This open-label study (n=30) found that ketamine (6 infusions) reduced PTSD symptoms in combat veterans.
Abstract
“Introduction:Combat veterans are at high risk for the development of posttraumatic stress disorder (PTSD) and substance use disorders. Ketamine has been shown to be an effective treatment for numerous mental health disorders, although research on its efficacy in combat-related PTSD in veterans is very limited.
Methods:The study population consisted of 30 US military veterans with combat-related PTSD. Participants underwent a standard induction series of six 1-hour ketamine infusions with the goal of obtaining a transpersonal dissociative experience. Participants were given a series of self-report questionnaires to assess for changes in symptoms of depression, PTSD, and substance use prior to the first and sixth infusions.
Results: Symptoms of depression as measured by change in score on the Patient Health Questionnaire decreased significantly from an average of 18.9 to 9.5 (P < .001). Similarly, symptoms of PTSD as measured by change in score on the PSTD Checklist for DSM-5 dropped significantly from an average of 56.2 to 31.3 (P < .001). Self-reported levels of substance use did not significantly decrease during the study period, although the level of use trended down.
Conclusions: This observational study suggests that high-dose ketamine infusion therapy, which induced a transpersonal dissociative experience, could be a valuable tool in the treatment of combat-related PTSD. Further study is needed to better elucidate ketamine’s mechanism of action with regards to the treatment of PTSD”
Authors: Cassie Ross, Rakesh Jain, Carl J. Bonnett & Philip Wolfson
Summary
High psychedelic doses were shown to stimulate hyper-associative thinking, increase mental imagery, intensify emotions and alter sense of meaning, which may explain why psychedelics promote creativity.
Microdosing of psychedelics (LSD, Psilocybin) has been linked to improved mood and creativity, but there is no robust, quantitative and double-blind research on the effect.
Creativity is a multi-layered set of processes consisting of dissociable and opposing subprocesses, including convergent and divergent thinking. Convergent thinking is the ability to combine remote concepts in order to derive a single logical solution, whereas divergent thinking generates many loosely associated ideas.
Divergent thinking is associated with cognitive flexibility and low top-down inhibition, whereas convergent thinking is associated with high top-down control, increasing mutual competition between representations, and steering cognitive search towards a single correct answer.
Psilocybin, an active compound in magic truffles, is a tryptamine that exerts its psychedelic effects through agonizing serotonergic 5-HT2A receptors. This signalling pathway has been linked to enhanced cognitive flexibility, improved associative and reversal learning, and functional neuro-plasticity.
A recent study showed that moderate doses of psilocybin decrease task-dependent creativity and that higher-order inhibitory performance is impaired under moderate doses of LSD. However, microdosing practice presents a promising approach for cognitive enhancement as well as avenue to study the interaction between psychedelics and cognition in a more controlled manner.
The efficacy of microdosing on cognition remains relatively unexplored, and the majority of published research is based on online prospective surveys. However, online qualitative research is limited in validity due to participants’ false memories and (un)intentional distortions of subjective experiences. In our previous research, we utilized quantitative measures of creativity and intelligence to substantiate the effect of microdosing on cognition beyond self-reports. However, open-label and quasi-experimental research does not control for placebo effects and expectation biases, making these results difficult to interpret.
The gold standard in quantitative clinical trials is to employ a double-blind placebo-control design, but restriction in drug policy renders such research financially and administratively challenging. Only one clinical placebo-controlled trial with healthy volunteers examined the effects of microdosing on creativity.
Existing clinical trials on microdosing suffer from low sample sizes and lack ecological validity. Furthermore, a clinical environment may interfere with microdosing effects.
We conducted three double-blind placebo-controlled longitudinal trials with 175 participants, combining well-controlled laboratory assessment with a naturalistic microdosing setting. The doses were post-hoc analysed for psychedelic content, and subjective drug effects and expectation effects were systematically assessed throughout all trials.
Three randomized, double-blind, placebo-controlled longitudinal trials with psychedelic truffles took place at two experimental testing sites at Leiden University and the University of Amsterdam from November 2018 to March 2019.
Experiments 1 and 2 were between-participant placebo-controlled designs, while experiment 3 was a within-participant crossover design. Data was mega-analyzed across the three trials with frequentist and Bayesian approaches.
Figure 1 shows the flowcharts of the experimental procedures for the between-subject design, between-subject design, and within-subject cross-over design.
Figure 2 shows the dosing and experimental schedule for Experiment 1 and Experiment 2. All measures were administered in the lab apart from Post-acute measures which were administered online.
All three trials were organized around public microdosing workshops organized by the MI & PSN. Healthy applicants free from contra-indications were invited to take part in the microdosing event and related study.
After screening and baseline measures, participants attended MI & PSN workshops. During the workshops, they put precisely pre-determined amounts and packed psilocybin-containing truffles into opaque capsules, and then self-administered the first dose.
Participants were asked to follow a regular microdosing schedule approximately every 3 days, and were reminded to self-administer their doses by MI & PSN through reminders sent online. They were tested 2 to 3 times in the university labs under the acute effects of the truffles.
Microdose was kept short-lasting to prevent fatigue and to assess the peak effect of microdosing. Creativity tasks were consistently performed as one of the first tasks to avoid fatigue.
Participants were given a computer screen in a university laboratory and were asked to reflect on their subjective experience and guess which group they believed to be (‘placebo’, ‘not sure’, ‘active’). They found out their group allocation after the last online assessment.
The doses of Psilocybin containing sclerotia (magic truffles) were pre-determined by the PSN team ahead of the workshop. All participants consumed the same dose size (regardless of participant weight) within each of the experimental trials.
Participants consumed 0.5, 1 and 1.5 grams of fresh truffles, respectively, to explore possible dose-dependent effects on outcome measures in the final mega-analyses. The samples of truffles were post-hoc analyzed at the University of Chemistry and Technology Prague to estimate microdosing strength.
Participants were required to take their microdoses up to 1 hour before every testing session. The effects of the truffle alkaloids peak approximately 6090 minutes after ingestion.
Data pre-processing was performed in Qualtrics software, and reliability analyses were conducted in IBM SPSS Statistics 24. Bayesian and regression analyses were conducted in JASP, and a power calculation was conducted with G*power version 3.1.
In the first experiment, participants were asked to perform two creativity tasks tapping into convergent and divergent thinking. The results indicated that microdosing psychedelics improved both convergent and divergent thinking.
Experiment 1 was set-up as a randomized, double-blind, placebo-controlled, longitudinal, design with three assessment time-points carried out in the labs of Leiden University. Participants were tested once at baseline before the MI & PSN workshop and twice acutely approximately one hour after participants took a microdose.
A total of 103 participants signed up for the psychedelic workshop, of which 77 were invited to attend the microdosing event and baseline measurement at the Leiden University. 59 participants completed the baseline and both follow-up sessions, and 57 completed the post-acute AUT measurement. The first MI & PSN workshop took place in Leiden and all participants provided informed consent before starting the study procedure.
The Alternate Uses Task (AUT) was used to assess divergent creativity in Experiments 1 and 2. The order of items presented across time was consistent, and the same pair of items were presented to all participants.
The AUT reports were rated by two different raters according to five different variables: fluency, flexibility, elaboration, originality, and the ratio between originality and fluency (originality/fluency), which was shown to be affected by psychedelics in previous research.
The Picture Concept Task (PCT) is a visual creativity task commonly used as a measure of convergent thinking. Participants had 30 seconds per item to find the common connection between one picture from each row.
Subjective effects were measured using several tailored questions. Participants were asked to rank the intensity of their experience and to guess whether they were using active psilocybin or a placebo.
We conducted independent samples t-tests and chi-square tests on demographic data, and rmANOVAs to analyze group differences in the perceived psychoactive strength of the microdose. We also explored to what degree previous psychedelic experience played a role in the ratings of the subjective effects.
To examine whether psilocybin, compared to placebo, altered creativity scores, two-way interactions between condition and session were examined and corrected for multiple comparisons with Bonferroni correction. Significant effects were followed-up by the appropriate univariate tests and were again Bonferroni corrected according to contrasts of interest.
To examine the role that expectation and previous psychedelic experience had on the creativity changes, mixed-design rmANOVAs were re-run and Pearson’s correlations were run. The results of these analyses were reported in the main text only when significant.
The results indicated that the acute AUT scores and PCT scores did not differ between randomized groups. A total of 78 participants were needed to detect a significant interaction with a moderate effect size.
The majority of participants were uncertain about their group allocation and showed a similar distribution of false positive and negative estimates. Two participants who were allocated in the control group experienced very strong placebo effects.
The results indicate that the blinding manipulation was successful and that the subjective microdosing strength changed over time while controlling for experimental condition. Nevertheless, the participants in the active psilocybin condition did not differ in ratings of psychedelic strength from placebo.
Subjective microdosing strength was measured at three different time points and was divided by treatment (placebo vs active).
We further assessed the effect of previous psychedelic experience on subjective drug ratings. Participants who had previous psychedelic experience and were in the placebo condition rated the microdosing drug effect stronger at the acute 2 session compared to those who did not have prior psychedelic experience.
The effects of microdosing on divergent thinking were tested by 2 x 3 Mixed-design rmANOVAs. The results indicated that the main effect reflected mixture of practice effects and variations in AUT items difficulty.
Significant interactions between session and condition were found for elaboration, originality, and originality ratio. The active psilocybin group improved in originality as compared to placebo after the last microdose, although not after the second microdose. The elaboration score was not different between groups in any of the two follow-up sessions.
The results indicate that the change in creativity scores was not significantly influenced by participant’s beliefs regarding their own group allocation or subjectively perceived strength of the acute microdose effect.
We explored to what degree prior psychedelic experience moderated the drug effects and creativity scores. Participants with prior psychedelic experience had a significant baseline difference in elaboration score as compared to naive participants.
Convergent thinking performance did not differ between the two conditions in the independent sample t-test or rmANOVA, and the effects of microdosing psilocybin on convergent thinking were not significant even after controlling for expectation effects.
A semi-naturalistic experiment was conducted to examine the effects of microdosing psychedelics on creativity.
We observed that taking microdoses of active psychedelic truffles enhanced performance on two out of five divergent measures compared to placebo. Participants with prior psychedelic experience showed higher placebo effects and more likely to believe to be in the active microdosing condition while actually dosing with placebos.
Previous psychedelic experience is an important moderator in microdosing effects, and no residual effects were observed two days after the last microdose.
The current results show that active microdosing increases originality, but does not increase fluency, flexibility, or the convergent score as compared to placebo. This result is consistent with previous research showing that moderately-large doses of psychedelic truffles increase divergent creativity. Anderson et al. (2019) found that microdosing participants performed significantly higher on three creativity indexes than non-microdosing controls.
Microdosing improves some aspects of creativity, but not all. The active condition produced a higher percentage of original solutions than the placebo condition.
Although the results are promising, the study was slightly underpowered and false-positive and false-negative errors cannot be ruled out. Additionally, participants self-administered microdoses in a naturalistic setting and therefore experimenters did not have a full control over the dosage.
The goal of experiment 2 was to replicate and build upon findings from experiment 1, yet several alterations were added. It was hypothesized that lower doses of psychedelic produce more pronounced positive effects on creativity in general, while large microdoses may render cognition too diverted. In Experiment 2, the duration of the microdosing period was extended to four weeks. This may have resulted in more salient microdosing benefits, or a negative relationship between the dosing period and its effects.
In line with Experiment 1, a second study was carried out using the same creativity tasks and subjective measures. This time the microdosing workshop was organized by MI & PSN in Amsterdam.
The duration of the trial was extended to approximately four weeks and consisted of 10 dosing days. The dosage was increased to 1 gram of fresh psychedelic truffles and the placebo doses contained non-psychedelic truffles mixed with rice to produce identical sound and weight effects.
100 healthy participants were invited to take part in the microdosing event, of which 96 were interested in taking part in the associated research. Of these 96 participants, 83 attended the baseline session and 71 attended the Acute 1 session. A total of 61 healthy participants completed both follow-up sessions in a good order, and 55 completed the PCT task. Of these, 8 participants had missing data at baseline, but these were mean imputed after the control analyses were carried out to preserve experimental power.
The Alternate Uses Task (AUT) required participants to think of creative uses of ordinary items. The AUT was rated by two different raers according to five 23 different variables.
In Experiment 2, participants were again asked to reflect on their subjective microdosing effects during every experimental session. The subjective effects were measured at every follow-up session.
After the 6th microdose in acute 1, the 10th dose in acute 2, PCT was tested only twice, and the perceived psychoactive microdosing strength was analyzed by rmANOVAs with session entered as the within-participant factor and group (placebo vs active microdose) as the between-participant factor.
The population in the second study was significantly older and had more cases of previous psychedelic experience than in the first experiment. The power calculation indicated that 78 participants were required for the AUT and 82 participants were required for the PCT.
Even after four weeks of dosing, participants in the active psilocybin condition did not correctly estimate their group allocation. This suggests that the blinding manipulation was successful. Participants perceived comparable psychedelic strength across the active and placebo condition, regardless of experimental condition. This indicates that participants did not break blind regarding their experimental condition.
The main effects of session were significant for all measures when controlling for the effect of condition. However, the interactions between session and condition were not significant for the divergent scores.
An independent samples t-test indicated that the experimental and control groups were similar in PCT performance at the baseline assessment, and a mixed-design rmANOVA indicated that active microdosing did not exert effect on convergent thinking as compared to placebo.
Figure 4 shows mean Z-scores for five divergent scores measured by AUT and one convergent score measured by PCT as a function of group (Placebo vs. Active psilocybin).
The results of Experiment 2 did not replicate the findings from Experiment 1, and the PCT analyses indicated that microdosing did not improve convergent thinking. The participants reported diminishing drug effects regardless of their experimental condition, and the strength of subjective drug effect was comparable across the two conditions.
Participants in Experiment 2 were approximately four years older than participants in Experiment 1. This could account for differences in baseline performance in all creativity measures across the two samples. In Experiment 2, participants consisted of the general public, while in Experiment 1, participants were mostly recruited among the Leiden University students with previous experience with psychological testing. The second experiment was potentially under-powered, so we carried out Experiment 3, implementing a within-participant cross-over design.
Experiment 3 aimed to replicate and build on previous findings while improving statistical power by means of utilizing a within-participant cross-over design. It was hypothesized that microdosing psychedelics would increase divergent scores and reduce convergent scores.
Experiment 3 used a within-participant cross-over design and excluded participants with a past medical history or clinical illness. It took place at the labs of University of Amsterdam. In Experiment 3, participants self-administered 14 microdoses in total in cross-over fashion. The order of active psychedelic doses vs. placebo was switched after the 7th dose, and participants were aware that they would either receive active microdoses or inactive placebos at one of the two experimental blocks.
Twenty-five participants dropped out after the first block of testing and additional 16 participants dropped out during the second block of testing. This yielded a final sample of 27 healthy participants between the age of 20 and 48 with mean age 31.3 years (SD = 10.00).
We used a divergent version of the Picture Concept Task (PCT) to measure convergent and divergent thinking. The PCT-d consisted of 18 trials, and participants had 2 minutes to find a single convergent solution by connecting one picture in all the picture rows presented.
Subjective effects were measured at every testing block, but we did not have any quantifiable data regarding past psychedelic experience due to data collection error.
The differences in subjective beliefs concerning own group allocation and microdosing strength across the two drug conditions were analyzed with 2 tests at each of the two experimental blocks. The post-hoc comparisons were corrected for multiple comparisons, using Bonferroni correction.
Participants’ expectations over own group allocation (e.g., active, placebo, not-sure) affected the change in the outcome measures. ANOVAs were run with type of treatment and creativity scores as within-participant factors and expectation regarding group allocation as a between-participant factor.
All participants had prior psychedelic experience and the reliability scores ranged from excellent (i.e., fluency) to good (i.e., originality). A total of 24 participants should be included within the analyses in order to detect differences between conditions with a moderate effect size.
The placebo manipulation was successful during the first block of testing, however at the following block participants were breaking blind. Furthermore, the subjective microdosing effects diminished over time regardless of condition between the workshop and first follow-up session.
The 2 x 4 rmANOVA indicated no main effect of condition, but the interaction between creativity and condition reached significance, suggesting that at least one of the creativity scores significantly differed between the two conditions. The effect of microdosing on divergent scores was significant.
The post-hoc paired-sample t-test revealed that there was no difference in convergent scores between the active microdosing condition and the placebo condition.
The analysis showed no main effect of a block on creativity, and no significant interaction between condition and block or between condition, block and creativity. However, the key interaction between condition and creativity was insignificant.
The results indicate that participants’ expectations did not significantly interact with the results. However, the key interaction between condition and creativity was insignificant, and the key interaction between condition and creativity was also insignificant.
In Experiment 3, a similar pattern of results as in Experiment 1 was found, but only one out of two prior effects was replicated. This effect suggests that participants produce a lower quantity but a higher quality of creative responses after the active microdose than after placebo.
The current result showed some promise in terms of replicability of microdosing effect on the originality ratio, but we did not replicate the effect on unweighted originality observed in Experiment 1, which is a more commonly used creativity index.
We decided to re-examine the data through exploratory mega-analyses, which increased statistical power and reduced heterogeneity across trials.
Data from the second acute measurement in Experiment 1, the first acute measurement in Experiment 2, and the first experimental block in Experiment 3 were pooled-together to allow for between-participant comparison. Only the indexes that conceptually overlapped across the three trials were selected for the mega-analyses.
Participants were pooled from Experiments 1, 2 and 3 and 138 participants were used for the convergent scores. The mean age of the sample was 27.22 (SD = 7.4), mean weight 70.2 kg (SD = 7.45) and mean BMI 23.55 (SD = 10.35).
We examined whether subjective microdosing effects interacted with increments in dose across trials and whether the relative dose size of microdosing had significant effects on creativity at a single time point.
We performed a series of two-stage hierarchical regressions to determine the degree to which subjective and demographic factors interact with the creativity scores. The relative dose-dependent effects of microdosing on creativity were examined by dose size corrected for participants’ weight.
The same two-step hierarchical analysis was repeated with the relative dose size entered in the second step. A total of 82 participants were needed to detect differences between conditions with a moderate effect size.
The results showed that the blinding procedure was successful at this time point, and that subjective strength of microdosing increased with higher dose. The correlation between-participants weight and subjective microdosing effects was negatively correlated, suggesting mediating effects of weight on the psychoactive microdosing effects.
Independent-samples t-tests showed non-significant differences between the active (M = -0.074, SD = 1.01) and placebo (M = 0.056, SD = 0.97) condition for the fluency score, originality score, and originality ratio.
The regression analyses replicated previous analyses and showed that relative dose size (dose/participant’s weight) predicted the originality ratio and fluency score. However, the unweighted originality score was significantly predicted by relative dose size (dose/participant’s weight).
The result for convergent thinking showed that there was no significant difference between the active microdosing condition and placebo. The regression analysis also indicated moderate evidence towards the null effect.
Figure 5 shows the mean Z-scores for three divergent scores and one convergent score measured by PCT-d and AUT as a function of group (Placebo vs. Active psilocybin).
We ran a hierarchical regression for each of the four creativity scores separately with demographic information and subjective drug effects as predictors.
Multiple linear regressions indicated that demographics and drug effects did not significantly predict any of the four creativity scores in the first step of the analyses. However, when the drug condition was added as a predictor, the full model became statistically significant for unweighted originality and originality ratio.
This study aimed to investigate whether microdosing psilocybin induces cognitive flexibility and, thus, promotes divergent thinking through 5-HT-2A signaling.
Data from 171 attendees indicated that microdosing psilocybin positively predicts the overall originality of creative responses. This effect was present even after controlling for expectation biases and demographic factors.
Microdosing can increase originality ratio, which is relevant to hypothesis suggesting increased cognitive flexibility in psychedelic states. Original solutions are derived through an object’s de-construction into its sub-components, known as object feature maps.
The shape of a balloon is round, which can be exploited to search for novel, creative solutions. Retrieval from long-term memory plays a vital role in generating divergent but relatively common ideas, while original ideas require higher spread of activation within the semantic networks.
Previous studies indicate that high doses of psychedelics may have positive effects on divergent thinking, but the underlying mechanisms remain relatively unexplored. Microdosing may introduce a novel tool to study the role of serotonin in human creativity.
The contemporary theoretical (REBUS) framework proposes that perception is combined through a predictive coding process that combines bottom-up sensory signals and top-down prior beliefs. Psychedelics are suggested to relax such high-level priors and liberate bottom-up signals which can in turn access conscious experience more easily.
Psychedelics were observed to desynchronize neural populations within the prefrontal and associative regions and enhance global functional connectivity, which may explain the increased switching between functional networks observed under psychedelics. The breakdown of the neuro-cognitive hierarchy in the psychedelic state was hypothesized to increase the brain’s global flexibility, which in turn increases the richness of subjective experience and the volume of sensory and mnemonic information, which can facilitate novel insights.
Subjective effects were well-tolerated, dose dependent and diminished over dosing period, independent of experimental condition. Prominent placebo effects were found in all three trials, and these effects could be interpreted as a by-product of state-conditioning account of placebo effects.
While the results of the current study are promising, the semi-naturalistic setting limited the control over the drug administration, and the exact amount of psychedelic alkaloids at every dose could not be controlled. A question of selection-bias arises, because participants with prior psychedelic experience may have already altered their brain connectivity with psychedelics prior to the study, or may induce psychopharmacological reactions mimicking psychedelic effects.
The current study suggests that microdosing does not improve all facets of creativity, but increases the number of original answers and the ratio of original solutions. The effects of microdosing on divergent quality are more subtle than initially anticipated.