This January we were treated to a mix of novel psychedelic trials and an unusually large amount of re-analyses of earlier studies.
Ibogaine was researched for traumatic brain injury (TBI) in veterans, DMT was researched in two separate trials, and psilocybin for chronic cluster headaches (CCHs) was put to the test. The re-analyses investigated the effects of psychedelics in the brain, the role of the therapeutic relationship in MDMA-assisted therapy, and the effects of visual information during an LSD trip.
Other studies examined the relationship between SSRIs and psychedelics, the role of expectancy, and the effects of microdosing on the heart.
For all the latest papers, check out the database and those that weren’t added in Blossom’s January Link Overview.
Ibogaine Beyond Addiction & Other Trials
An observational trial in veterans (SOF) got a lot of press, including being published in Nature Medicine (usually reserved for controlled trials). The factors behind the high-profile nature of the study? A combination of a stellar research team, a novel indication (TBI), immense results, and a population (veterans) that are currently not receiving the help they need.
The study investigated the effects of a high-dose of ibogaine (up to 1g) in 30 veterans with mild traumatic brain injury (mTBI). mTBI refers to a head trauma where unconsciousness was limited to 30 minutes or shorter, although the long-term effects in this population were anything but mild. Many participants also suffered from PTSD, depression, and anxiety.
At the end of the treatment, at a well-known Mexico-based center, the disability score (WHODAS) went down from 30 (mild-to-moderate disability) to 20 immediately following treatment, and to 5 (no disability) a month later. Even more dramatic responses were seen in the PTSD (CAPS-5), depression (MADRS), and anxiety (HAM-A) scores, each reducing by 81-88%, and achieving a remission rate of 83-86%.
One final note on the study, it used a protocol where magnesium was administrated at the start and during treatment (MISTIC protocol). This has been used in treatment centers for quite a while, but this marks the first research study that investigates this more formally. As ibogaine treatment (especially with powdered iboga root with varying purity/strength) has been associated with several deaths, this may be a way to protect the heart and pave the way for ibogaine to become a medicine.
An open-label study in ten participants finds that three moderate doses of psilocybin reduces the frequency of chronic cluster headaches by 30% (on average). Although a small study, it adds to the literature on psychedelics for headache disorders (of which we currently only have 17 published studies in the database). I covered the study back in the summer of 2022 when it was released as a pre-print, but now the full paper is out.
The participants received a pill with a low to moderate amount of psilocybin (10mg/70kg) once a week for three weeks. The weeks before, and the weeks following were compared, the latter showing a reduction of 30% in headaches. A very similar study (with 14 participants; published in 2022) also showed a trend in this direction, but failed to reach significance.
Then, two separate clinical trials investigated the effects of DMT.
The first trial investigated the safety of DMT fumarate (among other things, this dissolves better in water) administrated via infusion (iv) in healthy participants. The study provided data on administrations between 9 and 22 milligrams and marks the next step for Small Pharma (the sponsor of the study; acquired by Cybin) in developing DMT for depression. Earlier, the company had also shared positive top-line findings on their first cohort of patients receiving the drug (plus supportive therapy).
The second trial looked at the effect of vaporized DMT in patients with treatment-resistant depression (TRD). The six-person study reported that five were responders, and four were in remission from depression at day seven. Although there is no reference to the Biomind Labs product in this study (and there might be no relationship), the same group of researchers conducted a Phase I trial in healthy participants with this inhaled DMT product.
Finally, a crossover trial investigated a harmine and DMT mix (ayahuasca-inspired, or pharmahuasca) in healthy participants. The combination, but not harmine alone, led to a psychedelic trip and long-term positive outcomes up to four months later.
Same Participants, New Findings
In just about any study, more than one thing is being measured. As we saw with the ibogaine study, at least four different mental health/well-being measures were examined. And there is just a certain amount you can fit in one research article, or sometimes two very different things are being measured (e.g. brain measures and behavioural outcomes). So many studies are re-analysed through a different. Here are those studies from the last month.
A re-analysis of the psilocybin versus escitalopram (SSRI) data finds that expectancy effects played a role in the SSRI, but not in the psilocybin treatment arm. The expectancy effect measures the role of expectancy in participants (that a treatment will work) in the final outcome. For those who expected the SSRI to work, it worked better than for those who didn’t think it would help them (similar effects have been found where more side-effects also lead to more efficacy – ‘something is happening, so it must work’). Conversely, negative expectations for escitalopram may also be seen as a “know-cebo” effect, knowing you didn’t receive psilocybin and being disappointed in being assigned this treatment arm (participants were randomized in the two arms).
A lack of expectancy effect may be a positive sign for psychedelic treatments, providing a signal that it might work for those outside of controlled trials (with motivated patients). Still, this article did find an effect of suggestibility on outcomes.
What the study didn’t look at, was the therapeutic relationship, that is the topic of the next re-analysis.
Looking back, all the way to the early MAPS trials in 2014, the role of therapeutic alliance in MDMA-assisted psychotherapy is examined. The data from 22 participants provides a signal that the therapeutic alliance in the mid and late (4th and 9th session) significantly predicts the self-reported and clinician-assessed PTSD severity after treatment. Still, as a relatively recent review argued, there is little research on what therapeutic method works best in these treatments.
Two other studies analysed data from MDMA trials, one looked at the effect on self-expience, the other examined the response to social feedback.
The first of these two studies examined 90 participants in the Phase IIIa study of MDMA (plus therapy) for PTSD. It found that participants reported improvements in self-experience (e.g. alexithymia – the inability to identify & describe emotions experienced by oneself). The change in scores of self-experience correlated with recovery from PTSD. I also covered this study as a pre-print back in January 2023.
The second wanted to know how people respond to social feedback under the influence of different stimulants (MDMA and methamphetamine; meth). The study concludes that the higher dose of MDMA increases positive affective responses to social feedback, suggesting a potential mechanism by which MDMA may enhance social connection. Surprisingly, to the researchers, MDMA had no influence on feelings of rejection (i.e. not reducing the impact). Meth had no impact on social feedback.
But those weren’t the only re-analyses, so here is the rest in a whirlwind:
Reviews: Microdosing, Older Adults, and Number Needed to Treat
Starting with a brief analysis of the psychedelic trials, a review investigated the prevalence of older adults that were included. Of the 36 studies they looked at, with over 1400 participants, only 19 participants were 65 years or older. The data from ten of these participants (all that were available) didn’t immediately show anything out of the ordinary, but also represent a very small population on which there is clinical data available.
A meta-analysis of six trials took another look at the effectiveness of ketamine for PTSD. The study finds that there was an initial reduction within the first 24 hours, but (as we often see with ketamine studies for depression) the results became murkier in the days and weeks after that.
Microdosing has become increasingly popular over the last 5 years. Still, we don’t know to what extend psychedelics influence the heart (as some ‘serotonin’ receptors also live here). As with the ibogaine research, it’s important to also protect the downside, especially when doing something more chronically. Still, the review finds no smoking gun, but argues there need to be more long-term studies into the possibility of inducing cardiac fibrosis (leading to heart failure).
Looking at the short-term effects of microdosing, a systematic review brings together results from 14 double-blind studies. It reports that acute low doses of LSD affect blood pressure, sleep, neural connectivity, mood, social cognition, and perceptions of pain and time, with noticeable effects at 10-20μg but not at 5μg. While no serious adverse effects were noted, repeated microdosing didn’t significantly change mood or cognition.
Finally, a review of studies looking at psilocybin and esketamine (Spravato) examines at a commonly used metric of the effectiveness called ‘Number Needed to Treat’ (NNT). The metric tries to capture how many people would need to receive the treatment before you are (statistically) helping one person. Psilocybin came out favourably in the study (NNT of 5 vs 7), but noted should be that the results were measured only weeks after treatment, with data coming from different studies (not head-to-head).
The Other Psychedelic Studies From January 2024
A prospective survey looked at the interactions between psychedelics and serotonergic antidepressants (SRI; SSRIs & SNRIs). The researchers wanted to know if taking an SRI would have an influence on the mood and well-being outcomes of psychedelics. It found no such effect, but did find that the acute trips of those on SRIs were less intense.
Another survey dove deep into the coping mechanisms people used after challenging psychedelic experiences. Predominant individual coping strategies included meditation and prayer, along with self-educational activities like reading and journaling. Social coping methods were commonly seeking support from friends or family, and obtaining assistance from a therapist or coach, with reported benefits including feeling heard, accepted, and sharing similar experiences.
A final survey reported on real-world impacts of ketamine on suicidality. The researchers split up the participants based on initial severity and treatment response, providing some insights into who might benefit (or not) from this type of treatment.
Two studies (of note) looked at novel psychedelics and the effects they had on cells and mice.
The first investigated MDMA-like compounds (5/6-MABB) and looked specifically at the left and right-handed isomers, finding the left-handed variation exhibiting efficacy as releasing agents for serotonin, norepinephrine, and dopamine transporters.
The second examined DOI-like compounds (R-DOTFM/DOI) for inflammation in a mice asthma model. R-DOTFM didn’t prevent inflammation, but the right-handed version of DOI did, suggesting distinct anti-inflammatory mechanisms associated with certain psychedelics.
And for the last study we covered this month, a qualitative study explored the roles and competencies of spiritual health practitioners in psychedelic-assisted therapy (PAT). The findings reveal seven themes, categorizing unique contributions like competency with spiritual material and awareness of power dynamics, as well as general contributions such as utilizing a therapeutic repertoire and fostering interdisciplinary collaboration. The study emphasizes the importance of delineating the roles and qualifications of spiritual health practitioners to enhance the quality and standards of care in PAT teams.
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