February presented another productive month for psychedelic research. This recap of the 21 most exciting articles covers intracellular neuroplasticity, brain measures, outcomes from psychedelic-assisted therapy (PAT), psychedelics for new indications, and well-being measures.
Psychedelics promote neuroplasticity through intracellular serotonin receptors
For many years it’s been known how psychedelics interact with the serotonin receptors in the brain. The places of interest, the binding, and the resulting neuroplasticity have been studied in detail. However, what happened inside a brain cell (neuron) wasn’t studied in such detail.
New research from the Olson lab forever changes how we look at (classical) psychedelics. Imagine a neuron as a house. Before, we only looked at who was at the door (receptors on the surface of a neuron). Now, we also know what happens inside the house (receptors inside the neuron).
Through several clever experiments, Maxemiliano Vargas and colleagues find that the activation of serotonin 2a receptors inside the neurons is causing neuroplasticity. No neuroplasticity was observed in experiments where they only activated the outside neurons (by preventing psychedelics from entering). But the downstream effects were observed if they let non-psychedelic compounds, like serotonin itself, inside a neuron.
The researchers theorize (and show in mice) that possibly the psychedelic (hallucinogenic) effects are caused by the receptors on the outside of a neuron (which still elicit effects inside a neuron), and thus that this effect can be separated from the neuroplastic (which is likely related to therapeutic outcomes – but again still hotly debated).
Analysing the outcomes of psychedelic-assisted therapies
A re-analysis of the COMPASS Phase IIb trial dives deeper into the outcomes experienced by participants. It confirms that the 25mg dose of psilocybin elicited significantly better outcomes than the 10mg and the placebo (1mg) dose. It expands by analysing positive (increased) and negative (decreased) affect scores, ratings of anxiety (improved), and fewer lost (and unproductive) days. On the quality of life measures, only one measure (EQ-5D-3L) reached significance between the 25mg and placebo groups.
A survey study found that a reduction in death anxiety mediates the relationship between the subjective mystical experience of psychedelics and life satisfaction. Though the study is correlational, it fits within the narrative that a reduction in death anxiety (due to the mystical experience) is related to subsequent improvements in well-being. The study also found that psychological insight was a better predictor (than MEQ) of subsequent well-being outcomes (which is also echoed in a recent publication in March).
Next to the mystical experience or insights gained during therapy, the setting also dramatically influences how PAT is experienced. The COMPASS study (from two paragraphs earlier) is described as having a minimally interventive setting, but this can’t be said of the smoking cessation study. A retrospective analysis breaks apart the room attributes (e.g. scented oil), tasks given to the participants (e.g. smoking diary), and prompts given (e.g. adopting a non-smoker identity). An important, yet understudied aspect of what aspects of PAT specifically lead to or amplify the positive outcomes.
One way of analysing the outcomes of PAT is through the lens of wellness. Two articles analyse wellness; the first is a survey of non-recreational users of psychedelics. It finds common benefits from different psychedelics (e.g. increased self-awareness, improved social connection). A second survey, which compared psychedelic users to those using cannabis and alcohol, finds greater psychological strengths and well-being scores in psychedelic users.
Measuring the effects of psychedelics on the brain
Several studies investigate brain measures during and after using psychedelics (including ketamine). How psychedelics, believed to leave the body within 24 hours, affect these changes is an active area of research.
The first study we cover here indicates that six ketamine infusions increase the connectivity (RSFC) between the left amygdala and the left medial superior frontal gyrus in patients with depression. The amygdala is a brain region associated with processing emotions, including fear and anxiety, while the medial superior frontal gyrus is involved in executive functions such as decision-making, working memory, and attentional control. This change correlated with improvements in depression scores.
The second study investigated changes in brainwaves after treatment with six ketamine tablets. During the experience, there were significant changes in alpha waves, and after the experience, significant in theta and low-beta waves were observed.
Looking at the brain under the influence of LSD has been done with fMRI (BOLD). Compared to placebo, LSD increased the complexity of brain dynamics (which is in line with earlier research around increased entropy under the influence of psychedelics). This study used the Ising model and concepts from statistical physics to measure the increased disordered state.
A study on EEG measures (brain activity over time) of the influence of DMT brings together the results from the previous two studies. It records a suppression in alpha brain waves (and partial beta suppression), and increased complexity of brain signals under the influence of DMT. Though psychedelics (and ketamine) work through different routes, similar underlying dynamics are expected to occur.
Finally, a pre-print study in rodents finds that DOI (a lesser-known psychedelic substance of the amphetamine class; effects somewhat similar to LSD) causes a decrease in synchronization.
Psychedelics for new indications
A recurring theme of these monthly recaps is the variety of indications where psychedelics can be helpful. A review covers the four studies (with 150 patients) that have studied the effects of psilocybin on addiction. Overall, the results are positive, but this coverage shows that we’re working with very limited datasets.
Ketamine as a possible treatment for cocaine use disorder (CUD) is currently not something that is widely investigated. Researchers did have data on using ketamine as an anaesthetic (versus other compounds) and analysed the outcomes of 3800 patients. This analysis suggests that ketamine may help treat CUD. Currently, eight trials with ketamine are planned, ongoing, or completed studying the use in addictions (6 for alcoholism, 2 for opioid use).
The use of ibogaine for addiction is better known but still very risky as heart problems (e.g. arrhythmia) aren’t uncommon. Researchers are studying a new class of oxa-iboga alkaloids (related compounds) that present a better safety profile. In the second edition of a pre-print, researchers examine the efficacy and safety in rats.
Psychedelic studies on borderline can be counted on one hand. A small trial (22 participants) adds to this literature by studying the effects of ketamine versus an active placebo (midazolam). The study doesn’t find a significant difference between the two groups, though this could be because the study is underpowered (a trend was found in favour of ketamine).
Comparing different psychedelics
Descriptions of psychedelic experiences and brain measures give us some insight into the differences between the different compounds. But changes could result from different participants, the setting (as discussed above), and many other factors. Two studies sidestep these challenges by comparing two psychedelics in a randomized study (participants randomly get one psychedelic or the other – and the other a week or so later).
The first study compared 2C-B (20mg; one of the most popular ‘research chemicals’) to psilocybin (15mg). It finds that 2C-B elicited alterations in consciousness of a psychedelic nature but with a shorter duration of self-reported effects than psilocybin. The study categorised 2C-B (at least at that dose) as a subjectively “lighter” psychedelic.
The second study compared methylone (200mg; a common MDMA alternative) to MDMA (100mg). The results showed that methylone could significantly increase blood pressure and heart rate and induce pleasurable effects similar to MDMA, including stimulation, euphoria, well-being, enhanced empathy, and altered perception. The effects did come up faster with methylone and dissipated faster too.
The other studies that came out in February
A survey of psychedelic therapists (who participated in the Usona Phase II trial) finds that most (88%) had experience with psychedelics. The reasons for use ranged from personal development to recreation (fun).
A review of 33 studies concludes that psychedelics aren’t addictive or toxic at low doses but can be harmful at high doses. Physiologically the most considerable risk was identified for MDMA, though psychological (relating to set & setting) risks may be more critical.
All the talk about the measures and effects of psychedelic-assisted therapy is just hot air if we don’t look at how this will be implemented in practice. That is where a new commentary by the European equivalent of the FDA (the EMA) comes into play. The authors (including researchers from the University of Copenhagen) propose how drug developers can get psychedelics approved in the EU, and how the EMA can help to get regulatory approval.
And finally, another study investigates how psychedelics and group therapy can be combined. Again, no more than a handful of studies have looked at this possibility, and the analysis is a welcome addition. The authors analyse current literature and use Irvin Yalom’s 11 therapeutic factors of group therapy to discuss the benefits of group PAT, including increased group connectedness and interpersonal learning.
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