OPEN Foundation

Floris Wolswijk

The psychoactive aminoalkylbenzofuran derivatives, 5-APB and 6-APB, mimic the effects of 3,4-methylenedioxyamphetamine (MDA) on monoamine transmission in male rats

Abstract

Rationale: The nonmedical use of new psychoactive substances (NPS) is a worldwide public health concern. The so-called “benzofury” compounds, 5-(2-aminopropyl)benzofuran (5-APB) and 6-(2-aminopropyl)benzofuran (6-APB), are NPS with stimulant-like properties in human users. These substances are known to interact with monoamine transporters and 5-HT receptors in transfected cells, but less is known about their effects in animal models.

Methods: Here, we used in vitro monoamine transporter assays in rat brain synaptosomes to characterize the effects of 5-APB and 6-APB, together with their N-methyl derivatives 5-MAPB and 6-MAPB, in comparison with 3,4-methylenedioxyamphetamine (MDA) and 3,4-methylenedioxymethamphetamine (MDMA). In vivo neurochemical and behavioral effects of 5-APB (0.3 and 1.0 mg/kg, i.v.) and 6-APB (0.3 and 1.0 mg/kg, i.v.) were assessed in comparison with MDA (1.0 and 3.0 mg/kg, i.v.) using microdialysis sampling in the nucleus accumbens of conscious male rats.

Results: All four benzofuran derivatives were substrate-type releasers at dopamine transporters (DAT), norepinephrine transporters (NET), and serotonin transporters (SERT) with nanomolar potencies, similar to the profile of effects produced by MDA and MDMA. However, the benzofurans were at least threefold more potent than MDA and MDMA at evoking transporter-mediated release. Like MDA, both benzofurans induced dose-related elevations in extracellular dopamine and serotonin in the brain, but benzofurans were more potent than MDA. The benzofuran derivatives also induced profound behavioral activation characterized by forward locomotion which lasted for at least 2 h post-injection.

Conclusions: Overall, benzofurans are more potent than MDA in vitro and in vivo, producing sustained stimulant-like effects in rats. These data suggest that benzofuran-type compounds may have abuse liability and could pose risks for adverse effects, especially if used in conjunction with abused drugs or medications which enhance monoamine transmission in the brain.

Brandt, S. D., Walters, H. M., Partilla, J. S., Blough, B. E., Kavanagh, P. V., & Baumann, M. H. (2020). The psychoactive aminoalkylbenzofuran derivatives, 5-APB and 6-APB, mimic the effects of 3, 4-methylenedioxyamphetamine (MDA) on monoamine transmission in male rats. Psychopharmacology237(12), 3703-3714; 10.1007/s00213-020-05648-z

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Historic psychedelic drug trials and the treatment of anxiety disorders

Abstract

Introduction: In this paper, we systematically review literature from 1940 to 2000 relating to the combined use of psychological therapies and psychedelic drugs in the treatment of ICD-10 anxiety disorders.

Methods: The databases Ovid MEDLINE(R), PsycINFO, and Multidisciplinary Association for Psychedelic Studies (MAPS) were searched for case reports and trials involving humans in the treatment of ICD-10 anxiety and related disorders. Twenty-four studies are described; four describe anxiety symptoms in diverse patient groups, 14 studies describe historic diagnoses that usefully correspond with ICD-10 anxiety disorders, six studies pooled results or failed to detail results specific to contemporary ICD-10 anxiety disorders. Two of the 24 studies reported are individual case reports while two of them were inadequate in terms of the reporting of outcome measures. Thus 20 studies were ultimately included in the summary analysis.

Results: Three of the 20 studies reviewed described improvements in anxiety by standardized measures (p < .05) and two studies found that this effect was dose related. Of the 20 studies included in the final analysis, 94 of 145 (65%) cases of “psychoneurotic anxiety reaction” as defined by Diagnostic and Statistical Manual of Mental Disorders-I showed improvement that ranged from moderate improvement to full recovery. Despite methodological inadequacies, the results from previous studies are encouraging and should be used to guide and inform further investigation.

Conclusion: The majority of studies indicate that a combination of psychedelic drug administration and psychological therapy was most beneficial. We found no study suggesting that the pharmacological action of psychedelic drugs in isolation is sufficient.

Weston, N. M., Gibbs, D., Bird, C. I., Daniel, A., Jelen, L. A., Knight, G., … & Rucker, J. J. (2020). Historic psychedelic drug trials and the treatment of anxiety disorders. Depression and Anxiety37(12), 1261-1279; 10.1002/da.23065
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Serotonergic psychedelics LSD & psilocybin increase the fractal dimension of cortical brain activity in spatial and temporal domains

Abstract

Psychedelic drugs, such as psilocybin and LSD, represent unique tools for researchers investigating the neural origins of consciousness. Currently, the most compelling theories of how psychedelics exert their effects is by increasing the complexity of brain activity and moving the system towards a critical point between order and disorder, creating more dynamic and complex patterns of neural activity. While the concept of criticality is of central importance to this theory, few of the published studies on psychedelics investigate it directly, testing instead related measures such as algorithmic complexity or Shannon entropy. We propose using the fractal dimension of functional activity in the brain as a measure of complexity since findings from physics suggest that as a system organizes towards criticality, it tends to take on a fractal structure. We tested two different measures of fractal dimension, one spatial and one temporal, using fMRI data from volunteers under the influence of both LSD and psilocybin. The first was the fractal dimension of cortical functional connectivity networks and the second was the fractal dimension of BOLD time-series. In addition to the fractal measures, we used a well-established, non-fractal measure of signal complexity and show that they behave similarly. We were able to show that both psychedelic drugs significantly increased the fractal dimension of functional connectivity networks, and that LSD significantly increased the fractal dimension of BOLD signals, with psilocybin showing a non-significant trend in the same direction. With both LSD and psilocybin, we were able to localize changes in the fractal dimension of BOLD signals to brain areas assigned to the dorsal-attenion network. 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.

Varley, T. F., Carhart-Harris, R., Roseman, L., Menon, D. K., & Stamatakis, E. A. (2020). Serotonergic psychedelics LSD & psilocybin increase the fractal dimension of cortical brain activity in spatial and temporal domains. NeuroImage220, 117049; 10.1016/j.neuroimage.2020.117049
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A randomized, double-blind, active placebo-controlled study of efficacy, safety, and durability of repeated vs single subanesthetic ketamine for treatment-resistant depression

Abstract

The strategy of repeated ketamine in open-label and saline-control studies of treatment-resistant depression suggested greater antidepressant response beyond a single ketamine. However, consensus guideline stated the lack of evidence to support frequent ketamine administration. We compared the efficacy and safety of single vs. six repeated ketamine using midazolam as active placebo. Subjects received either six ketamine or five midazolam followed by a single ketamine during 12 days followed by up to 6-month post-treatment period. The primary end point was the change from baseline in the Montgomery-Åsberg Depression Rating Scale (MADRS) score at 24 h after the last infusion. Fifty-four subjects completed all six infusions. For the primary outcome measure, there was no significant difference in change of MADRS scores between six ketamine group and single ketamine group at 24 h post-last infusion. Repeated ketamine showed greater antidepressant efficacy compared to midazolam after five infusions before receiving single ketamine infusion. Remission and response favored the six ketamine after infusion 4 and 5, respectively, compared to midazolam before receiving single ketamine infusion. For those who responded, the median time-to-relapse was nominally but not statistically different (2 and 6 weeks for the single and six ketamine group, respectively). Repeated infusions were relatively well-tolerated. Repeated ketamine showed greater antidepressant efficacy to midazolam after five infusions but fell short of significance when compared to add-on single ketamine to midazolam at the end of 2 weeks. Increasing knowledge on the mechanism of ketamine should drive future studies on the optimal balance of dosing ketamine for maximum antidepressant efficacy with minimum exposure.
Shiroma, P. R., Thuras, P., Wels, J., Albott, C. S., Erbes, C., Tye, S., & Lim, K. O. (2020). A randomized, double-blind, active placebo-controlled study of efficacy, safety, and durability of repeated vs single subanesthetic ketamine for treatment-resistant depression. Translational psychiatry10(1), 1-9., https://doi.org/10.1038/s41398-020-00897-0
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[From Adam to ecstacy; legal use of MDMA in the 1970s and 1980s]

Abstract

MDMA is currently a controversial psychedelic in the Netherlands: it is banned under the Opium Act, but widely used as a recreational drug. According to the government, the normalization of MDMA must be combated, others argue in favour of legalization. Meanwhile, in recent years psychiatry has become interested in renewed therapeutic use of MDMA.<br/> AIM: To place the current discussion of MDMA in the context of recent history. What can we learn from the way MDMA was used in America and Western Europe in the period between the (re)discovery of the drug in the 1970s and its legal prohibition in the 1980s?<br/> METHOD: Survey of the literature on the history of MDMA, and additional source research.<br/> CONCLUSION: In the period before MDMA became illegal, its use was closely linked to the pursuit of self-actualisation in therapeutic, spiritual and recreational contexts. History shows that the meaning that people attach to a psychoactive substance like MDMA is highly dependent on the context of use. Like all drugs, MDMA also has multiple functionalities and ‘framings’. The psychoactive substance cannot be reduced to one valuation or essence.
Blok, G. (2020). From Adam to ecstacy; legal use of MDMA in the 1970s and 1980s. Tijdschrift Voor Psychiatrie62(8), 702-706., https://pubmed.ncbi.nlm.nih.gov/32816299/
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Ayahuasca's 'afterglow': improved mindfulness and cognitive flexibility in ayahuasca drinkers.

Abstract

RATIONALE:
There is a growing body of evidence demonstrating the therapeutic potential of ayahuasca for treating depression and anxiety. However, the mechanisms of action involved in ayahuasca’s therapeutic effects are unclear. Mindfulness and cognitive flexibility may be two possible psychological mechanisms. Like other classic psychedelics, ayahuasca also leads to an ‘afterglow’ effect of improved subjective well-being that persists after the acute effects have subsided. This period may offer a window of increased therapeutic potential.
OBJECTIVE:
To explore changes in mindfulness and cognitive flexibility before and within 24 h after ayahuasca use.METHODS:
Forty-eight participants (54% female) were assessed on measures of mindfulness (Five Facets Mindfulness Questionnaire (FFMQ)), decentering (Experiences Questionnaire (EQ)), and cognitive flexibility (Cognitive Flexibility Scale (CFS)), and completed the Stroop and Wisconsin Picture Card Sorting Task (WPCST) before drinking ayahuasca, and again within 24 h.
RESULTS:
Mindfulness (FFMQ total scores and four of the five mindfulness facets: observe, describe, act with awareness, and non-reactivity) and decentering (EQ) significantly increased in the 24 h after ayahuasca use. Cognitive flexibility (CFS and WPCST) significantly improved in the 24 h after ayahuasca use. Changes in both mindfulness and cognitive flexibility were not influenced by prior ayahuasca use.
CONCLUSIONS:
The present study supports ayahuasca’s ability to enhance mindfulness and further reports changes in cognitive flexibility in the ‘afterglow’ period occur, suggesting both could be possible psychological mechanisms concerning the psychotherapeutic effects of ayahuasca. Given psychological gains occurred regardless of prior ayahuasca use suggests potentially therapeutic effects for both naïve and experienced ayahuasca drinkers.
Murphy-Beiner, A., & Soar, K. (2020). Ayahuasca’s ‘afterglow’: improved mindfulness and cognitive flexibility in ayahuasca drinkers. Psychopharmacology, 1-9., https://doi.org/10.1007/s00213-019-05445-3
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Psychedelics in Western culture: unnecessary psychiatrisation of visionary experiences

Abstract

Historical research about the use of psychedelics in specific religious contexts can provide rational explanations for visionary experiences that could otherwise be cause to question the mental health of religious actors. Reversely, if historians ignore or overlook empirical evidence for the use of psychedelics, the result can be that normal and even predictable reactions of healthy subjects to the effects of psychedelic substances are arbitrarily interpreted as ‘irrational’.

AIM: To describe the meaning of the psychedelic factor in historical visionary experiences.

METHOD: Discussion based on three examples of selective use of historical sources on psychedelics.

RESULTS: This theme is of broader relevance to cultural history and scientific theory because we are typically dealing with religious practices that have traditionally been categorized as ‘magic’ and thereby classified in advance as irrational and potentially pathological. The article discusses three historical examples: the so-called Mithras Liturgy from Roman Egypt, early modern witches’ ointments, and spiritual use of hashish in the nineteenth century.

CONCLUSION: Established academics often deny the significance of psychedelics in visionary experiences. Discussion of pre-Enlightenment source material appears to be of considerable importance for the correct interpretation of important religious and cultural traditions. Critical empirical source research without prejudices or implicit agendas is the appropriate method.

Hanegraaff, W. J. (2020). Psychedelics in Western culture: unnecessary psychiatrisation of visionary experiences. Tijdschrift Voor Psychiatrie62(8), 713-720.
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Meet ICPR 2020 Keynote Speaker, Wade Davis

We are pleased to announce that acclaimed anthropologist, ethnobotanist, best-selling author, and photographer, Wade Davis, will be presenting as a keynote speaker at the Interdisciplinary Conference on Psychedelic Research 2020.
Wade Davis is well-known for his work among indigenous communities around the world, more specifically those of North and South America, honing in on the traditional uses and practices surrounding psychoactive plants. 
Davis has degrees in both anthropology and biology, and received his PhD in the field of ethnobotany, completing all of his studies at Harvard University. Whilst working for the Harvard Botanical Museum, Davis spent over three years researching the plants of the Amazon and the Andes, living amongst several indigenous groups and cataloguing almost 6,000 botanical samples. 
Between 1999 and 2013, Davis served as Explorer-in-Residence at the National Geographic Society (NGS). Later he was named by the NGS as one of the ‘Explorers for the Millennium’, and subsequently has been described by David Suzuki as “a rare combination of scientist, scholar, poet and passionate defender of all of life’s diversity.
Further, Davis has published over 200 academic and popular articles on a wide range of subjects, including the Haitian practise of Vodou, the traditional use of psychoactive plants, Amazonian cosmogony and ethnobotany, and the global crisis in biodiversity. 
One River by Wade DavisOne of Davis’ most celebrated books, One River: Explorations and discoveries in the Amazon Rainforest, recounts his ethnobotanical adventures in the Colombian Amazon as a student of the famed botanical explorer Richard Evans Schultes. Schultes is often referred to as ‘the father of ethnobotany,’ and spent his life investigating how indigenous peoples used plants in medicinal, ritual, and everyday contexts, being the first man to scientifically document the visionary Amazonian brew, ayahuasca or yagé as it is called in Colombia. 
In recent years, psychedelic substances and psychoactive plant medicines have made a resurgence into public awareness and are becoming increasingly accepted as tools for psychological and spiritual healing in mainstream culture. To an extent, the heightened demand for traditional healing plants such as ayahuasca has created a booming tourist industry, taking the plant out of its traditional context.
Davis has participated in ayahuasca ceremonies with indigenous groups since his student days in the 1970s. Having spent forty years developing an understanding of how indigenous communities relate to and conceptualise the sacred Ayahuasca vine, he advocates that we should approach it with reverence whilst remaining aware of the issues surrounding its cultural appropriation.
In a recent interview, he cautioned that:

“[…] the more we can, not necessarily in a scientific, but in a serious, reverent way acknowledge this movement, remain always cognizant of the challenges of appropriation, the better. Ayahuasca is a very powerful medicine. Despite all of my experience with psychedelics going back over 40 years, I would never presume to lead an ayahuasca session. It’s probably wise to cast a cautious eye on those who do take on the mantle of spiritual leadership. Mail order mystics abound, conmen of the night.”

Going forward, this begs the question: what does the future hold for the cultural integrity of psychedelic plant sacraments? ICPR 2020 concerns itself with critical perspectives, aiming to facilitate dialogue between the diverse academic disciplines that study psychedelics, constructively exploring the future approaches to psychedelic substances. 


More about the International Conference on Psychedelic Research 2020

ICPR 2020 LogoThis is the fourth edition of the Interdisciplinary Conference on Psychedelic Research. ICPR 2020 takes place from Friday 24 to Sunday 26 April 2020 in the beautiful city of Haarlem, The Netherlands.

ICPR 2020 is an academic conference focused on high quality scientific and scholarly research into psychedelics. Many academic disciplines have important contributions to make within the field of psychedelic studies. ICPR aims to bridge and connect these disciplines, and to facilitate a dialogue between the diverse academic fields and researchers involved in the study of psychedelics.

Find out more about ICPR 2020, and buy tickets here

 

Modulation of Social Cognition via Hallucinogens and "Entactogens".

Abstract

Social cognition is a fundamental ability in human everyday lives. Deficits in social functioning also represent a core aspect of many psychiatric disorders. Yet, despite its significance, deficits in social cognition skills are insufficiently targeted by current treatments. Hallucinogens and entactogens have been shown to have the potential to modulate social processing. This article reviews the literature on the influence of hallucinogens and entactogens on social processing in controlled experimental studies in humans and elucidates the underlying neurobiological and neuropharmacological mechanisms. Furthermore, it identifies current knowledge gaps and derives implications for hallucinogen-assisted treatment approaches as well as the development of novel medication for trans-diagnostic impairments in social cognition.

Preller, K. H., & Vollenweider, F. X. (2019). Modulation of Social Cognition via Hallucinogens and “Entactogens”. Frontiers in Psychiatry10., https://doi.org/10.3389/fpsyt.2019.00881
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