OPEN Foundation

Mushrooms / Psilocybin

Lysergic Acid Diethylamide and Psilocybin Revisited

Abstract

The past decade brought the beginnings of a renaissance in research on psychedelic drugs. Two articles in this issue of Biological Psychiatry signify that the resurrection of this long-ignored topic has begun to mature and bear at least the promise of fruit. In the early 1970s, the onset of the “War on Drugs” brought with it a near-total hiatus in serious research on psychedelic drugs, especially in the United States. The resumption of credible work in this area has come from Switzerland, where many of the original pioneering studies were initiated in the 1950s and 1960s.

Geyer, M. A. (2015). Lysergic Acid Diethylamide and Psilocybin Revisited. Biological psychiatry, 78(8), 516-518. http://dx.doi.org/10.1016/j.biopsych.2015.08.003
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[Interview] Michael Bogenschutz likens psilocybin treatment to ‘reverse PTSD’

Addiction psychologist Michael P. Bogenschutz currently works at the Department of Psychiatry at NYU. Prior to New York, he worked at the Department of Psychiatry and Behavioral Sciences, University of New Mexico.

Much of Bogenschutz’s work has involved searching for new applications of existing treatments for addictions. The OPEN Foundation talked to him to learn more about his research on psilocybin-assisted treatment for alcohol dependence, the first trial of its kind.

Could you briefly describe your career, and what led you to pursue psychedelic research?

My career has focused on clinical treatment and, particularly in the last 10-15 years, clinical research on treating addictions. I have always been deeply interested in how people change and how we can facilitate change in problematic behaviours.

Working with patients, you’ll find people who will tell you they came to a point where they just quit suddenly, while some gradually become abstinent or the problem diminished over time, and others have relapse episodes for years, never improve, or get worse. There is a very real and not uncommon phenomenon of sudden and categorical change in behaviour, which is not unique to addiction. I find that interesting scientifically, psychologically and clinically. Why does this happen to some people and not to others?

I really became interested in research with psychedelics shortly after joining the faculty at the University of New Mexico (UNM) in 1994. At that time, Rick Strassman was doing work with the intravenous administration of DMT. Dr. Strassman left UNM not long afterwards and as I was a junior faculty member, it didn’t seem realistic to pursue my own research in that area. I didn’t think much about it again until I saw Roland Griffiths’ 2006 paper on the effects of psilocybin on healthy volunteers.

I was immensely impressed with both the findings and the fact that it was possible to do these kinds of studies. In that paper, the authors describe the acute effects of psilocybin in volunteers and the relatively high frequency of mystical types of experiences. More importantly, from a clinical perspective, there was a report of the persisting change in attitudes, emotional states and relationships. The follow-up paper two years later documented the persistence of these effects on the basis of a single experience with relatively high doses. I found it immensely interesting and it made sense to start investigating the clinical potential of these types of drugs myself.

Addiction obviously has a huge public health impact. Why are you interested in alcohol-related issues and treatments in particular?

I’m interested in addiction in general but for me alcohol, which is a very common, devastating addiction throughout the world, was a logical place to start. As I learned when I started investigating the topic, a considerable amount of research on the use of psychedelic treatment (mainly LSD) and alcohol had already been conducted in the late 1950s.

In the United States, the Alcoholics Anonymous (AA) philosophy is prevalent in addiction treatment. It’s a philosophy that emphasizes the spiritual component of the addiction process and the importance of becoming healthier spiritually in order to recover. This also interests me.

What are the benefits of using psilocybin over LSD in a study?

Psilocybin has two practical advantages. For one, the duration of action is significantly shorter, in the order of six hours instead of ten with LSD. This makes psilocybin easier to use in an outpatient model. In other words, you can administer it in the course of a normal workday, whereas LSD sessions could easily continue late into the evening. Another important reason is that there is much more stigma attached to LSD. Many people think of LSD as a very dangerous and frightening drug. Certainly in the 1960s, there were many adverse reactions to LSD. Much of this had to do with taking extremely high doses of a substance with unknown potency, as well as a lack of understanding at the time about how important setting was in determining an experience’s outcome. Clinically speaking, both LSD and psilocybin appear to be very safe when used under carefully controlled research conditions. Also, even though the psilocybin we administer is actually a synthetic version, people often think of the substance as “mushrooms” or a naturally occurring compound, which is reassuring to some people.

Could you generalise about what types of persons were interested in joining this trial?

We recruited from the community, using advertisements aimed specifically at people who were not engaged in treatment. We wanted this to be a stand-alone treatment. We required people to be alcohol dependent, in general good health, and not suffering from any serious psychiatric illness. In our Albuquerque study, participants were working and had some intact social structure or support. They had been alcohol-dependent for an average of 15 years, the mean age was 40, and there were six men and four women. Some had limited amounts of experience with psychedelics in the past, but we excluded those with extensive use.

One concern was that people might volunteer because they wanted a psilocybin experience. We wanted to attract those seriously interested in changing their drinking and open to the possibility of novel treatments.

Can you describe the setting you provided for your patients?

The outpatient clinic was set up to look as much as possible like a comfortable living room with a large couch. We asked participants for most of the session to wear eyeshades and headphones – there was a standard program of music – and instructions were to focus on their internal experience, to accept and explore whatever came up. We prepared them for what they might experience during sessions, what the possible range of experiences could be, and advised them to manage those experiences in order to make the most of them. We believed that setting an intention was important. In this context, the general intention might have been to use the session to learn or experience something to help them make a positive change in drinking or other issues related to drinking they wanted to explore. There was very little direct intervention. Two therapists provided support and were available to intervene when needed, otherwise they checked in every 30 minutes to an hour to make sure the participant was doing okay. At the end of that session, the participants could start talking about what they had experienced. (The volunteers received psilocybin in one or two supervised sessions; this was in addition to Motivational Enhancement Therapy and therapy sessions devoted to preparation for and debriefing from the psilocybin sessions, ed.)

In some of the initial LSD trials, the therapists’ aim was to recreate an experience akin to delirium tremens (DT), a severe withdrawal symptom sometimes experienced by alcohol-dependent patients. These DTs were often a turning point for alcoholics, and they felt LSD could have similar consequences. What they found was that some participants had mystical, transcendent experiences that affected their long-term behaviour. Could you describe how peak experiences affected the patients in your study?

On a psychological and biological level, we don’t have theories, let alone data to explain these phenomena. In the context of a person trying to address a problem and make a kind of change, what we’ve seen is that participants often have an experience of oneness, the hallmark of a mystical experience. They have a sense of unity with all of creation or the universe or God, and they also have a very powerful experience of love and connection on a deep emotional level. This includes self-love and self-compassion, that feeling of being okay. This sounds almost trivial, but for some of these folks who’ve experienced a lifetime of feeling unloved, it’s a very powerful experience. In some cases, they told us their drinking had been motivated by the lack of feeling loved or lovable, and that this experience made them feel less like they needed to drink for that reason.

Other changes accompany this kind of experience. People emerge with a sense of optimism that change is possible, that life can be different because they have experienced something that is so different from anything they could have imagined. We’ve seen people spend a lot of time during sessions thinking about family and relationships, about the grief, guilt and harm their drinking has brought to others, as well as themselves. People emerge from sessions talking about pro-social values like being a good parent or contributing to society. We’ve measured significant decreases in craving and an increase in confidence that they will be able to make a change in their drinking.

How can taking a drug once or twice cause lasting behaviour change? What evidence speaks to this question?

I don’t really have an answer. Clearly things are going on in the brain and we are beginning to conduct studies that look at brain function using MRI scans before and after the psilocybin sessions. But we can’t say yet why a single acute experience can produce such lasting changes.

The best analogy we have come up with is Post Traumatic Stress Disorder (PTSD), in which a single traumatic event can impact someone’s day-to-day experience. These traumas can be of a purely psychological nature, though they often involve physical violence as well. PTSD is an example of how an acute event can cause persistent psychological and measurable biological changes in brain function and structure. Maybe what we are seeing with psilocybin is something like the opposite of PTSD—an experience so powerfully positive it can actually make lasting impact on one’s psyche and brain.

Addiction is a misguided search for spirituality. Can you comment on this or elaborate?

Carl Jung is really the person who expanded on this idea, which was that through intoxicants people (in some limited way) were able to experience connection, unity, a sense of wellness and being loved. You can think of it as a misguided search for mystical or human connection, a way to experience a reliable emotional attachment to something external in order to receive comfort. This can be a useful way of understanding and reframing people’s struggle with addictive substances as not simply seeking hedonistic pleasure, but a genuine desire for wholeness. Though if this isn’t found in healthier ways, it can readily become a trap.

The outcome of your study seems to be very promising: all of the patients experienced a definite improvement. However it was a small sample. Do you have plans to do another clinical trial?

This was a small trial without a control group, done to demonstrate the feasibility of conducting such a study. We were able to demonstrate clinical improvement, and the degree of improvement correlated with the strength of the subject’s experience during sessions. It is suggestive and by no means conclusive or convincing evidence. We need to do much larger controlled trials. Our current trial aims to recruit 180 alcohol-dependent patients, which will provide a much more rigorous test of efficacy. This will take a few years—we estimate five—to complete the trial.

Do you think there may be obstacles other than scientific that might bring psychedelic research to a halt all over again? Or do you think it will evolve into standard practice?

We understand these drugs better scientifically than we did in the 1960s, in terms of effects, potential dangers, and how to minimise those dangers in a clinical research setting. The people doing clinical research with psychedelics now are serious, experienced scientists who approach their work cautiously and with scientific rigour. The general public also has a much better understanding of psychedelics than it did 50 years ago. We need to stay balanced in our approach and avoid extrapolating beyond the data, guard against exaggerated claims and expectations, and remind people of the significant risks that exist with these drugs when used outside of structured and controlled settings.

While I and others in the field are hopeful that what we discover will lead to important advances in addiction treatment, no drug is a magic cure. There are limitations to any treatment. Addiction is a complex, chronic disorder and you cannot cure everyone in one or two sessions, nor reduce the risks to zero. But it’s reasonable to hope that we will be able to demonstrate reproducible benefits, and learn a lot about the psychology and biology of behaviour change in the process.

Psilocybin-induced spiritual experiences and insightfulness are associated with synchronization of neuronal oscillations

Abstract

Rationale

During the last years, considerable progress has been made toward understanding the neuronal basis of consciousness by using sophisticated behavioral tasks, brain-imaging techniques, and various psychoactive drugs. Nevertheless, the neuronal mechanisms underlying some of the most intriguing states of consciousness, including spiritual experiences, remain unknown.

Objectives

To elucidate state of consciousness-related neuronal mechanisms, human subjects were given psilocybin, a naturally occurring serotonergic agonist and hallucinogen that has been used for centuries to induce spiritual experiences in religious and medical rituals.

Methods

In this double-blind, placebo-controlled study, 50 healthy human volunteers received a moderate dose of psilocybin, while high-density electroencephalogram (EEG) recordings were taken during eyes-open and eyes-closed resting states. The current source density and the lagged phase synchronization of neuronal oscillations across distributed brain regions were computed and correlated with psilocybin-induced altered states of consciousness.

Results

Psilocybin decreased the current source density of neuronal oscillations at 1.5–20 Hz within a neural network comprising the anterior and posterior cingulate cortices and the parahippocampal regions. Most intriguingly, the intensity levels of psilocybin-induced spiritual experience and insightfulness correlated with the lagged phase synchronization of delta oscillations (1.5–4 Hz) between the retrosplenial cortex, the parahippocampus, and the lateral orbitofrontal area.

Conclusions

These results provide systematic evidence for the direct association of a specific spatiotemporal neuronal mechanism with spiritual experiences and enhanced insight into life and existence. The identified mechanism may constitute a pathway for modulating mental health, as spiritual experiences can promote sustained well-being and psychological resilience.

Kometer, M., Pokorny, T., Seifritz, E., & Vollenweider, F. X. (2015). Psilocybin-induced spiritual experiences and insightfulness are associated with synchronization of neuronal oscillations. Psychopharmacology, 1-14. https://dx.doi.org/10.1007/s00213-015-4026-7

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The potential utility of some legal highs in CNS disorders

Abstract

Over the last decade there has been an explosion of new drugs of abuse, so called legal highs or novel psychoactive substances (NPS). Many of these abused drugs have unknown pharmacology, but their biological effects can be anticipated from their molecular structure and possibly also from online user reports. When considered with the findings that some prescription medications are increasingly abused and that some abused drugs have been tested clinically one could argue that there has been a blurring of the line between drugs of abuse and clinically used drugs. In this review we examine these legal highs/NPS and consider whether, based on their known or predicted pharmacology, some might have the potential to be clinically useful in CNS disorders.

Davidson, C., & Schifano, F. (2015). The potential utility of some legal highs in CNS disorders. Progress in Neuro-Psychopharmacology and Biological Psychiatry. https://dx.doi.org/10.1016/j.pnpbp.2015.07.010
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Neurovascular and neuroimaging effects of the hallucinogenic serotonin receptor agonist psilocin in the rat brain.

Abstract

The development of pharmacological magnetic resonance imaging (phMRI) has presented the opportunity for investigation of the neurophysiological effects of drugs in vivo. Psilocin, a hallucinogen metabolised from psilocybin, was recently reported to evoke brain region-specific, phMRI signal changes in humans. The present study investigated the effects of psilocin in a rat model using phMRI and then probed the relationship between neuronal and haemodynamic responses using a multimodal measurement preparation. Psilocin (2 mg/kg or 0.03 mg/kg i.v.) or vehicle was administered to rats (N = 6/group) during either phMRI scanning or concurrent imaging of cortical blood flow and recording of local field potentials. Compared to vehicle controls psilocin (2 mg/kg) evoked phMRI signal increases in a number of regions including olfactory and limbic areas and elements of the visual system. PhMRI signal decreases were seen in other regions including somatosensory and motor cortices. Investigation of neurovascular coupling revealed that whilst neuronal responses (local field potentials) to sensory stimuli were decreased in amplitude by psilocin administration, concurrently measured haemodynamic responses (cerebral blood flow) were enhanced. The present findings show that psilocin evoked region-specific changes in phMRI signals in the rat, confirming recent human data. However, the results also suggest that the haemodynamic signal changes underlying phMRI responses reflect changes in both neuronal activity and neurovascular coupling. This highlights the importance of understanding the neurovascular effects of pharmacological manipulations for interpreting haemodynamic neuroimaging data.

Spain, A., Howarth, C., Khrapitchev, A., Sharp, T., Sibson, N. R., & Martin, C. (2015). Neurovascular and neuroimaging effects of the hallucinogenic serotonin receptor agonist psilocin in the rat brain. Neuropharmacology. https://dx.doi.org/10.1016/j.neuropharm.2015.07.018
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Psychedelics and creativity: a review of the quantitative literature

Abstract

After a 40-year hiatus, the question of whether psychedelics can increase creativity is being asked with renewed vigor. This article critically reviews the conceptual issues of studying psychedelic-induced creativity by summarizing the limited evidence on the question and suggesting two broader frameworks. There are two important challenges to researchers on this topic. One is to separate creativity from other effects of the drug that may be mistaken for creativity. The second is to develop operational measures to quantify it. This article reviews the major studies assessing creativity (or related constructs) induced by psychedelics, including a reanalysis of raw data from one study. Results are modest and inconclusive but are consistent with reports that psychedelics give rise to unusual or novel thoughts. Given the lack of robust changes in creativity measures, I suggest creativity may be too specific of a construct to accurately and fully characterize the putatively beneficial cognitive changes that psychedelic users report. Feelings of creativity may be an inconsistent result of a more general effect of these drugs, such as alterations in availability of mental representations or changes in Bayesian inference. Ultimately, creativity may not be a sufficiently creative construct to capture the beneficial effects of psychedelics.

Baggott, M. J. (2015). Psychedelics and creativity: a review of the quantitative literature. PeerJ PrePrints, 3, e1468. https://dx.doi.org/10.7287/peerj.preprints.1202v1
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Restructuring consciousness -the psychedelic state in light of integrated information theory

Abstract

The psychological state elicited by the classic psychedelics drugs, such as LSD and psilocybin, is one of the most fascinating and yet least understood states of consciousness. However, with the advent of modern functional neuroimaging techniques, the effect of these drugs on neural activity is now being revealed, although many of the varied phenomenological features of the psychedelic state remain challenging to explain. Integrated information theory (IIT) is one of the foremost contemporary theories of consciousness, providing a mathematical formalization of both the quantity and quality of conscious experience. This theory can be applied to all known states of consciousness, including the psychedelic state. Using the results of functional neuroimaging data on the psychedelic state, the effects of psychedelic drugs on both the level and structure of consciousness can be explained in terms of the conceptual framework of IIT. This new IIT-based model of the psychedelic state provides an explanation for many of its phenomenological features, including unconstrained cognition, alterations in the structure and meaning of concepts and a sense of expanded awareness. This model also suggests that whilst cognitive flexibility, creativity, and imagination are enhanced during the psychedelic state, this occurs at the expense of cause-effect information, as well as degrading the brain’s ability to organize, categorize, and differentiate the constituents of conscious experience. Furthermore, the model generates specific predictions that can be tested using a combination of functional imaging techniques, as has been applied to the study of levels of consciousness during anesthesia and following brain injury.

Gallimore, A. R. (2015). Restructuring Consciousness–the Psychedelic State in Light of Integrated Information Theory. Name: Frontiers in Human Neuroscience, 9, 346. https://dx.doi.org/10.3389/fnhum.2015.00346
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Psychedelic drugs should be legally reclassified so that researchers can investigate their therapeutic potential

Abstract

Trials of physiologically safe and non-addictive drugs such as LSD are almost impossible, writes James J H Rucker, calling on the authorities to downgrade their unnecessarily restrictive class A, schedule 1 classification.

Rucker, J. J. (2015). Psychedelic drugs should be legally reclassified so that researchers can investigate their therapeutic potential. BMJ, 350, h2902. http://dx.doi.org/10.1136/bmj.h2902
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Finding the self by losing the self: Neural correlates of ego-dissolution under psilocybin

Abstract

Ego-disturbances have been a topic in schizophrenia research since the earliest clinical descriptions of the disorder. Manifesting as a feeling that one’s “self,” “ego,” or “I” is disintegrating or that the border between one’s self and the external world is dissolving, “ego-disintegration” or “dissolution” is also an important feature of the psychedelic experience, such as is produced by psilocybin (a compound found in “magic mushrooms”). Fifteen healthy subjects took part in this placebo-controlled study. Twelve-minute functional MRI scans were acquired on two occasions: subjects received an intravenous infusion of saline on one occasion (placebo) and 2 mg psilocybin on the other. Twenty-two visual analogue scale ratings were completed soon after scanning and the first principal component of these, dominated by items referring to “ego-dissolution”, was used as a primary measure of interest in subsequent analyses. Employing methods of connectivity analysis and graph theory, an association was found between psilocybin-induced ego-dissolution and decreased functional connectivity between the medial temporal lobe and high-level cortical regions. Ego-dissolution was also associated with a “disintegration” of the salience network and reduced interhemispheric communication. Addressing baseline brain dynamics as a predictor of drug-response, individuals with lower diversity of executive network nodes were more likely to experience ego-dissolution under psilocybin. These results implicate MTL-cortical decoupling, decreased salience network integrity, and reduced inter-hemispheric communication in psilocybin-induced ego disturbance and suggest that the maintenance of “self”or “ego,” as a perceptual phenomenon, may rest on the normal functioning of these systems.

Lebedev, A. V., Lövdén, M., Rosenthal, G., Feilding, A., Nutt, D. J., & Carhart‐Harris, R. L. (2015). Finding the self by losing the self: Neural correlates of ego‐dissolution under psilocybin. Human brain mapping. https://dx.doi.org/10.1002/hbm.22833
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The use of illicit drugs as self-medication in the treatment of cluster headache: Results from an Italian online survey

Abstract

BACKGROUND:

Cluster headache (CH) patients often receive unsatisfactory treatment and may explore illicit substances as alternatives. We aimed to explore this use of illicit drugs for CH treatment.

METHODS:

We invited CH patients from an Internet-based self-help group to complete a questionnaire regarding their therapeutic use of illicit substances.

RESULTS:

Of the 54 respondents, 29 were classified as chronic and 39 were drug-resistant cases. Fifty patients had previously tried subcutaneous sumatriptan, 40 had tried O2, and 48 had tried at least one prophylactic treatment. All 54 patients specified that they were dissatisfied with conventional treatments. Thirty-four patients had used cannabinoids, 13 cocaine, 8 heroin, 18 psilocybin, 12 lysergic acid amide (LSA), and 4 lysergic acid diethylamide (LSD).

DISCUSSION:

Some patients with intractable CH decided to try illicit drugs concomitantly with cessation of medical care. Most of these patients found suggestions for illicit drug use on the Internet. Many patients seemed to underestimate the judicial consequences of, and had an overestimated confidence in the safety of, such illicit treatments. Physicians are often not informed by patients of their choice to use illicit drugs. This leads to questions regarding the true nature of the physician-patient relationship among dissatisfied CH patients.

Di Lorenzo, C., Coppola, G., Di Lorenzo, G., Bracaglia, M., Rossi, P., & Pierelli, F. (2015). The use of illicit drugs as self-medication in the treatment of cluster headache: Results from an Italian online survey. Cephalalgia. https://dx.doi.org/10.1177/0333102415583145
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