European Addiction Research
September 25, 2024
Ioanna A. Vamvakopoulou, David Nutt
13 citations
Classic psychedelics (psilocybin, LSD, DMT, mescaline) and atypical ones (ketamine, ibogaine, 5-MeO-DMT, MDMA) show promise as therapeutic alternatives for addiction, improving psychological and physiological symptoms of dependence. The review covers pharmacology, properties from pre-clinical and clinical research, and evidence from controlled studies and naturalistic or ceremonial settings, identifying proposed therapeutic mechanisms. Understanding ancient and present-day knowledge of these substances may offer hope for treating addiction, especially in individuals who have not responded to conventional methods.
British Journal of Clinical Pharmacology
July 17, 2023
Balázs Szigeti, Lawrence D. Phillips, David Nutt
13 citations
Randomized controlled trials (RCTs) are often considered the gold standard in medical research, but they have limitations including reliance on null hypothesis significance testing and poor generalizability. Bayesian analysis of real-world evidence (RWE) offers a complementary approach. In a case series of 20 children with epilepsy treated with medical cannabis, all experienced reduced seizures; Bayesian analysis with a flat prior gives a 95% probability that the next patient will improve (95% credible interval 87%–100%). For treatment-resistant depression treated with psilocybin, the probability of a favorable response ranges from 62% (QIDS-16) to 82% (MADRS). These analyses require fewer patients than traditional RCTs and provide directly actionable probabilities for clinicians and patients.
JAMA Netw Open
July 1, 2024
Leor Roseman, David Erritzøe, David Nutt et al.
12 citations
Interruptions during psychedelic therapy sessions are associated with lower ratings of the intensity of the experience. This quality improvement study examined how breaks or disruptions affect the subjective depth of the psychedelic session, suggesting that maintaining a continuous, uninterrupted setting may be important for achieving a more intense experiential state.
Frontiers in Psychiatry
June 4, 2024
Julia Bornemann, James B Close, Kirran Ahmad et al.
11 citations
Psilocybin-assisted therapy may help treat fibromyalgia, a chronic widespread pain condition with limited treatment options. A protocol describes a mechanistic study with 20 participants who will attend 8 visits over 8 weeks, including two dosing sessions where psilocybin is given at least once, with doses up to 25 mg. The primary focus is on brain mechanisms, measured via electroencephalography during the acute psychedelic state and magnetic resonance imaging before and after treatment. Primary outcomes are Lempel-Ziv complexity from EEG and experiential avoidance via questionnaire. Secondary measures include pain, physical and mental function, and additional neuroimaging. Results aim to clarify how psilocybin-therapy works in the brain and inform a future randomized controlled trial.
Research Square
May 20, 2021
Richard E. Daws, Christopher Timmerman, Bruna Giribaldi et al.
11 citations
Across two clinical trials, psilocybin therapy produced robust antidepressant effects that were linked to a decrease in brain network modularity measured by resting-state fMRI. In an open-label study of 16 adults with treatment-resistant depression, Beck Depression Inventory scores dropped sharply at one week and six months, and the reduction in network modularity one day after treatment correlated with clinical improvement at six months. In a double-blind randomized trial of 43 adults with major depressive disorder, the psilocybin arm showed superior antidepressant effects at two and six weeks compared with escitalopram, and improvements correlated with decreased modularity. These convergent findings suggest that psilocybin therapy may work by reducing the brain's network modularity.
Neurosci Appl
January 11, 2024
Drummond E-Wen McCulloch, Matthias E. Liechti, Kim PC. Kuypers et al.
10 citations
Psychedelic drugs like psilocybin and LSD are being tested in clinical trials for psychiatric and neurological conditions, with phase 2 studies showing particular promise for depression. At a 2023 European College of Neuropsychopharmacology meeting, experts identified key knowledge gaps that need addressing for successful medical implementation. These include understanding how these drugs work in the body (pharmacokinetics and pharmacodynamics), comparing different psychedelics, exploring the link between the duration of subjective effects and therapeutic outcomes, studying polypharmacology, and assessing the role of psychological support. The article also presents perspectives from the European Medicines Agency and Health Technology Assessors on what is most needed for medical adoption in Europe.
Research Square
September 20, 2022
Jakub Vohryzek, Joana Cabral, Louis-David Lord et al.
10 citations
Psilocybin therapy for depression shows promise, but how it works is unclear. By comparing responders (those with >50% reduction in symptoms) to non-responders after 10mg and 25mg doses, whole-brain modeling identified specific brain regions whose dynamics shift from a depressive to a healthy state. These regions overlap with maps of serotonin 5-HT2A and 5-HT1A receptors, which psilocin—the active metabolite of psilocybin—activates. The findings provide causal evidence linking serotonergic transmission and recovery from depression via psilocybin.
bioRxiv (Cold Spring Harbor Laboratory)
July 25, 2018
Louis-David Lord, Paul Expert, Selen Atasoy et al.
10 citations
preprint
Brain activity can be viewed as exploring a landscape of different activity patterns over time, shifting between stable states of functional connectivity that support various mental processes. In a study using fMRI data from healthy participants given intravenous psilocybin (the active compound in magic mushrooms), researchers analyzed how this dynamical landscape changes during the psychedelic state. They found that a connectivity state linked to the fronto-parietal control system became strongly destabilized, while transitions toward a globally synchronized state increased. These changes suggest the psychedelic state biases the brain toward global integration at the cost of local network segregation, offering a mechanistic perspective on the subjective psychedelic experience and potential guidance for pharmacological interventions in neuropsychiatric disorders.
Drug Science Policy and Law
September 1, 2025
David Nutt, David Erritzøe, Anne Katrin Schlag et al.
9 citations
The field of psychedelic research lacks standardized terminology for clinical development, dosing, safety monitoring, and regulatory classification. A comprehensive framework is proposed that classifies psychedelics by pharmacology (serotonergic, glutamatergic, kappaergic, GABAergic, and atypical), introduces dose-dependent categories (microdose, minidose, mididose, macrodose), and standardizes terms like “short-acting” with specific pharmacokinetic parameters. Safety considerations include cardiovascular and psychological effects, with risk mitigation protocols for higher-risk compounds like ibogaine. A three-phase treatment model—preparation, dosing, and integration—is recommended as a minimum standard. The lack of comparative research on psychotherapy modalities is identified as a critical gap.
PsyArXiv
April 13, 2023
Lisa Xiaolu Luan, Emma Eckernäs, Michael Ashton et al.
9 citations
preprint
A within-subjects, placebo-controlled study tested a novel method of administering N,N-Dimethyltryptamine (DMT) by combining a bolus injection with a constant-rate infusion to extend the experience to 30 minutes. The method effectively maintained stable and tolerable subjective effects over the infusion period. Anxiety ratings remained low, and heart rate habituated within 15 minutes, indicating psychological and physiological safety. Plasma DMT concentrations increased consistently starting ten minutes into administration, while psychological effects plateaued, suggesting acute psychological tolerance to DMT. These findings demonstrate the safety and effectiveness of continuous intravenous DMT administration for basic and clinical research.
Drug Science Policy and Law
January 1, 2022
Plinio Ferreira, Adam Winstock, Anne Katrin Schlag et al.
9 citations
Nitrous oxide (laughing gas) and alkyl nitrites (poppers) rank among the least harmful recreational drugs when assessed on 16 criteria including dependence, injury, and economic cost. An expert panel using Multi-Criteria Decision Analysis scored nitrous oxide at 6 and poppers at 5 on a 0–100 overall harm scale, placing them just above magic mushrooms (psilocybin). Nitrous oxide scored higher for dependence, environmental damage, mental impairment, and family adversities; poppers scored higher for injury, drug-related damage, economic cost, and mortality. The findings aim to inform UK policy decisions, as nitrous oxide possession is not currently controlled under the Misuse of Drugs Act.
Psychopharmacology
May 1, 2018
Mendel Kaelen, Bruna Giribaldi, Jordan Raine et al.
9 citations
correction
Music plays a central role in psychedelic therapy by helping to guide and support the therapeutic process. The article synthesizes evidence that music can influence emotional states, facilitate psychological insights, and enhance the overall therapeutic outcome when combined with psychedelic substances. The authors argue that music acts as a "hidden therapist" by directing the trajectory of the psychedelic experience, promoting emotional release, and supporting the integration of the experience afterward. This suggests that careful selection and use of music is crucial for optimizing the therapeutic benefits of psychedelic therapy.
bioRxiv (Cold Spring Harbor Laboratory)
February 15, 2022
Matthew B. Wall, Cynthia Lam, Natalie Ertl et al.
8 citations
preprint
Psychedelic-assisted psychotherapy with psilocybin, which often incorporates music, may enhance the brain's response to emotional stimuli. In nineteen patients with treatment-resistant depression, functional MRI scans taken before and after two psilocybin dosing sessions showed that music listening, compared to resting-state, triggered greater brain activity in the bilateral superior temporal cortex after treatment. The right ventral occipital lobe showed increased activity during the resting-state scan post-treatment. Activity in music-related brain regions correlated with the intensity of subjective effects experienced during dosing. These results suggest psilocybin therapy specifically elevates responsiveness to music, linked to the drug's subjective effects.
medRxiv
June 3, 2023
Matthew B. Wall, Lysia Demetriou, Bruna Giribaldi et al.
7 citations
preprint
Psilocybin therapy for major depressive disorder may work through a different brain mechanism than the SSRI escitalopram. In a trial comparing two groups—one receiving two 25 mg psilocybin doses plus daily placebo, the other receiving daily escitalopram plus two inactive 1 mg psilocybin doses—brain responses to emotional faces were measured with fMRI before and after six weeks of treatment. The escitalopram group showed significantly reduced brain activity in response to fear, happy, and neutral faces, including a specific reduction in amygdala response to fear faces. The psilocybin group showed no such reduction and even a slight increase in brain responsiveness, despite large improvements in depressive symptoms. Reduced emotional responsiveness may be a biomarker of SSRIs' antidepressant action not shared by psilocybin therapy.
Frontiers in Psychology
June 6, 2025
William Roseby, Hannes Kettner, Leor Roseman et al.
6 citations
Psychedelics like psilocybin strongly increase the sense that life has meaning, based on three different studies: a clinical trial for depression, a healthy volunteer study, and naturalistic retreats. The 'presence of meaning' rose substantially after a psychedelic experience, while the 'search for meaning' dropped only slightly. These meaning enhancements were moderately linked to improvements in mental health, such as greater wellbeing and reduced depression. Mystical, ego dissolution, and emotional breakthrough experiences were associated with increased meaning, though the strength varied by context. The evidence converges to show a robust, lasting positive effect of psychedelics on meaning in life, with context influencing outcomes.
Communications biology
March 11, 2025
Juan Ignacio Piccinini, Yonatan Sanz Perl, Carla Pallavicini et al.
6 citations
The transition into a psychedelic brain state is often overlooked in favor of static descriptions of acute effects. Using a time-dependent whole-brain model and fMRI data from 15 volunteers given intravenous DMT, the work shows that a transient of heightened reactivity in fronto-parietal regions and visual cortices correlates with serotonin 5HT2a receptor density. Simulated perturbations suggest that minimal disturbances can achieve maximal effects during this brief period, and the temporal evolution of these features aligns with pharmacokinetics. These findings indicate a mechanism for how short psychedelic episodes may exert a lasting influence over time.
CNS spectrums
January 30, 2025
Steve O'Brien, David Nutt
5 citations
MDMA-assisted therapy (MDMA-AT) for PTSD and other behavioral disorders has a controversial history, moving from research to recreational use and back to medicine. Pivotal trials have been conducted, but recent setbacks have hindered clinical application. The chapter argues that MDMA-AT still holds potential to transform psychiatry, though its future is uncertain due to ongoing debates over ethics, methodology, and political influence.
bioRxiv (Cold Spring Harbor Laboratory)
April 28, 2024
Kenneth Shinozuka, Prejaas Tewarie, Andrea I. Luppi et al.
5 citations
preprint
LSD weakens the brain's directed connectivity hierarchy by increasing the balance between senders and receivers of neural signals. This finding supports the REBUS theory, which proposes that psychedelics flatten the hierarchy of information flow in the brain. Analyzing magnetoencephalography data from 16 healthy participants given 75 micrograms of intravenous LSD, the study found that LSD diminishes the asymmetry of directed connectivity averaged over time. Machine learning classifiers distinguished LSD from placebo more accurately when trained on hierarchy metrics than on traditional functional connectivity measures.
Biochemistry
February 7, 2024
Vito F. Palmisano, Claudio Agnorelli, Andrea Fagiolini et al.
5 citations
Classic psychedelics, which resemble serotonin, act on 5-HT2A receptors inside neurons. This computational study used molecular dynamics simulations to examine how 12 tryptamines cross cell membranes. Dimethylation of the amine group and a methoxy group at position 5 increased permeability. Positional substitutions on the indole ring also influenced permeation, while protonation raised the energy barrier at the bilayer center, making molecules highly impermeable. These simulation-based trends can guide future drug design for psychedelics with improved activity.
Lancet
March 12, 2016
Polly Taylor, David Nutt, Val Curran et al.
5 citations
No Summary
Nat Med
February 16, 2026
David Erritzøe, Tommaso Barba, Tiffanie Benway et al.
4 citations
A single 21.5-mg intravenous dose of the psychedelic DMT, given with psychotherapeutic support, produced a rapid and significant reduction in depressive symptoms in adults with moderate-to-severe major depressive disorder. In a double-blind, placebo-controlled trial with 34 participants, those receiving DMT showed a greater decrease in depression scores at two weeks compared to placebo. Antidepressant effects persisted up to three months in an open-label phase. Adverse events were mostly mild to moderate, and no serious adverse events occurred.
Molecular Psychiatry
April 26, 2025
Rebecca Harding, Neomi Singer, Talma Hendler et al.
4 citations
Psilocybin therapy reduces anhedonia more than the SSRI escitalopram in major depressive disorder, yet escitalopram dampens emotional responses to musical surprises while psilocybin therapy preserves them. Escitalopram increases brain activity in memory and emotion regions during musical surprises, whereas psilocybin therapy decreases activity in the ventromedial prefrontal cortex and angular gyrus and increases sensory region activation. These contrasting neural and behavioral effects suggest fundamentally different treatment mechanisms: psilocybin may maintain subjective responses by reducing the salience of prediction errors or strengthening hedonic expectations, while escitalopram may weaken hedonic priors.
bioRxiv (Cold Spring Harbor Laboratory)
November 7, 2024
Lorenzo Pasquini, Jakub Vohryzek, Anira Escrichs et al.
4 citations
preprint
Psilocybin induces fast and sustained improvements in mental well-being, yet its long-term mechanisms are not fully understood. Four weeks after a full dose, fronto-striatal-thalamic (FST) circuitry—involved in goal-directed behavior and motivation—shows increased dynamic activity and flexibility in healthy volunteers. Computational modeling indicates that reduced structural constraints on functional dynamics cause this increased flexibility. Long-term changes include increased bottom-up and reduced top-down information flow, mediated by serotonergic (5-HT2A) and dopaminergic (D2) receptor systems. This functional re-organization of FST circuits may represent a common mechanism underlying clinical improvements across neuropsychiatric disorders such as substance abuse, major depression, and anorexia.
March 1, 2023
David Nutt, David Castle
4 citations
Psychedelic agents such as psilocybin, MDMA, ayahuasca, and LSD are being reinvestigated for their therapeutic potential in psychiatry. Psilocybin, found in 'magic mushrooms,' has been used to reduce distress in people with depression and anxiety related to life-ending cancers. MDMA has shown lasting efficacy for severe posttraumatic stress disorder. These compounds integrate psychotherapy with biological treatments, challenging established psychiatric practice and offering new insights into brain function and healing. The book covers the history, clinical aspects, risks, side effects, and precautions of these drugs.
bioRxiv (Cold Spring Harbor Laboratory)
November 21, 2020
Matthew B. Wall, Tom P. Freeman, Chandni Hindocha et al.
4 citations
preprint
Cannabidiol (CBD) and Δ9-tetrahydrocannabinol (THC) are two major cannabis constituents with contrasting actions: THC is psychoactive and addiction-promoting, while CBD may have opposite effects. In two placebo-controlled, double-blind studies, inhaled THC (8 mg) strongly disrupted functional connectivity in associative and sensorimotor striatal networks, and this disruption was selectively alleviated in the limbic striatum when co-administered with CBD (10 mg). Oral CBD (600 mg) alone increased connectivity in the associative network but caused minor decreases in limbic and sensorimotor networks. The insula emerged as a key region affected by cannabinoid-induced connectivity changes, with implications for cannabis-related disorders and cannabinoid therapeutics.