEAEs were reported.
• The Cambridge Neuropsychological Test Automated Battery (CANTAB) Panel assessed measures of cognitive function. There were slight differences in cognitive measures between groups, but the study identified no clinically relevant negative findings.
• Psilocybin was found to have no consistent short- or long-term effects on any measures of social cognition.

Overall, the findings of this study support the use of psilocybin for the treatment of mental health disorders such as depression. Furthermore, given that the administration of psilocybin took place in a group setting, the findings also support the use of psilocybin in this context providing there is adequate preparation and psychological support given in a supportive environment. If psilocybin-assisted therapies are to become available, the group context may prove to be both a cost- and time-effective method.

The authors do acknowledge several limitations to their study. Given that the efficacy of blinding was not assessed, it is not possible to rule out the unblinding of participants (i.e. guessing their treatment) did not impact results. 37% of trial participants had previously used psilocybin, so it is plausible to assume that these participants could have determined their treatment group. Practice effects may also have influenced results as a familiarisation session with testing procedures occurred before treatment administration. While psychedelic research must overcome limitations such as these, the overall results of this trial are a positive step toward realising the therapeutic potential of psychedelics.

Synthesizing pharmaceutical-grade MDMA at Scale

Under The Controlled Substance Act MDMA remains a Schedule I substance, the most restrictive category. Substances in this category are thought to be devoid of any medical value but now thanks to the pioneering work of organizations like MAPS and other research groups across the globe, we now have the clinical evidence that supports the use of MDMA for treating mental health disorders like PTSD. Carrying out clinical research with MDMA is no mean feat as its current scheduling makes the substance both difficult and expensive to procure.

Synthesising MDMA can be a costly process given the regulatory standards one must comply with when working with a Schedule I substance. Furthermore, precursor chemicals for the synthesis process, like safrole or piperonal, have become highly regulated given the popularity of MDMA on illicit markets.

The present paper overcomes the inherent issues in the synthesis of pharmaceutical-grade MDMA by presenting a novel four-step process that does not involve the use of a controlled substance like safrole. Importantly, this process is fully validated and compliant with Current Good Manufacturing Practice (cGMP) regulations enforced by the FDA, which ensures the identity, strength, quality, and purity of drug products. This proposed method by researchers at MAPS can be considered cost-effective, yielding up to 5kg of MDMA, which could be used to treat roughly 30,000 patients, making it highly beneficial to both patients and the research community.

The synthesis:

• The synthesis pathway begins with 5-bromo-1,3-benzodioxole, which currently does not appear on any controlled substance list globally.
• All reagents used in the process are visually inspected and tested prior to use. The researchers also tested for the presence of residual solvents and ensured that impurity profiles were of an acceptable level. These factors, amongst others, helped to ensure cGMP compliance.
• The four-step process yielded up to 5 kg of MDMA was reproducibly synthesised, with an overall yield of 41.8−54.6% and a minimum purity of 99.4% (w/w).

The paper at hand presents the first method of synthesizing MDMA at scale in a manner that is cGMP compliant. This method will help improve access to MDMA for clinical research and potential therapeutic use, pending FDA approval. The publication of this process in an open-access format emphasizes the value of taking an Open Science approach to the manufacturing of psychedelics. The Open Science approach increases patients accessibility and the cost-effectiveness of the therapies they need, something which seems to be forgotten by many in an industry which seek to address the global mental health crisis.

Taking a similar Open Science approach, an earlier publication by the team at the Usona Institute details how one could synthesize psilocybin on a large scale. Prior to this publication, psilocybin for research purposes was generally produced on a small scale and faced challenges when scaling up its production. The Usona team addressed these challenges through the second-generation synthesis of up to 100g of high purity psilocybin under cGMPs. Moreover, the methods detailed in the paper could be adjusted to provide over 1kg of psilocybin.

Researchers have reportedly been paying in excess of $7,000 per gram of psilocybin. While it would take a significant amount of dried mushrooms to yield this amount of pure psilocybin, the cost greatly exceeds the current street value of $10 per gram of dried mushrooms. Similarly, the street value of MDMA is roughly $5-$10 per tablet (at least one full therapeutic dose) making its current price for research purposes very costly in comparison. However, it must be noted that the purity of black-market MDMA would never come close to the 99.4% achieved by the researchers.

Much of the high costs associated with clinical research and Schedule I substances stems from the paperwork that accompanies working with controlled substances. Not only do the substances themselves have to meet high regulatory standards but so too does the equipment and even the people working with these substances. The rules and regulations surrounding controlled substances leave little commercial incentive for companies to manufacture them and therefore, keeps the prices high.

While regulatory oversight and cGMP procedures are necessary for developing any drug and ensuring it is safe, those that come with Schedule I substances are arguably preventing patients from accessing the therapies they need. While further clinical evidence is undoubtedly needed, the healing potential of these substances to treat disorders like PTSD, depression, and anxiety cannot be overlooked. Thus, a change in drug policy is needed to ensure these substances are easier to manufacture and work with in order to generate the evidence required to transform these substances into viable therapy options.

Overall, the papers presented here emphasize the value of taking an Open Science approach within the psychedelic industry and the accompanying need to reschedule substances like MDMA and psilocybin. Together, these factors will improve patient access, decrease costs and truly help to address the global mental health crisis.

Can Nitrous Oxide be used to treat depression?

As the name suggests, there is a significant unmet need when it comes to treating treatment-resistant depression (TRD). This significant subset of people living with major depressive disorder (MDD) remains unresponsive to conventional antidepressant medications such as SSRIs. Given this unmet need, researchers are continuously searching for new treatments. In the realm of psychedelic research, this particular subset of people with depression has been the main focus of researchers and industry players alike. Ketamine is already available off-label to those with TRD while trials with psilocybin have shown great promise in alleviating symptoms of this disorder. This promise has spurred research into the possibilities of using other psychedelic compounds as well as the potential off-label use of readily available medications.

The present paper is one of the first to make a case for the use of Nitrous Oxide (NO2) to treat TRD. NO2, also known as laughing gas, is a gas that is commonly used for general anaesthesia, procedural sedation, dental anaesthesia, and to treat severe pain. The authors of this paper argue that NO2 could be used for TRD given its antagonism at the NMDA receptor, which is the same property through which the antidepressant effects of ketamine are believed to be mediated.

No laughing matter:

• Recent studies using NO2 to treat TRD directly or as an adjunctive therapy found that it is a fast-acting antidepressant with effects that can last up to two weeks in certain individuals.
• As well as the NMDA receptor, NO2 has been shown to act on other receptors such as opioid receptors, which may explain its potential pain-relieving effects.
• Compared to ketamine, NO2 has different electrophysiological effects at the NMDA receptor, and from a safety perspective, there have been no reports of psychosis related to NO2.

Overall, the present study provides food for thought on the possibilities of using NO2 to treat TRD. While further research is clearly needed to establish dosing protocols, the safety profile, mechanisms of action and more, the fact NO2 is widely used means it could be a cheap alternative to alleviate the symptoms of TRD in comparison to the costs of other psychedelic therapies.

Research Report Readout

A comprehensive review of clinical trials involving either ibogaine or noribogaine provides further evidence that these substances can be used to treat various aspects of substance use disorders (SUDs). The severe side effects recorded in the trials are also discussed.

An open-label study compared the effects of six intravenous ketamine infusions (0.5 mg/kg) on anhedonia (the inability to feel pleasure) in patients with major depressive disorder (MDD) (n=77) or bipolar depression (BD) (n=20). Similar significant reductions in the MADRS anhedonia subscale score were observed and maintained with repeated infusions in both groups.

A study involving esketamine in people with TRD found there to be no sex differences when using esketamine in this population. This posthoc analysis found the efficacy and overall safety of esketamine to be similar for both men and women.

Using fMRI, researchers found that LSD (100 mg) decreased inhibitory effective connectivity from the salience network (SN) to the default mode network (DMN) as well as decreasing inhibitory effective connectivity from DMN to dorsal attention network (DAN). These findings suggest anticorrelation between resting networks may be a key neural mechanism of LSD peak experiences.

Eduardo Schenberg and Konstantin Gerber question the epistemic authority of western science and medicine in over 30 years of research on ayahuasca. The researchers propose new approaches to maintain epistemically fair research and ensure indigenous peoples traditional knowledge and biocultural heritage is maintained.

In a survey study (n=803) participants with depressive symptoms rated cognitive-behavioural therapy (CBT) as being more credible than psilocybin-assisted therapy (PAT). Men and lifetime psychedelic users rated PAT more credible than women and non-users.