Recommended Readings 1

for Psychedelic Novices 

 

This list was made by Jagoda Mackowiak in cooperation, and co-published, with Blossom

 

If you’re a student, researcher, or otherwise interested in psychedelic research, we have selected 10 publications for you to begin with.

These papers will give you a solid foundation to start your psychedelic research journey. You will gain an overview of the stateoftheart of psychedelic research, the history of psychedelic exploration, the many applications of psychedelic substances ivarious research fields, and most importantly, their therapeutic potential. 

In order to keep up with the growing popularity of psychedelic research, we will walk you through our current understanding of the pharmacology of psychedelics in the brain, their acute and long-term effects on human psyche, and finally, of their promise of mental health improvement. Alongside with the research findings, you will also get to know the most important players of today’s psychedelic research. 

Although targeted for beginners and newcomers, our selection features articles diving deep into the science of psychedelics, which is a crossroad between multiple disciplines; not only neuroscience and psychology, but also philosophy, social sciences and chemistry. This briefing, in combination with our Drug Science Program and uniMIND discussion groups, will make you well equipped to continue your psychedelic exploration. 

The quickest overview of psychedelic research has been published by Robin Carhart-Harris, who has been the icebreaker of psychedelic research for more than a decade. In ‘How do psychedelics work?’ (2019) he summarizes multiple levels of research developments, as well as future perspectives. A must-read for everyone!

Carhart-Harris, R. L. (2018). How do psychedelics work? Current Opinion in Psychiatry, 32(1):16-21.

Purpose of review

Psychedelics are reawakening interest from psychiatry, cognitive neuroscience and the general public with impressive outcomes in small-scale clinical trials, intriguing human brain imaging work and high-impact journalism.

Recent findings

This brief opinion piece offers a perspective on how psychedelics work in the brain that may help contextualize these developments. It attempts to link various scales of action, from the molecular (serotonin 2A receptor agonism) through to the anatomical and functional (heightened plasticity) and up to the dynamic (increased brain entropy), systems level (network disintegration and desegregation) and experiential.

Summary

It is proposed that psychedelics initiate a cascade of neurobiological changes that manifest at multiple scales and ultimately culminate in the relaxation of high-level beliefs. The purpose of psychedelic therapy is to harness the opportunity afforded by this belief-relaxation to achieve a healthy revision of pathological beliefs.

In September 2020, Franz X. Vollenweider and Katrin H. Preller published a comprehensive, yet accessible review of the mechanisms of action of psychedelic drugs in the brain. Together they developed a stunning visual representation of the effects of psychedelic drugs on brain circuits. ‘Psychedelic drugs: neurobiology and potential for treatment of psychiatric disorders‘ summarizes several decades of discoveries in psychedelic research.

Vollenweider, F. X. and Preller, K. H. (2020). Psychedelic drugs: neurobiology and potential for treatment of psychiatric disorders. Nature Reviews Neuroscience, 21:611-624

Renewed interest in the use of psychedelics in the treatment of psychiatric disorders warrants a better understanding of the neurobiological mechanisms underlying the effects of these substances. After a hiatus of about 50 years, state-of-the art studies have recently begun to close important knowledge gaps by elucidating the mechanisms of action of psychedelics with regard to their effects on receptor subsystems, systems-level brain activity and connectivity, and cognitive and emotional processing. In addition, functional studies have shown that changes in self-experience, emotional processing and social cognition may contribute to the potential therapeutic effects of psychedelics. These discoveries provide a scientific road map for the investigation and application of psychedelic substances in psychiatry.

If the previous article left you craving for more neuroscience research, you should reach out to another article by Robin Carhart-Harris, written in collaboration with Karl J. Friston. ‘REBUS and the Anarchic Brain: Toward a Unified Model of the Brain Action of Psychedelics’ proposes a model named ‘Relaxed Beliefs Under Psychedelics (REBUS) that investigates how a high amount of bottom-up information is incorporated when the brain is influenced by psychedelics.

For more on this topic, check out this MIND Blog post by Andy Meijer.

Carhart-Harris, R. L. and Friston K. J. (2019) REBUS and the Anarchic Brain: Toward a Unified Model of the Brain Action of Psychedelics
Pharmacological Reviews, 71(3):316-344

This paper formulates the action of psychedelics by integrating the free-energy principle and entropic brain hypothesis. We call this formulation relaxed beliefs under psychedelics (REBUS) and the anarchic brain, founded on the principle that—via their entropic effect on spontaneous cortical activity—psychedelics work to relax the precision of high-level priors or beliefs, thereby liberating bottom-up information flow, particularly via intrinsic sources such as the limbic system. We assemble evidence for this model and show how it can explain a broad range of phenomena associated with the psychedelic experience. With regard to their potential therapeutic use, we propose that psychedelics work to relax the precision weighting of pathologically overweighted priors underpinning various expressions of mental illness. We propose that this process entails an increased sensitization of high-level priors to bottom-up signaling (stemming from intrinsic sources), and that this heightened sensitivity enables the potential revision and deweighting of overweighted priors. We end by discussing further implications of the model, such as that psychedelics can bring about the revision of other heavily weighted high-level priors, not directly related to mental health, such as those underlying partisan and/or overly-confident political, religious, and/or philosophical perspectives.

A review by Link R. Swanson (2018) looks further back at ‘Unifying Theories of Psychedelic Drug Effects.’ In his article, Swanson discusses over a century of psychedelic research theories, including key concepts from Freud to modern predictive processing. The article suggests that the common denominator among theories is the fact that default brain processes are disturbed, thus leading to more unconstrained thought flow under the influence of psychedelics.

Swanson, L. R. (2018) Unifying theories of psychedelic drug effects. Frontiers in Pharmacology, 9:172

How do psychedelic drugs produce their characteristic range of acute effects in perception, emotion, cognition, and sense of self? How do these effects relate to the clinical efficacy of psychedelic-assisted therapies? Efforts to understand psychedelic phenomena date back more than a century in Western science. In this article I review theories of psychedelic drug effects and highlight key concepts which have endured over the last 125 years of psychedelic science. First, I describe the subjective phenomenology of acute psychedelic effects using the best available data. Next, I review late 19th-century and early 20th-century theories—model psychoses theory, filtration theory, and psychoanalytic theory—and highlight their shared features. I then briefly review recent findings on the neuropharmacology and neurophysiology of psychedelic drugs in humans. Finally, I describe recent theories of psychedelic drug effects which leverage 21st-century cognitive neuroscience frameworks—entropic brain theory, integrated information theory, and predictive processing—and point out key shared features that link back to earlier theories. I identify an abstract principle which cuts across many theories past and present: psychedelic drugs perturb universal brain processes that normally serve to constrain neural systems central to perception, emotion, cognition, and sense of self. I conclude that making an explicit effort to investigate the principles and mechanisms of psychedelic drug effects is a uniquely powerful way to iteratively develop and test unifying theories of brain function.

Keywords: psychedelic drugs, LSD, psilocybin, ego dissolution, cognitive flexibility, entropic brain theory, integrated information theory, predictive processing

Psychedelics. (2016)                                                                                                                

After more than 300 publications dating back to 1969, David Nichols, who is also a founder of Heffter Research Institute and the originator of the term ‘entactogen,’ published an updated version of his extensive compendium of the chemistry of psychedelic substances. ‘Psychedelics (2016) is a near 100-page summary of the research on the serotonergic system, explaining how serotonergic hallucinogens affect the 5-hydroxytryptamine (serotonin) 2A receptors and what that means for patients and therapists.

Nichols, D. E. (2016) Psychedelics. Pharmacological Reviews, 68(2):264-355

Psychedelics (serotonergic hallucinogens) are powerful psychoactive substances that alter perception and mood and affect numerous cognitive processes. They are generally considered physiologically safe and do not lead to dependence or addiction. Their origin predates written history, and they were employed by early cultures in many sociocultural and ritual contexts. After the virtually contemporaneous discovery of (5R,8R)-(+)-lysergic acid-N,N-diethylamide (LSD)-25 and the identification of serotonin in the brain, early research focused intensively on the possibility that LSD and other psychedelics had a serotonergic basis for their action. Today there is a consensus that psychedelics are agonists or partial agonists at brain serotonin 5-hydroxytryptamine 2A receptors, with particular importance on those expressed on apical dendrites of neocortical pyramidal cells in layer V. Several useful rodent models have been developed over the years to help unravel the neurochemical correlates of serotonin 5-hydroxytryptamine 2A receptor activation in the brain, and a variety of imaging techniques have been employed to identify key brain areas that are directly affected by psychedelics. Recent and exciting developments in the field have occurred in clinical research, where several double-blind placebo-controlled phase 2 studies of psilocybin-assisted psychotherapy in patients with cancer-related psychosocial distress have demonstrated unprecedented positive relief of anxiety and depression. Two small pilot studies of psilocybin-assisted psychotherapy also have shown positive benefit in treating both alcohol and nicotine addiction. Recently, blood oxygen level–dependent functional magnetic resonance imaging and magnetoencephalography have been employed for in vivo brain imaging in humans after administration of a psychedelic, and results indicate that intravenously administered psilocybin and LSD produce decreases in oscillatory power in areas of the brain’s default mode network.

Since the molecular grounds of psychedelic active principles is just one of the dimensions of the research on psychedelics, researchers from Johns Hopkins University School of Medicine led by Roland Griffiths aimed at compiling our hitherto knowledge of subjective psychedelic experience. ‘Classic psychedelics: An integrative review of epidemiology, therapeutics, mystical experience, and brain network function’ (Johnson et al. 2019) gathers reflections on the therapeutic effects of psychedelic substances, while revising various types of research methods throughout history.

Johnson, M. W., Hendricks, P. S., Barrett, F. S., and Griffiths, R. R. (2018) Classic Psychedelics: An integrative review of epidemiology, mystical experience, brain network function, and therapeutics. Pharmacology & Therapeutics, 197:83-102

The purpose of this paper is to provide an integrative review and offer novel insights regarding human research with classic psychedelics (classic hallucinogens), which are serotonin 2A receptor (5-HT2AR) agonists such as lysergic acid diethylamide (LSD), mescaline, and psilocybin. Classic psychedelics have been administered as sacraments since ancient times. They were of prominent interest within psychiatry and neuroscience in the 1950s to 1960s, and during this time contributed to the emergence of the field of molecular neuroscience. Promising results were reported for treatment of both end-of-life psychological distress and addiction, and classic psychedelics served as tools for studying the neurobiological bases of psychological disorders. Moreover, classic psychedelics were shown to occasion mystical experiences, which are subjective experiences reported throughout different cultures and religions involving a strong sense of unity, among other characteristics. However, the recreational use of classic psychedelics and their association with the counterculture prompted an end to human research with classic psychedelics in the early 1970s. We provide the most comprehensive review of epidemiological studies of classic psychedelics to date. Notable among these are a number of studies that have suggested the possibility that nonmedical naturalistic (non-laboratory) use of classic psychedelics is associated with positive mental health and prosocial outcomes, although it is clear that some individuals are harmed by classic psychedelics in non-supervised settings. We then review recent therapeutic studies suggesting efficacy in treating psychological distress associated with life-threatening diseases, treating depression, and treating nicotine and alcohol addictions. We also describe the construct of mystical experience, and provide a comprehensive review of modern studies investigating classic psychedelic-occasioned mystical experiences and their consequences. These studies have shown classic psychedelics to fairly reliably occasion mystical experiences. Moreover, classic-psychedelic-occasioned mystical experiences are associated with improved psychological outcomes in both healthy volunteer and patient populations. Finally, we review neuroimaging studies that suggest neurobiological mechanisms of classic psychedelics. These studies have also broadened our understanding of the brain, the serotonin system, and the neurobiological basis of consciousness. Overall, these various lines of research suggest that classic psychedelics might hold strong potential as therapeutics, and as tools for experimentally investigating mystical experiences and behavioral-brain function more generally.

Robin Carhart-Harris, together with Guy M. Goodwin, investigates challenges (e.g., the subjectivity of effects) and promises (e.g., the large positive outcomes) of psychedelic-assisted therapyIn ‘The Therapeutic Potential of Psychedelic Drugs: Past, Present, and Future‘ (2017), the two researchers discuss the steady revival of human psychedelic research’ and share their opinions on the perspective of psilocybin-assisted therapy becoming one of the mainstream depression treatment methods.

Carhart-Harris, R. L. and Goodwin, G. M. (2017) The Therapeutic Potential of Psychedelic Drugs: Past, Present, and Future. Neuropsychopharmacology, 42(11):2105-2113

Plant-based psychedelics, such as psilocybin, have an ancient history of medicinal use. After the first English language report on LSD in 1950, psychedelics enjoyed a short-lived relationship with psychology and psychiatry. Used most notably as aids to psychotherapy for the treatment of mood disorders and alcohol dependence, drugs such as LSD showed initial therapeutic promise before prohibitive legislature in the mid-1960s effectively ended all major psychedelic research programs. Since the early 1990s, there has been a steady revival of human psychedelic research: last year saw reports on the first modern brain imaging study with LSD and three separate clinical trials of psilocybin for depressive symptoms. In this circumspective piece, RLC-H and GMG share their opinions on the promises and pitfalls of renewed psychedelic research, with a focus on the development of psilocybin as a treatment for depression.

The therapeutic action of psychedelic substances is mediated by subjective experiences, such as ‘peak-experiences’ (mystical experience) or ‘afterglow’ phenomena. Tomislav Majić together with colleagues Timo Schmidt and Jürgen Gallinat investigate how the subjective effects of psychedelics influence their therapeutic effects in ‘Peak experiences and the afterglow phenomenon: When and how do therapeutic effects of hallucinogens depend on psychedelic experiences?‘ (2015) 

Majić, T., Schmidt, T. T., and Gallinat, J. (2015). Peak experiences and the afterglow phenomenon: When and how do therapeutic effects of hallucinogens depend on psychedelic experiences? Journal of Psychopharmacology, 29(3):241-253

Interest in the therapeutic potential of psychedelic substances has recently resumed. During an early phase of human psychedelic research, their therapeutic application in different pathologies had been suggested, and the first evidence for efficacy was provided. The range of recent clinical applications of psychedelics spans from cluster headaches and obsessive-compulsive disorder to addiction and the treatment of fear and anxiety in patients suffering from terminal illness, indicating potentially different therapeutic mechanisms. A variety of approaches in psychotherapy emphasize subjective experiences, such as so-called peak experiences or afterglow phenomena, as differentially mediating therapeutic action. This review aims to re-evaluate earlier and recent concepts of how psychedelic substances may exert beneficial effects. After a short outline of neurophenomenological aspects, we discuss different approaches to how psychedelics are used in psychotherapy. Finally, we summarize evidence for the relationship between subjective experiences and therapeutic success. While the distinction between pharmacological and psychological action obviously cannot be clear-cut, they do appear to contribute differently from each other when their effects are compared with regard to pathologies.

So far, we recommended reviews discussing large pieces of the psychedelic puzzle. It is worth mentioning, however, that double-blind, placebo-controlled clinical trials are also integral to the understanding of psychedelic research development. Luoma and colleagues (2020) performed ‘A Meta-Analysis of Placebo-Controlled Trials of Psychedelic-Assisted Therapy.’ This cooperation between several labs resulted in a detailed comparison of psychedelic-assisted therapy trials published since 1994. The authors’ analysis suggests that psychedelic-assisted therapy is effective in all four investigated mental health conditions.

Luoma, J. B., Chwyl, C., Bathje, G. J., Davis, A.K. and Lancelotta, R. (2020) A Meta-Analysis of Placebo-Controlled Trials of Psychedelic-Assisted Therapy, Journal of Psychoactive Drugs, 52(4):289-299

After a two-decade hiatus in which research on psychedelics was essentially halted, placebo-controlled clinical trials of psychedelic-assisted therapy for mental health conditions have begun to be published. We identified nine randomized, placebo-controlled clinical trials of psychedelic-assisted therapy published since 1994. Studies examined psilocybin, LSD (lysergic acid diethylamide), ayahuasca (which contains a combination of N,N-dimethyltryptamine and harmala monoamine oxidase inhibitor alkaloids), and MDMA (3,4-methylenedioxymethamphetamine). We compared the standardized mean difference between the experimental and placebo control group at the primary endpoint. Results indicated a significant mean between-groups effect size of 1.21 (Hedges g), which is larger than the typical effect size found in trials of psychopharmacological or psychotherapy interventions. For the three studies that maintained a placebo control through a follow-up assessment, effects were generally maintained at follow-up. Overall, analyses support the efficacy of psychedelic-assisted therapy across four mental health conditions – post-traumatic stress disorder, anxiety/depression associated with a life-threatening illness, unipolar depression, and social anxiety among autistic adults. While study quality was high, we identify several areas for improvement regarding the conduct and reporting of trials. Larger trials with more diverse samples are needed to examine possible moderators and mediators of effects, and to establish whether effects are maintained over time.

Last but not least, we would like to recommend an article discussing microdosing, which is a practice of administration of sub-therapeutic doses of psychedelic substances, with the hope of improving mood, concentration, and creativity among healthy subjects. This practice receives a lot of hype lately, however, there is still no sufficient proof of its benefits. ‘A systematic study of microdosing psychedelics’ performed by Vince Polito and Richard J. Stevenson in 2019, analyses two trials examining the perceived well-being effects of microdosing.

Polito, V. and Stevenson, R. J. (2019) A systematic study of microdosing psychedelics. PLoS ONE 14(2):e0211023

The phenomenon of ‘microdosing’, that is, regular ingestion of very small quantities of psychedelic substances, has seen a rapid explosion of popularity in recent years. Individuals who microdose report minimal acute effects from these substances yet claim a range of long-term general health and wellbeing benefits. There have been no published empirical studies of microdosing and the current legal and bureaucratic climate makes direct empirical investigation of the effects of psychedelics difficult. In Study One we conducted a systematic, observational investigation of individuals who microdose. We tracked the experiences of 98 microdosing participants, who provided daily ratings of psychological functioning over a six week period. 63 of these additionally completed a battery of psychometric measures tapping mood, attention, wellbeing, mystical experiences, personality, creativity, and sense of agency, at baseline and at completion of the study. Analyses of daily ratings revealed a general increase in reported psychological functioning across all measures on dosing days but limited evidence of residual effects on following days. Analyses of pre and post study measures revealed reductions in reported levels of depression and stress; lower levels of distractibility; increased absorption; and increased neuroticism. To better understand these findings, in Study Two we investigated pre-existing beliefs and expectations about the effects of microdosing in a sample of 263 naïve and experienced microdosers, so as to gauge expectancy bias. All participants believed that microdosing would have large and wide-ranging benefits in contrast to the limited outcomes reported by actual microdosers. Notably, the effects believed most likely to change were unrelated to the observed pattern of reported outcomes. The current results suggest that dose controlled empirical research on the impacts of microdosing on mental health and attentional capabilities are needed.