Tripping up addiction: the use of psychedelic drugs in the treatment of problematic drug and alcohol use
Current Opinion in Behavioral Sciences November 15, 2016 Celia J. A. Morgan, Amy Mcandrew, Tobias Stevens et al. 41 citations
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David Nutt
Imperial College London, NIHR Imperial Biomedical Research Centre
208 papers in the library · 21,656 citations · publishing 2007-2026
Papers
Neuroimaging in psychedelic drug development: past, present, and future.
Molecular Psychiatry September 1, 2023 Matthew B. Wall, Rebecca Harding, Rayyan Zafar et al. 39 citations
Psychedelic therapy shows promise for treating depression, addiction, PTSD, and other psychiatric disorders. Classic serotonergic psychedelics like psilocybin and LSD act primarily at the 5-HT2A receptor, while ketamine, MDMA, and ibogaine also show potential. Modern neuroimaging techniques, especially PET and MRI, now allow precise measurement of brain effects. Key knowledge gaps remain: the link between acute drug effects and long-term clinical outcomes, detailed characterization of 5-HT2A receptor effects, and the role of neuroplasticity. Future studies combining PET with 5-HT2A-selective ligands like [11C]Cimbi-36 and MRI could bridge molecular, functional, and clinical understanding.
Effects of external stimulation on psychedelic state neurodynamics
bioRxiv (Cold Spring Harbor Laboratory) November 2, 2020 Pedro A. M. Mediano, Fernando E. Rosas, Christopher Timmermann et al. 39 citations preprint
Psychedelics reliably increase brain entropy (neural signal diversity), an effect linked to psychological changes and opposite to the decrease seen during loss of consciousness. This study investigated how context—specifically stimulus manipulation—modulates that entropy increase. Participants under LSD or placebo experienced eyes-closed versus eyes-open conditions, or no stimulus, music, or video. Brain entropy rose with LSD across all conditions but was largest with eyes closed. Entropy changes consistently matched subjective ratings of the psychedelic experience, except during video viewing, suggesting competition between external stimuli and internal LSD-induced imagery. The findings provide quantitative evidence that context shapes neural dynamics during psychedelic experiences, supporting the practice of eyes-closed psychedelic psychotherapy, and challenge simplistic views of brain entropy as a direct measure of conscious level.
MDMA, politics and medical research: Have we thrown the baby out with the bathwater?
Journal of Psychopharmacology November 1, 2007 Ben Sessa, David Nutt 39 citations
MDMA, originally used as a clinical tool in couples therapy on the West Coast of America after LSD was banned, leaked into recreational use and was prohibited in the mid-1980s. Despite its growing recreational use in rave and party scenes, medical research on MDMA stopped, and the drug became demonized by politicians. Doctors and pharmacologists debated its short-, medium-, and long-term dangers, while its therapeutic potential was forgotten. The paper argues that political restrictions, such as MDMA's classification as a class A schedule 1 drug in the UK, severely limit human research and threaten scientific objectivity and evidence-based clinical excellence. It calls for exploring MDMA's potential medical and research uses without political influence.
Personality change in a trial of psilocybin therapy v. escitalopram treatment for depression.
Psychological Medicine January 1, 2024 Brandon Weiss, Induni Ginige, Lu Shannon et al. 38 citations
In a trial comparing psilocybin therapy with the antidepressant escitalopram for moderate-to-severe major depressive disorder, both treatments led to personality changes in a direction consistent with improved mental health. Psilocybin was linked to decreases in neuroticism, introversion, disagreeableness, and impulsivity, and increases in absorption, conscientiousness, and openness at six weeks, with some changes lasting six months. Escitalopram was linked to decreases in neuroticism, disagreeableness, and impulsivity, and increases in openness at six weeks, with neuroticism remaining decreased at six months. No significant differences between the two treatments were observed, except that patients' pre-trial positive expectations for escitalopram moderated personality changes after that treatment, but not after psilocybin.
Changes in music-evoked emotion and ventral striatal functional connectivity after psilocybin therapy for depression
Journal of Psychopharmacology November 26, 2022 Melissa Shukuroglou, Leor Roseman, David Nutt et al. 38 citations
Listening to music after psilocybin therapy for treatment-resistant depression increases the pleasure people feel from music, and this increase correlates with a reduction in anhedonia (loss of pleasure). Nineteen patients received a low dose (10 mg) and then a high dose (25 mg) of psilocybin one week apart. Functional MRI scans before and after treatment showed that during music listening, functional connectivity between the nucleus accumbens (a brain reward region) and areas resembling the default mode network decreased after treatment. The findings suggest psilocybin therapy enhances music-evoked pleasure and point to a possible brain mechanism involving reduced connectivity in the default mode network.
Effects of DMT on mental health outcomes in healthy volunteers
Scientific Reports February 7, 2024 Christopher Timmermann, Richard J. Zeifman, David Erritzøe et al. 37 citations
Intravenous DMT, a fast-acting psychedelic, improved depression scores in healthy volunteers one to two weeks after administration. In a placebo-controlled comparison (13 participants) and a prospective dataset (17 participants), depression severity decreased significantly. Reductions in trait neuroticism appeared only in the placebo-controlled sample. Changes in depression and anxiety correlated with the intensity of acute peak experiences, suggesting that DMT may reduce depressive symptoms by inducing such experiences. The short half-life and flexible dosing of intravenous DMT make it a practical candidate for psychedelic medicine, though further research in clinical samples is needed.
Psychedelic experience dose-dependently modulated by cannabis: results of a prospective online survey.
Psychopharmacology (Berl) November 4, 2021 Joanna Kuć, Hannes Kettner, Fernando E. Rosas et al. 37 citations
People who use cannabis at the same time as a classic psychedelic report more intense subjective effects, with higher cannabis doses linked to stronger mystical, visual, and ego-dissolution experiences. The relationship between cannabis dose and challenging experiences followed a U-shaped pattern, while emotional breakthrough showed no connection to cannabis dose. The findings suggest an interaction between cannabis and psychedelics, but the study's design cannot establish cause or clinical implications.
Acute effects of MDMA on trust, cooperative behaviour and empathy: A double-blind, placebo-controlled experiment.
J Psychopharmacol June 15, 2020 Anna Borissova, Bart Ferguson, Matthew B. Wall et al. 37 citations
MDMA did not increase prosocial behavior in a controlled laboratory setting, despite raising blood levels of the drug and self-reported feelings of closeness and euphoria. In a double-blind, placebo-controlled experiment with 20 healthy volunteers, MDMA (100 mg) failed to significantly change task-based measures of empathy, trust, or cooperative behavior compared to placebo. Bayesian analyses supported the conclusion that MDMA and placebo had equivalent effects on empathy and cooperation. The drug also did not alter mood three days after administration. These findings suggest that the acute prosocial effects of MDMA observed in naturalistic or therapeutic contexts may not replicate under controlled experimental conditions.
Increased low-frequency brain responses to music after psilocybin therapy for depression.
Journal of Affective Disorders July 15, 2023 Matthew B. Wall, Cynthia Lam, Natalie Ertl et al. 36 citations
Psilocybin-assisted therapy for depression alters the brain's response to music, suggesting an elevated responsiveness to music after treatment that is related to subjective drug effects during dosing. Nineteen patients with treatment-resistant depression underwent two psilocybin dosing sessions. Brain scans before and after treatment showed increased activity in the superior temporal cortex when listening to music, and decreased activity in the medial frontal lobes during rest. These changes in music-related brain activity correlated with the intensity of subjective effects felt during the psilocybin sessions. The findings imply that psychedelic therapy may enhance emotional responsiveness to music, which could be relevant for treating depression.
Making a medicine out of MDMA.
The British journal of psychiatry : the journal of mental science January 1, 2015 Ben Sessa, David Nutt 36 citations
MDMA has been recognized for its therapeutic potential since its first use, but research halted when it became a recreational drug. Over the past decade, studies have slowly resumed, and there is now enough evidence to reclassify MDMA from Schedule 1 ('no medical use') to Schedule 2, alongside other misused but medically useful drugs like heroin and amphetamine. This regulatory change would allow its use as a medicine for patients with severe mental illnesses, such as treatment-resistant post-traumatic stress disorder.
Cost-effectiveness of psilocybin-assisted therapy for severe depression: exploratory findings from a decision analytic model.
Psychological Medicine December 1, 2023 Paul McCrone, Henry Fisher, Clare Knight et al. 34 citations
Psilocybin-assisted psychotherapy (PAP) may be a cost-effective treatment for severe depression, depending on the price of the drug and the level of therapist support. A decision model compared PAP with conventional medication, cognitive behavioural therapy (CBT), and their combination over six months. PAP produced the highest quality-adjusted life years (0.310) but also the highest expected healthcare cost (£6,132 to £7,652). PAP became cost-effective when therapist support costs were reduced by 50% and the psilocybin price dropped to £400–£800 per person. From a societal perspective, PAP's cost-effectiveness improved further. More long-term outcome data are needed.
The entropic tongue: Disorganization of natural language under LSD.
Conscious Cogn December 8, 2020 Camila Sanz, Carla Pallavicini, Facundo Carrillo et al. 34 citations
Language produced under the influence of LSD shows increased entropy and reduced semantic coherence, consistent with a state of heightened neural entropy. Non-semantic analysis of speech organization revealed increased verbosity and a reduced lexicon, changes more similar to manic psychoses than to schizophrenia, as confirmed by direct comparison with reference samples. Features related to language organization allowed machine learning classifiers to identify speech under LSD with accuracy comparable to that obtained by examining semantic content. These results provide a quantitative characterization of disorganized natural speech as a landmark feature of the psychedelic state.
Brain dynamics predictive of response to psilocybin for treatment-resistant depression.
Brain Communications January 1, 2024 Jakub Vohryzek, Joana Cabral, Louis-David Lord et al. 33 citations
Psilocybin therapy for depression shows promise, but its causal mechanisms are unknown. By comparing brain dynamics in treatment responders (those with >50% symptom reduction) and non-responders before treatment, researchers used large-scale brain modeling to identify brain regions whose perturbation could shift a depressive brain state to a healthy one. The identified regions correlated with density maps of serotonin receptors 5-HT2a and 5-HT1a, where psilocin (psilocybin's active metabolite) acts as an agonist. These findings provide causal mechanistic evidence linking specific brain regions and serotonergic transmission to recovery from depression via psilocybin.
The difference between 'placebo group' and 'placebo control': a case study in psychedelic microdosing.
Sci Rep July 26, 2023 Balázs Szigeti, David Nutt, Robin Carhart-Harris et al. 33 citations
Blinding in medical trials aims to evenly distribute expectancy effects between treatment groups, but it often fails. Using computational modeling, this work shows that weak blinding combined with positive treatment expectancy creates an 'activated expectancy bias' (AEB), which can inflate treatment effect estimates and produce false positive results. The authors introduce the Correct Guess Rate Curve (CGRC) to estimate outcomes of a perfectly blinded trial from imperfectly blinded data. Re-analyzing a self-blinding psychedelic microdose trial dataset, they find that observed placebo-microdose differences are susceptible to AEB and may be false positives, suggesting microdosing acts as an active placebo. The findings highlight the distinction between trials with a placebo control group and genuinely placebo-controlled trials.
Predicting the outcome of psilocybin treatment for depression from baseline fMRI functional connectivity.
J Affect Disord February 27, 2024 Debora Copa, David Erritzøe, Bruna Giribaldi et al. 31 citations
Brain connectivity patterns measured before psilocybin treatment can predict how much depression symptoms will improve. In people with treatment-resistant depression given two doses of psilocybin (25 mg each, one week apart), baseline resting-state functional MRI scans showed that connectivity within visual, default mode, and executive networks predicted early symptom improvement, while salience network connectivity predicted who would respond up to 24 weeks later, with about 90% accuracy. Similar patterns appeared in a separate trial comparing psilocybin to escitalopram. Fronto-occipital and fronto-temporal connections predicted early and late symptom reduction, respectively. Small sample sizes and differences between datasets limit generalizability, and the lack of a placebo arm limits specificity.
LSD and psilocybin flatten the brain’s energy landscape: insights from receptor-informed network control theory
bioRxiv (Cold Spring Harbor Laboratory) May 17, 2021 S. Parker Singleton, Andrea I. Luppi, Robin Carhart-Harris et al. 30 citations preprint
LSD and psilocybin reduce the amount of energy the brain needs to transition between different activity states, as measured by functional MRI. This flattening of the brain's control energy landscape allows for more frequent state transitions and more diverse (entropic) brain activity. The effects are linked to the spatial distribution of serotonin 2a receptors, the main target of these psychedelics. The findings suggest that these compounds make brain state transitions more facile and temporally diverse, offering a mechanistic explanation for the altered subjective experience induced by psychedelics.
Interactions between classic psychedelics and serotonergic antidepressants: Effects on the acute psychedelic subjective experience, well-being and depressive symptoms from a prospective survey study.
J Psychopharmacol January 27, 2024 Jessica Barbut Siva, Tommaso Barba, Hannes Kettner et al. 29 citations
A prospective survey study examined how serotonergic antidepressants affect the acute subjective experience of classic psychedelics and subsequent well-being and depressive symptoms. People taking antidepressants reported less intense mystical-type experiences and greater anxiety during psychedelic sessions compared to those not on antidepressants. Despite this blunting, both groups showed similar improvements in well-being and reductions in depressive symptoms after the session. The findings suggest that while antidepressants may dampen the acute psychedelic experience, they do not necessarily hinder long-term mental health benefits.
Ketamine for the treatment of mental health and substance use disorders: comprehensive systematic review - CORRIGENDUM.
BJPsych Open January 18, 2022 Zach Walsh, Özden Merve Mollaahmetoğlu, Joseph M. Rootman et al. 28 citations
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Effects of classic psychedelic drugs on turbulent signatures in brain dynamics
Network Neuroscience January 1, 2022 Josephine Cruzat, Yonatan Sanz Perl, Anira Escrichs et al. 28 citations
Psychedelic drugs like LSD and psilocybin may treat neuropsychiatric disorders by dose-dependently altering the brain's functional hierarchy—the organization of neural activity across regions. Using a turbulence framework that measures local synchronization (vorticity) in both space and time, researchers found that both drugs produce consistent and distinct effects, particularly compressing the default mode network, a higher-level network. These findings support the hypothesis that psychedelics modulate the functional hierarchy and provide a quantitative comparison of how LSD and psilocybin change brain dynamics, with implications for therapeutic use.
LSD-induced changes in the functional connectivity of distinct thalamic nuclei.
Neuroimage December 1, 2023 Stefano Delli Pizzi, Piero Chiacchiaretta, Carlo Sestieri et al. 27 citations
LSD selectively alters the functional connectivity between specific thalamic nuclei and sensory and associative cortical areas. Using structural and resting-state functional MRI in healthy volunteers under acute LSD administration, researchers found increased coupling of the ventral complex, pulvinar, and non-specific thalamic nuclei with somatosensory and auditory cortices, as well as with associative cortex regions rich in serotonin 2A receptors. At subcortical levels, LSD increased connectivity among these thalamic nuclei but decreased striatal-thalamic connectivity. These nucleus-specific changes help explain LSD's modulation of subcortical-cortical circuits and associated behavioral effects.
Effects of discontinuation of serotonergic antidepressants prior to psilocybin therapy versus escitalopram for major depression
Journal of Psychopharmacology March 22, 2024 Tommaso Barba, David Erritzøe, Meg J. Spriggs et al. 26 citations
In a clinical trial comparing psilocybin plus psychological support to escitalopram plus psychological support for major depressive disorder, patients who discontinued their SSRI or SNRI medication before receiving psilocybin showed a reduced treatment effect on all depression severity and well-being measures compared with those who were unmedicated at trial entry. Discontinuation did not affect the intensity of the acute psychedelic experience. The findings are exploratory and hypothesis-generating, not confirmatory, and the study did not test SSRI/SNRI continuation. A controlled trial comparing discontinuation versus continuation before psilocybin is needed.
Unique Psychological Mechanisms Underlying Psilocybin Therapy Versus Escitalopram Treatment in the Treatment of Major Depressive Disorder
International Journal of Mental Health and Addiction March 7, 2024 Brandon Weiss, Leor Roseman, Bruna Giribaldi et al. 26 citations
Acute psychological experiences, particularly mystical experience and ego dissolution, partially account for how psilocybin therapy improves depression compared to escitalopram. In a phase 2 trial of patients with moderate-to-severe major depressive disorder, mystical experience and ego dissolution uniquely mediated the effect of treatment on depressive response. Higher levels of mystical experience, emotional breakthrough, and intense music-listening responses were also linked to greater antidepressant improvement. These findings suggest that acute psychological experiences play a causal mechanistic role in psilocybin therapy for depression.
A role for the serotonin 2A receptor in the expansion and functioning of human transmodal cortex.
Brain January 1, 2024 Andrea I. Luppi, Manesh Girn, Fernando E. Rosas et al. 25 citations
Serotonin 2A receptor (5-HT2AR) signaling drives both the evolutionary expansion and ongoing modulation of the human cerebral cortex's most complex cognitive centers. The cortex is organized along a gradient from simple sensory processing to high-level integration, with the transmodal cortex at the apex—a region disproportionately enlarged in humans and rich in 5-HT2AR expression. During early brain development, 5-HT2AR signaling on neural progenitor cells stimulates their proliferation, contributing to cortical expansion. In the adult brain, 5-HT2AR agonism promotes neuroplasticity, learning, and cognitive flexibility with therapeutic potential. The receptor thus plays a dual role in enabling cortical growth and sophisticated functioning.
Psychedelics and sexual functioning: a mixed-methods study
Scientific Reports February 7, 2024 Tommaso Barba, Hannes Kettner, Caterina Radu et al. 24 citations
Psychedelics may improve sexual functioning and satisfaction days or weeks after use, according to two studies. In a large naturalistic study, people who used psychedelics reported greater pleasure, communication during sex, and satisfaction with their partner and appearance. A controlled clinical trial comparing psilocybin therapy with the SSRI escitalopram for depression found that those given psilocybin reported positive changes in sexual functioning after treatment, while those given escitalopram did not. This is the first quantitative investigation of psychedelics' post-acute effects on sexual functioning, suggesting a potential benefit and a need for further research.