Changes in brain functioning, new synthesis methods, and psychotherapy dominate this year’s most-cited psilocybin papers.
DECEMBER 30, 2020 – BY BARBARA E. BAUER, MS
As 2020 draws to a close, Psychedelic Science Review is acknowledging the work that psychedelic researchers published this year. Last year, we presented the Top 10 psilocybin research papers for the last 20 years. Now, PSR recognizes the top psilocybin research papers of 2020.
Finding the top 10 psilocybin papers of 2020 was done using the program Publish or Perish to extract psychedelic study data from Google Scholar. Searching was done using the keyword “psilocybin” in the title from January 1st to November 23rd, 2020.
Readers should note that a high citation count for a paper does not necessarily mean a high-quality study. A quick internet search reveals there are several ways to artificially inflate the citation count of scientific papers. Conversely, there are likely current ground-breaking psilocybin papers that did not make the top 10 list for 2020 because they were published toward the end of the year and do not have enough citations yet.
This top 10 list is meant to be a retrospective for general reference. It contains work done by several distinguished and respected psychedelic researchers, which adds validity to the citation counts.
Here are the top 10 psilocybin papers for 2020. There are actually 13 studies in the list due to three tie scores.
1. FS Barrett, MK Doss, ND Sepeda, et al. – Emotions and brain function are altered up to one month after a single high dose of psilocybin.1 (16 citations)
In this open-label pilot study, Barrett et al. set out to examine the long-term impact on emotions and brain function of a 25 mg/70 kg dose of pure psilocybin on 12 healthy volunteers. The participants were given assessments one day before dosing and at one week and one month after. They also underwent an fMRI (functional magnetic resonance imaging) scan at the same time intervals.
At one week post-dosing, the data showed reductions in negative affect and the amygdala response to facial affect stimuli compared to controls (i.e., the participants felt better about themselves and had fewer negative emotions). Also, “positive affect and dorsal lateral prefrontal and medial orbitofrontal cortex responses to emotionally conflicting stimuli were increased” (i.e., they had more control over their emotions).
One month after dosing, the data showed that the negative affect and amygdala responses returned to baseline levels. However, positive affect remained elevated along with a reduction in trait anxiety. Most intriguing was that “the number of significant resting-state functional connections across the brain increased from baseline to 1-week and 1-month post-psilocybin.” From the results, the authors hypothesized that psilocybin increases brain neuroplasticity, and negative affect may present a therapeutic target for psilocybin.
2. SB Goldberg, BT Pace, CR Nicholas, et al. – The experimental effects of psilocybin on symptoms of anxiety and depression: A meta-analysis.2 (15 citations)
This review article describes the results of a meta-analysis of studies using psilocybin along with behavioral interventions to treat elevated symptoms of anxiety and depression. The goal of the analysis was to identify limitations and suggest new treatment approaches. Out of 864 studies retrieved from the literature, only four (N = 117) met the criteria for study selection. Nonetheless, the data analysis revealed some significant findings.
Large reductions in anxiety and depression resulted within treatment groups after psilocybin dosing and at the six months follow-up. One point of concern that Goldberg et al. found was that the “Qualitative assessment of risk of bias was more concerning [than publication bias], with high risk in several domains.” They suggested that future meta-analyses consider other study features such as dosage.
Three of the four psilocybin studies were randomized, double-blind, and placebo-controlled. The data indicated that psilocybin with behavioral intervention was effective in relieving anxiety and depression. Goldberg et al. stated, “the additive benefit of psilocybin may be substantial” as evidenced by both the test and control groups receiving “equivalent behavioral interventions.” However, they voiced some concern regarding publication bias. The authors recommend more placebo-controlled studies. They also suggest focusing on psilocybin for treatment-resistant depression and evaluating various behavioral interventions.
3. GI Agin-Liebes, T Malone, MM Yalch, et al. – Long-term follow-up of psilocybin-assisted psychotherapy for psychiatric and existential distress in patients with life-threatening cancer.3 (12 citations)
A follow-up study published in the Journal of Psychopharmacology revealed the long-lasting beneficial effects of a single dose of psilocybin for people with life-threatening cancer. This study followed up a 2016 psilocybin single-dose (0.3 mg/kg), double-blind, placebo-controlled, crossover trial of 29 patients with cancer-related anxiety and depression. Data from the 2016 study showed that 60-80% of the participants experienced significant antidepressant and anxiolytic (decreased anxiety) effects at their 6.5-month follow-up. They also experienced beneficial changes in existential stress, quality of life, and attitudes toward death. The data also showed that the mystical experience induced by psilocybin mediated the therapeutic effects.
The current study followed up approximately 3.2 and 4.5 years later, with 15 of the 16 participants who were still alive. At 4.5 years, 60-80% still reported clinically significant antidepressant and anxiolytic effects. They also experienced reduced hopelessness, demoralization, and death anxiety. An overwhelming majority (71-100%) of the participants said that their psilocybin-assisted psychotherapy experience was responsible for the positive changes. They also “rated it among the most personally meaningful and spiritually significant experiences of their lives.”
4. F Blei, S Dörner, J Fricke, et al. – Simultaneous production of psilocybin and a cocktail of β‐carboline monoamine oxidase inhibitors in “magic” mushrooms.4 (10 citations)
Note: This paper was chosen for Psychedelic Science Review’s 2020 Editor’s Choice Award for the best study on psychedelics and nature.
For the first time, researchers discovered compounds called ß-carbolines in several species of magic mushrooms. Using 1D and 2D NMR (nuclear magnetic resonance) spectroscopy, Dr. Felix Blei and his colleagues analyzed extracts from Psilocybe cubensis, P. mexicana, P. cyanescens, and P. semilanceata. They identified the following ß-carboline compounds in the extracts: Cordysinin C, Cordysinin D, Harmane, Harmol, Norharmane, and Perlolyrine.
Further testing using stable-isotope labeling with 13C11-L-tryptophan showed that the ß-carbolines were biosynthetic products of the Psilocybe species, not contaminants or just molecules that the mushrooms absorbed from the soil.
5. J Sloshower, J Guss, R Krause, et al. – Psilocybin-assisted therapy of major depressive disorder using Acceptance and Commitment Therapy as a therapeutic frame.5 (9 citations)
In the Journal of Contextual Behavioral Science, Sloshower et al. describe their psilocybin-assisted psychotherapy work, which “delineate[s] an explicit and replicable, evidence-based model that intentionally builds upon both the neurobiological actions of the medication and the phenomenology of the drug experience.”
Psychedelic Science Review writer David Sugarbaker discussed this study in November 2020 article.
The research team’s model lays out how to combine therapy using antidepressant medication (like psilocybin) with evidence-based psychotherapy. Although these two methods are often used together, they typically follow different treatment paths.
6. LJ Mertens, MB Wall, L Roseman, et al. – Therapeutic mechanisms of psilocybin: Changes in amygdala and prefrontal functional connectivity during emotional processing after psilocybin for treatment-resistant depression.6 (8 citations)
This study examined the effects of psilocybin on the amygdala, which is a critical component of the default mode network (DMN). The research team used fMRI scans to monitor connections in the brains of volunteers after receiving 25 mg of oral psilocybin.
Former Psychedelic Science Review writer Shane O’Connor covered this study in February 2020.
The researchers found increased amygdala activation in the participants the day after psilocybin treatment. There was also hyperactivation of the amygdala when the participants viewed images of negative facial expressions. And, the amygdala showed decreased connectivity to the ventromedial prefrontal cortex, which plays a vital role in processing emotions. Decreased connectivity between these two areas of the brain may underlie disturbed emotional processing, possibly leading to neuropsychiatric disorders.
7. NL Mason, KPC Kuypers, F Müller, et al. – Me, myself, bye: regional alterations in glutamate and the experience of ego dissolution with psilocybin.7 (7 citations, tie)
This study examined what happens in the brain during ego death brought on by psilocybin. Part of the analysis included monitoring levels of glutamate, the brain’s primary excitatory neurotransmitter. Using a double-blind design, 30 participants underwent fMRI imaging while under the influence of psilocybin and another 30 after taking a placebo. Afterward, the participants completed a questionnaire about their experience.
Psychedelic Science Review writer Abigail Calder covered this study in August 2020.
In the end, Mason et al. hypothesized that glutamate signaling is part of the domino effect by which psychedelics enhance neuroplasticity in some areas of the brain, and glutamate activity also strongly correlates with the level of activity in a brain region.
8. MK Madsen, PMD Fisher, DS Stenbæk, et al. – A single psilocybin dose is associated with long-term increased mindfulness, preceded by a proportional change in neocortical 5-HT2A receptor binding.8 (7 citations, tie)
In this study, Dr. Martin Madsen and his research team reported on serotonin 5-HT2A receptor binding in the brain and the long term subjective effects after a single dose of psilocybin in human volunteers. This was the first molecular neuroimaging study examining the underlying mechanisms behind the long term effects of psilocybin.
Psychedelic Science Review published a summary of this study in March.
The authors hypothesized that the persistent increase in mindfulness they observed might be an important component of psilocybin therapy. They added that the negative correlation between mindfulness and individual changes in 5-HT2A occupancy may offer some clues as to the mechanism of psilocybin’s persistent effects on mindfulness.
9. KH Preller, P Duerler, JB Burt, et al. – Psilocybin induces time-dependent changes in global functional connectivity.9 (6 citations, tie)
Using MRI imaging and cortical gene expression maps, this research team examined the effects of psilocybin on global functional connectivity in the human brain over time. This was a double-blind, randomized, counterbalanced, cross over study in which 23 healthy participants received 0.2 mg/kg of psilocybin orally on two different days.
The data indicated that psilocybin reduced associative brain-wide connectivity. But at the same time, it increased sensory brain-wide connectivity. The researchers saw this pattern become clear over time from the first administration of psilocybin to its peak effects. They also observed that baseline connectivity was associated with the degree of functional connectivity changes brought on by psilocybin. The third primary finding of the study was “Psilocybin induced changes correlated time-dependently with spatial gene expression patterns of the 5-HT2A and 5-HT1A.” Preller et al. summarized the study by saying, “these results deepen our understanding of the mechanism of action of psychedelic compounds and disclose important targets for the development of novel therapeutics and potential psychedelic therapy.”
10. N Milne, P Thomsen, N Malgaard Knudsen, et al. – Metabolic engineering of Saccharomyces cerevisiae for the production of psilocybin and related tryptamine derivatives.10 (6 citations, tie)
Nick Milne and a research team published a study in the journal Metabolic Engineering describing how they bioengineered the yeast Saccharomyces cerevisiae to produce psilocybin and other related tryptamine derivatives.
Psychedelic Science Review published a summary of this study in April 2020.
This research provides another method for producing meaningful amounts of psilocybin analogs for scientific study and downstream applications. Also, synthesis of the novel compounds N-acetyl-4-hydroxytryptamine and unphosphorylated aeruginascin by strains of S. cerevisiae provides more opportunities for research into their chemistry and pharmacology.
11. AM Sherwood, P Meisenheimer, G Tarpley, et al. – An improved, practical, and scalable five-step synthesis of psilocybin.11 (5 citations, tie)
In the journal Synthesis, Alexander Sherwood and his colleagues described a method they developed for the large-scale synthesis of psilocybin. Specifically, they created the method for “clinical development of psilocybin for the treatment of MDD [major depressive disorder] in participants considered medically healthy and in patients with potentially life-threatening cancer diagnosis.” The primary goals of the study were to increase the yield, identify critical in-process parameters, and creating a method for isolating psilocybin without using chromatography or aqueous workup.
The team modified the general synthetic approach for making psilocybin, which had been published previously in several papers. Their efforts culminated in a 5-step process beginning with a less expensive starting compound, acetoxyindole. In addition to the improved practicality of the method, Sherwood et al. increased the yield of psilocybin in their method to 23% overall.
12. TF Varley, R Carhart-Harris, L Roseman, et al. – Serotonergic psychedelics LSD & psilocybin increase the fractal dimension of cortical brain activity in spatial and temporal domains.12 (5 citations, tie)
This study presented an alternate method for measuring the movement from order to disorder in the brain under the influence of LSD and psilocybin. Using observations from the field of physics, the authors proposed using two measures of the fractal dimension of functional activity to measure complexity in the brain. They utilized fMRI data from brain scans of volunteers given doses of LSD, psilocybin, or placebo.
The results showed that both psilocybin and LSD caused a significant increase in the fractal dimension of functional connectivity networks. Changes in the fractal dimension were localized in the dorsal-attention network. Varley et al. summarized the impact of their findings by stating, “These results show that psychedelic drugs increase the fractal dimension of activity in the brain and we see this as an indicator that the changes in consciousness triggered by psychedelics are associated with evolution towards a critical zone.”
13. SE Meikle, P Liknaitzky, SL Rossell, et al. – Psilocybin-assisted therapy for depression: How do we advance the field?13 (4 citations)
In this viewpoint article published in the Australian & New Zealand Journal of Psychiatry, Dr. Sally Meikle and her colleagues discuss the reemergence of psychedelics and outline several outstanding key issues pertaining to the use of psilocybin in clinical studies. These include who would be most likely to benefit, adverse effects, longer-term outcomes, and the role of psychotherapy in conjunction with psilocybin.
In addition, the authors emphasize the need for further research to understand the neurobiology that lies beneath the effects of psilocybin. They conclude the article with the following recommendations: “We suggest that in taking the next steps, the field needs to seek to refine therapeutic ‘best practice’ as well as use the opportunity to advance our understanding of the psychology and neurobiology of disorders of the mind.”