This open-label study (n=55) found that a high-dose of psilocybin at a retreat led to more divergent thinking and emotional empathy the day after (n=50). At seven days (n=22) enhancement of convergent thinking and well-being persisted.

Abstract

“Creative thinking and empathy are crucial for everyday interactions and subjective well-being. This is emphasized by studies showing a reduction in these skills in populations where social interaction and subjective well-being are significantly compromised (e.g., depression). Anecdotal reports and recent studies suggest that a single administration of psilocybin can enhance such processes and could therefore be a potential treatment. However, it has yet to be assessed whether effects outlast acute intoxication. The present study aimed to assess the sub-acute effects of psilocybin on creative thinking, empathy, and well-being. Participants attending a psilocybin retreat completed tests of creative (convergent and divergent) thinking and empathy, and the satisfaction with life scale on three occasions: before ingesting psilocybin (N = 55), the morning after (N = 50), and seven days after (N = 22). Results indicated that psilocybin enhanced divergent thinking and emotional empathy the morning after use. Enhancements in convergent thinking, valence-specific emotional empathy, and well-being persisted seven days after use. Subacute changes in empathy correlated with changes in well-being. The study demonstrates that a single administration of psilocybin in a social setting may be associated with sub-acute enhancement of creative thinking, empathy, and subjective well-being. Future research should test whether these effects contribute to the therapeutic effects in clinical populations.”

Authors: Natasha L. Mason, Elisabeth Mischler, Malin V. Uthaug, & Kim P. C. Kuypers

Notes

The participants took quite the high dose of psilocybin, 34.2 grams of truffles on average (8.9 standard deviation), which is normally sold and consumed per 10-15 grams. The average amount of psilocybin was 27.1 mg.

No significant effect on convergent thinking was found the day after, but this was so at seven days later (d = .46, medium effect size). This was measured with the Picture Concept Task (PCT) as was used by Kuypers and colleagues (2016).

Divergent thinking was increased the day after on both the measures of fluency (number of responses) and originality, but not on the ratio of those. This effect didn’t persist at seven days later.

On cognitive empathy there was no effect. Emotional empathy was measured both explicitly and implicitly and was influenced. Implicit emotional empathy was significantly higher for all three subscales (negative, positive, average) but only negative stimuli remained at seven days. Explicit emotional empathy was only found for the average and negative emotions, only the day after.

Participants rated their life as more satisfactory both at the day after and at 7 days later (d = .77 and d = .50 respectively). Those who had already used psychedelics before already had a higher life satisfaction score (as compared to those for whom it was the first time).

“In conclusion, the present study demonstrates that psilocybin, taken in a naturalistic setting, promotes constructs of creativity and empathy, and enhances subjective well-being. These findings highlight the possible underlying role of enhanced creativity and empathy in the therapeutic potential of psychedelics. Importantly, the effects outlast the acute state, potentially opening up a “window of opportunity” where therapeutic interventions could prove more effective. These findings add further support to growing evidence suggesting that psychedelics may hold therapeutic value for treating stress-related mood disorders.”

Summary

Introduction

Recent studies have suggested that psilocybin, a compound found in various genera of mushrooms, may have therapeutic effects in depression, anxiety, substance use, smoking cessation, migraine, and other disorders.

Psilocybin therapy produces acute and sustained antidepressant effects. Several cognitive/behavioral and neurobiological mechanisms have been proposed to explain these effects, including increased cognitive flexibility, decreased experiential avoidance, increased connectedness, relaxation and revision of high-level beliefs, and emotional breakthrough.

Serotonergic psychedelics may have antidepressant effects.

Single dose of these drugs promote neuroplasticity.

However, this has not been conclusively demonstrated in humans.

Psilocybin increased neuroplasticity and reduced neuronal plasticity.

In this double-blind, placebo-controlled, within-subject study, individuals with major depressive disorder were administered placebo followed by psilocybin in a fixed order. The EEG and depression measures were measured at several time-points after placebo and psilocybin.

Results: Theta power doubled in amplitude 2 weeks after psilocybin but not after placebo.

The increased theta power observed following psilocybin may represent a biomarker of the sustained effects of psilocybin, and shed light on potential mechanisms of psilocybin’s antidepressant effect.

Preclinical work suggests that psilocybin increases dendritic growth, spinogenesis, and synaptogenesis, and that these changes are accompanied by increases in synaptic density and synaptic strength. This could represent the underlying neurobiological substrate of the cognitive/behavioral antidepressant mechanisms.

The notion that the antidepressant effect of psychedelic drugs might occur via increased neural plasticity has biological plausibility, as evidenced by the fact that alterations in synaptic connections and neuroplasticity are associated with symptoms and behaviors in depression.

Despite evidence suggesting that psychedelics have neuroplastic effects, this has yet to be demonstrated electrophysiologically in humans. One form of synaptic plasticity is long-term potentiation (LTP), which is a persistent increase in synaptic strength following high-frequency stimulation.

Materials and methods

This study was conducted with approvals from the VA Connecticut Healthcare System and Yale University, and was registered on clinicaltrials. gov.

Study participants

Inclusion criteria included being 18-65 years old, having a moderate to severe major depressive episode, and having failed at least one adequate antidepressant trial. Participants had to be off of any conventional antidepressant or antipsychotic medications for at least 2 weeks prior to study enrollment.

Recruitment and screening procedures

Participants were recruited primarily through online postings, clinician referrals and word of mouth. They underwent a structured psychiatric assessment and medical screening.

Study design

This study utilized a double-blind, placebo-controlled, within-subject, fixed-order design with enhanced blinding. The study used a fixed-order design to minimize potential carryover effects and limit functional unblinding.

Drugs

Participants received placebo (microcrystalline cellulose) on the first session and psilocybin on the second session. This dose was sufficient to produce psychedelic effects.

Drug administration sessions and psychotherapeutic support

Participants were taken to a pre-decorated outpatient office furnished in an esthetically pleasing manner with a sofa, artwork, low lighting, and plants, and were administered a controlled substance. They were required to remain on site for a minimum of 6 h following drug administration.

EEG recording and preprocessing

EEG was recorded at 1000 Hz using 64 channels with a nose reference, and was bandpass filtered and notch filtered at 60 Hz. The EEG was segmented into epochs and ocular movement correction was applied using Gratton’s algorithm.

EEG LTP paradigm

EEG sessions took place 1 day and 2 weeks after each dosing session. A tone pips paradigm was utilized for the LTP, which consisted of 120 tone pips presented with a variable interstimulus interval between 1800 and 2600 ms.

EEG data processing and outcome measures

The primary outcome measure was evoked theta power before and after the auditory tetanus. Evoked theta power was determined via automated algorithms as described previously from our group, and a temporal – spectral region of interest approach was used.

Statistical analysis

Data were analyzed on an intent-to-treat basis using all available data within each subject. EEG data were analyzed using linear mixed models (LMM) with block, time, and drug as within-subjects factors, and clinical outcomes were analyzed using a Bayesian information criterion (BIC) to determine the best-fitting variance – covariance structure.

Results

Nineteen participants completed at least one dosing session and one EEG recording, with a mean age of 42.8 (13.8) years. Eight (42.1%) participants had prior exposure to psychedelic drugs, but not within the 3 years prior to enrollment.

EEG outcomes

The grand averaged ERPs and time – frequency plots for all drug conditions and time points assessed show that there was a significant effect of time, and that the drug – time and block – drug interaction effects approached significance.

Relationship between EEG theta power and depression symptoms

Based upon observed EEG and clinical results, a negative correlation was observed between change in depression scores and change in theta power from 1 day to 2 weeks after psilocybin.

Discussion

In contrast to observations in healthy individuals, neuroplasticity was not observed in MDD patients after auditory tetanic stimulation. However, the NMDAR antagonist ketamine enhanced tetanic-induced LTP in subjects with MDD 24 h after treatment compared to placebo.

Theta oscillations are primarily generated in the hippocampus/septum and are involved in long-range communication between distal brain networks. This may explain the increase in overall evoked theta power observed 2 weeks after psilocybin.

In an animal model of depression, increased network theta oscillations were related to neuroplasticity, and this was disrupted in the “depressed” animals after the chronic unpredictable stress paradigm. Interestingly, theta-burst stimulation is one of the more recent utilized transcranial magnetic stimulation protocols for the treatment of depression. Theta power increased 2 weeks after psilocybin administration, and synaptic density increased 7 days after. This suggests that neuroplastic-related functional and microstructural changes induced by psilocybin may involve downstream mechanisms that could take several days or weeks to emerge.

Limitations

This study had a number of strengths and limitations, including the use of EEG as an objective measure of psilocybin effects, a fixed order design, and a lack of a healthy control group. However, the novel finding of enhanced overall theta power is intriguing and biologically plausible.

Conclusion

A double-blind, placebo-controlled study assessed the effect of psilocybin on EEG indices of neuroplasticity and depression symptoms. The study found that psilocybin produced sustained neuroplastic changes in the brain.

Taken together, these results suggest that increased neural plasticity may be one important mechanism underlying the therapeutic benefits of psilocybin, and that increased theta power may be an EEG biomarker of the sustained effects of psilocybin, and potentially, other novel therapeutics.