OPEN Foundation

T. Williams

First study of safety and tolerability of 3,4-methylenedioxymethamphetamine-assisted psychotherapy in patients with alcohol use disorder

February 6, 2022 / Addiction, MDMA, Papers, Psychopharmacology, Psychotherapy, Safety / Leave a Comment / By / , , , , , , , , , , , , ,

Abstract

Background: 3,4-methylenedioxymethamphetamine (MDMA) therapy has qualities that make it potentially well suited for patients with addictions, but this has never been explored in a research study. We present data from the Bristol Imperial MDMA in Alcoholism (BIMA) study. This is the first MDMA addiction study, an open-label safety and tolerability proof-of-concept study investigating the potential role for MDMA therapy in treating patients with alcohol use disorder (AUD).

Aims: This study aimed to assess if MDMA-assisted psychotherapy can be delivered safely and can be tolerated by patients with AUD post detoxification. Outcomes regarding drinking behaviour, quality of life and psychosocial functioning were evaluated.

Methods: Fourteen patients with AUD completed a community alcohol detoxification and received an eight-week course of recovery-based therapy. Participants received two sessions with MDMA (187.5 mg each session). Psychological support was provided before, during and after each session. Safety and tolerability were assessed alongside psychological and physiological outcome measures. Alcohol use behaviour, mental well-being and functioning data were collected for nine months after alcohol detoxification.

Results: MDMA treatment was well tolerated by all participants. No unexpected adverse events were observed. Psychosocial functioning improved across the cohort. Regarding alcohol use, at nine months post detox, the average units of alcohol consumption by participants was 18.7 units per week compared to 130.6 units per week before the detox. This compares favourably to a previous observational study (the ‘Outcomes’ study) by the same team with a similar population of people with AUD.

Conclusions: This study provides preliminary support for the safety and tolerability of a novel intervention for AUD post detox. Further trials to examine better the therapeutic potential of this approach are now indicated.

Sessa, B., Higbed, L., O’Brien, S., Durant, C., Sakal, C., Titheradge, D., Williams, T. M., Rose-Morris, A., Brew-Girard, E., Burrows, S., Wiseman, C., Wilson, S., Rickard, J., & Nutt, D. J. (2021). First study of safety and tolerability of 3,4-methylenedioxymethamphetamine-assisted psychotherapy in patients with alcohol use disorder. Journal of psychopharmacology (Oxford, England), 35(4), 375–383. https://doi.org/10.1177/0269881121991792

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The paradoxical psychological effects of lysergic acid diethylamide (LSD).

February 5, 2016 / Consciousness, LSD, Other subjects, Papers, Personality, Psychiatry, Psychology, Publications / By / , , , , ,

Abstract

BACKGROUND: Lysergic acid diethylamide (LSD) is a potent serotonergic hallucinogen or psychedelic that modulates consciousness in a marked and novel way. This study sought to examine the acute and mid-term psychological effects of LSD in a controlled study.

METHOD: A total of 20 healthy volunteers participated in this within-subjects study. Participants received LSD (75 µg, intravenously) on one occasion and placebo (saline, intravenously) on another, in a balanced order, with at least 2 weeks separating sessions. Acute subjective effects were measured using the Altered States of Consciousness questionnaire and the Psychotomimetic States Inventory (PSI). A measure of optimism (the Revised Life Orientation Test), the Revised NEO Personality Inventory, and the Peter’s Delusions Inventory were issued at baseline and 2 weeks after each session.

RESULTS: LSD produced robust psychological effects; including heightened mood but also high scores on the PSI, an index of psychosis-like symptoms. Increased optimism and trait openness were observed 2 weeks after LSD (and not placebo) and there were no changes in delusional thinking.

CONCLUSIONS: The present findings reinforce the view that psychedelics elicit psychosis-like symptoms acutely yet improve psychological wellbeing in the mid to long term. It is proposed that acute alterations in mood are secondary to a more fundamental modulation in the quality of cognition, and that increased cognitive flexibility subsequent to serotonin 2A receptor (5-HT2AR) stimulation promotes emotional lability during intoxication and leaves a residue of ‘loosened cognition’ in the mid to long term that is conducive to improved psychological wellbeing.

Carhart-Harris, R. L., Kaelen, M., Bolstridge, M., Williams, T. M., Williams, L. T., Underwood, R., … & Nutt, D. J. (2016). The paradoxical psychological effects of lysergic acid diethylamide (LSD). Psychological medicine, 1-12. http://dx.doi.org/10.1017/S0033291715002901

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Broadband cortical desynchronization underlies the human psychedelic state

September 18, 2013 / Mushrooms / Psilocybin, Neuroscience, Other subjects, Papers, Psychopharmacology, Publications / By / , , , , , ,

Abstract

Psychedelic drugs produce profound changes in consciousness, but the underlying neurobiological mechanisms for this remain unclear. Spontaneous and induced oscillatory activity was recorded in healthy human participants with magnetoencephalography after intravenous infusion of psilocybin—prodrug of the nonselective serotonin 2A receptor agonist and classic psychedelic psilocin. Psilocybin reduced spontaneous cortical oscillatory power from 1 to 50 Hz in posterior association cortices, and from 8 to 100 Hz in frontal association cortices. Large decreases in oscillatory power were seen in areas of the default-mode network. Independent component analysis was used to identify a number of resting-state networks, and activity in these was similarly decreased after psilocybin. Psilocybin had no effect on low-level visually induced and motor-induced gamma-band oscillations, suggesting that some basic elements of oscillatory brain activity are relatively preserved during the psychedelic experience. Dynamic causal modeling revealed that posterior cingulate cortex desynchronization can be explained by increased excitability of deep-layer pyramidal neurons, which are known to be rich in 5-HT2A receptors. These findings suggest that the subjective effects of psychedelics result from a desynchronization of ongoing oscillatory rhythms in the cortex, likely triggered by 5-HT2A receptor-mediated excitation of deep pyramidal cells.

Muthukumaraswamy, S. D., Carhart-Harris, R. L., Moran, R. J., Brookes, M. J., Williams, T. M., Errtizoe, D., … & Feilding, A. (2013). Broadband cortical desynchronization underlies the human psychedelic state. The Journal of Neuroscience, 33(38), 15171-15183. 10.1523/JNEUROSCI.2063-13.2013
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Functional Connectivity Measures After Psilocybin Inform a Novel Hypothesis of Early Psychosis

October 8, 2012 / Mushrooms / Psilocybin, Neuroscience, Papers, Psychiatry, Psychology, Psychosis, Publications / By / , , , , , ,

Abstract

Psilocybin is a classic psychedelic and a candidate drug model of psychosis. This study measured the effects of psilocybin on resting-state network and thalamocortical functional connectivity (FC) using functional magnetic resonance imaging (fMRI). Fifteen healthy volunteers received intravenous infusions of psilocybin and placebo in 2 task-free resting-state scans. Primary analyses focused on changes in FC between the default-mode- (DMN) and task-positive network (TPN). Spontaneous activity in the DMN is orthogonal to spontaneous activity in the TPN, and it is well known that these networks support very differ -ent functions (ie, the DMN supports introspection, whereas the TPN supports externally focused attention). Here, inde -pendent components and seed-based FC analyses revealed increased DMN-TPN FC and so decreased DMN-TPN orthogonality after psilocybin. Increased DMN-TPN FC has been found in psychosis and meditatory states, which share some phenomenological similarities with the psy -chedelic state. Increased DMN-TPN FC has also been observed in sedation, as has decreased thalamocortical FC, but here we found preserved thalamocortical FC after psi -locybin. Thus, we propose that thalamocortical FC may be related to arousal, whereas DMN-TPN FC is related to the separateness of internally and externally focused states. We suggest that this orthogonality is compromised in early psychosis, explaining similarities between its phenomenol -ogy and that of the psychedelic state and supporting the utility of psilocybin as a model of early psychosis.

Carhart-Harris, R. L., Leech, R., Erritzoe, D., Williams, T. M.,  Stone, J. M.,  Evans, J., …. Nutt, D. J. (2012). Functional Connectivity Measures After Psilocybin Inform a Novel Hypothesis of Early Psychosis. Schizophrenia Bulletin, 39(6), 1343-1351. http://dx.doi.org/10.1093/schbul/sbs117
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Implications for psychedelic-assisted psychotherapy: Functional magnetic resonance imaging study with psilocybin

March 1, 2012 / Mushrooms / Psilocybin, Papers, Psychiatry, Psychology, Psychotherapy, Publications / By / , , , , , ,

Abstract

Background: Psilocybin is a classic psychedelic drug that has a history of use in psychotherapy. One of the rationales for its use was that it aids emotional insight by lowering psychological defences.

Aims: To test the hypothesis that psilocybin facilitates access to personal memories and emotions by comparing subjective and neural responses to positive autobiographical memories under psilocybin and placebo.

Method: Ten healthy participants received two functional magnetic resonance imaging scans (2 mg intravenous psilocybin v. intravenous saline), separated by approximately 7 days, during which they viewed two different sets of 15 positive autobiographical memory cues. Participants viewed each cue for 6 s and then closed their eyes for 16 s and imagined re-experiencing the event. Activations during this recollection period were compared with an equivalent period of eyes-closed rest. We split the recollection period into an early phase (first 8 s) and a late phase (last 8 s) for analysis.

Results: Robust activations to the memories were seen in limbic and striatal regions in the early phase and the medial prefrontal cortex in the late phase in both conditions (P<0.001, whole brain cluster correction), but there were additional visual and other sensory cortical activations in the late phase under psilocybin that were absent under placebo. Ratings of memory vividness and visual imagery were significantly higher after psilocybin (P<0.05) and there was a significant positive correlation between vividness and subjective well-being at follow-up (P<0.01).

Conclusions: Evidence that psilocybin enhances autobiographical recollection implies that it may be useful in psychotherapy either as a tool to facilitate the recall of salient memories or to reverse negative cognitive biases.

Carhart-Harris, R. L., Leech, R., Williams, T. M., Erritzoe, D., Abbasi, N., Bargiotas, T., … & Wise, R. G. (2012). Implications for psychedelic-assisted psychotherapy: functional magnetic resonance imaging study with psilocybin. The British Journal of Psychiatry, 200(3), 238-244. http://dx.doi.org/10.1192/bjp.bp.111.103309
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Neural correlates of the psychedelic state as determined by fMRI studies with psilocybin

January 29, 2012 / Mushrooms / Psilocybin, Neuroscience, Other subjects, Papers, Psychology, Publications / By / , , , , , ,

Abstract

Psychedelic drugs have a long history of use in healing ceremonies, but despite renewed interest in their therapeutic potential, we continue to know very little about how they work in the brain. Here we used psilocybin, a classic psychedelic found in magic mushrooms, and a task-free functional MRI (fMRI) protocol designed to capture the transition from normal waking consciousness to the psychedelic state. Arterial spin labeling perfusion and blood-oxygen level-dependent (BOLD) fMRI were used to map cerebral blood flow and changes in venous oxygenation before and after intravenous infusions of placebo and psilocybin. Fifteen healthy volunteers were scanned with arterial spin labeling and a separate 15 with BOLD. As predicted, profound changes in consciousness were observed after psilocybin, but surprisingly, only decreases in cerebral blood flow and BOLD signal were seen, and these were maximal in hub regions, such as the thalamus and anterior and posterior cingulate cortex (ACC and PCC). Decreased activity in the ACC/medial prefrontal cortex (mPFC) was a consistent finding and the magnitude of this decrease predicted the intensity of the subjective effects. Based on these results, a seed-based pharmaco-physiological interaction/functional connectivity analysis was performed using a medial prefrontal seed. Psilocybin caused a significant decrease in the positive coupling between the mPFC and PCC. These results strongly imply that the subjective effects of psychedelic drugs are caused by decreased activity and connectivity in the brain’s key connector hubs, enabling a state of unconstrained cognition.

Carhart-Harris, R. L., Erritzoe, D., Williams, T., Stone, J. M., Reed, L. J., Colasanti, A., … Nutt, D. J. (2012). Neural correlates of the psychedelic state as determined by fMRI studies with psilocybin. Proceedings of the National Academy of Sciences of the United States of America, 109(6), 2138-2143. http://dx.doi.org/10.1073/pnas.1119598109
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30 April - Q&A with Rick Strassman

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