Psychiatry Research
July 23, 2023
Otto Simonsson, Per Carlbring, Robin Carhart-Harris et al.
24 citations
In a meta-analysis of three psilocybin trials for depression involving 102 participants, clinically significant symptom worsening occurred for a minority of those receiving psilocybin or escitalopram (about 10%) and for a majority of those in the waitlist condition (63.6%). The psilocybin arm showed a lower likelihood of symptom worsening compared to waitlist and no difference compared to escitalopram. The authors note the limitation of a relatively small sample size.
Journal of Psychopharmacology
April 25, 2023
Brandon Weiss, David Erritzøe, Bruna Giribaldi et al.
24 citations
A reanalysis of data from a trial comparing psilocybin therapy (PT) to escitalopram (ET) for major depressive disorder found that 14 of 16 outcome measures favored PT, but the QIDS-SR-16 did not. The QIDS-SR-16 showed higher variance, imprecision from compound items and sum-scoring, vague response options, and lack of focus on a core depression factor. When the trial data were examined at item, facet, and factor levels, results suggested PT was superior in reducing depressed mood, anhedonia, a core depression factor, and specific symptoms like sexual dysfunction. This raises concerns about relying on individual scales that miss depression's multidimensional structure.
Psychological Medicine
April 28, 2020
Claire Mokrysz, Natacha D. C. Shaban, Tom P. Freeman et al.
24 citations
Inhaling cannabis reliably increases psychotic-like symptoms in healthy cannabis users and may raise the incidence of speech illusion—hearing words in meaningless white noise. Cannabidiol (CBD) did not blunt these effects. In one study, adults had stronger psychotic-like symptom responses than adolescents, suggesting adolescents may be less vulnerable to the acute psychotic-like effects of cannabis. The odds of experiencing speech illusion were 3.1 times higher after inhaling cannabis with THC and negligible CBD compared to placebo.
Neuroethics
November 6, 2023
Edward Jacobs, Ashleigh Murphy-Beiner, Ian Rouiller et al.
23 citations
In psychedelic clinical trials, the case for providing patients with continued access to the investigational drug after the trial ends is especially strong due to the drugs' broader legal status, the unique therapist-participant relationship, and the extended therapeutic process. Because the therapy's effectiveness relies heavily on non-drug factors and the cultural setting, the authors argue for expanding post-trial care beyond just drug access. They outline potential provisions and contend that viewing post-trial care as an integral part of research—and a proper use of funding—will help build the infrastructure needed for a future psychedelic medicine system after legalization.
Naunyn Schmiedebergs Arch Pharmacol
September 20, 2016
Jakob A. Shimshoni, Ilan Winkler, Ezekiel Golan et al.
23 citations
Four MDMA analogues—three benzofuran compounds (5-APB, 6-MAPB, 5-MAPB) and one indole compound (5-IT)—were screened as potential second-generation drugs for PTSD. All analogues showed high binding affinities for serotonin 5-HT2a,b,c and norepinephrine α2 receptors, and significantly inhibited serotonin, dopamine, and norepinephrine uptake. 5-APB acted as an agonist at all three 5-HT2 receptor subtypes, while 6-MAPB, 5-MAPB, and 5-IT were agonists at the 5-HT2c receptor. The analogues also emerged as potent and selective inhibitors of monoamine oxidase A. 6-MAPB, with a favorable pharmacological profile, was further tested for its potency at monoamine transporters. Overall, the analogues displayed higher binding affinities and greater agonist activity at 5-HT2a,c receptors compared to MDMA.
British Journal of Pharmacology
December 19, 2024
David Nutt, Peter Hunt, Anne Katrin Schlag et al.
21 citations
In 2023, the Australian Therapeutic Goods Administration (TGA) approved psilocybin for treatment-resistant depression and MDMA for PTSD, effective from 1 July 2023. The approval followed a campaign led by Mind Medicine Australia, Professor David Nutt, Drug Science, and Monash University professors, supported by clinical, academic, and patient groups. Prescribing rights are limited to psychiatrists authorized under the TGA's Authorised Prescriber Scheme. This paper reviews the background of the decision, its implications for approvals in other jurisdictions, and development pathways for other psychedelic drugs.
Journal of Psychopharmacology
May 20, 2022
Matthew B. Wall, Tom P. Freeman, Chandni Hindocha et al.
21 citations
THC strongly disrupts connectivity between the striatum and cortex, but co-administering CBD mitigates this effect in the limbic striatum network. In one study, inhaled cannabis with 8 mg THC or 8 mg THC plus 10 mg CBD disrupted associative and sensorimotor networks, while THC alone also disrupted the limbic striatum network. In a second study, oral 600 mg CBD increased connectivity in the associative network and caused minor disruptions in limbic and sensorimotor networks. The insula emerges as a key region affected by cannabinoid-induced changes in functional connectivity, with implications for understanding cannabis-related disorders and developing cannabinoid therapeutics.
bioRxiv (Cold Spring Harbor Laboratory)
June 25, 2017
Mendel Kaelen, Romy Lorenz, Frederick S. Barrett et al.
20 citations
preprint
Lysergic acid diethylamide (LSD) alters how the brain processes music, particularly by enhancing activity and connectivity in networks linked to music perception and emotion. Sixteen healthy volunteers listened to a 7-minute music piece during fMRI after taking either 75 mcg of LSD or a placebo. The acoustic feature of timbral complexity—the richness of the music's spectral distribution—drove the most pronounced changes in brain activity and connectivity under LSD. These changes correlated with increased feelings of wonder evoked by the music. The results suggest a neurobiological basis for why music is useful in psychedelic therapy.
J Psychopharmacol
December 1, 2016
David Nutt
19 citations
Psilocybin therapy shows promise for alleviating anxiety and depression in cancer patients, drawing on lessons from past research to guide future applications. The text reviews historical studies and outlines prospects for integrating psilocybin-assisted psychotherapy into cancer care, suggesting it may provide significant mental health relief. It emphasizes the need for careful clinical implementation and further investigation to confirm efficacy and safety.
The British Journal of Psychiatry
May 20, 2024
David Nutt, Ilana B Crome, Allan H. Young
18 citations
Australia has reclassified psilocybin and MDMA from prohibited substances to prescription medicines for treatment-resistant depression and post-traumatic stress disorder, respectively. The feature examines the rationale behind these regulatory changes, the potential benefits and difficulties they present to psychiatric practice, and how mental health professionals and healthcare systems can adapt to integrate these treatments.
Biological psychiatry. Cognitive neuroscience and neuroimaging
July 1, 2023
Stefano Delli Pizzi, Piero Chiacchiaretta, Carlo Sestieri et al.
18 citations
LSD alters brain functional connectivity and local signal amplitude in opposite directions depending on the type of serotonin receptor involved. In healthy volunteers, LSD increased activity and connectivity in cortical regions of the default mode and attention networks, which have high densities of 5-HT2A receptors; these changes correlated with visual hallucinations. Conversely, LSD decreased activity and connectivity in limbic areas rich in 5-HT1A receptors. The spatial patterns of these functional changes overlapped with the distribution of the two serotonin receptor subtypes, suggesting distinct receptor-mediated mechanisms underlie LSD's reorganization of brain networks.
J Psychopharmacol
December 13, 2021
Ben Sessa, Jacob S. Aday, Steve O’Brien et al.
18 citations
An open-label study of 14 participants found that mood remained positive during the week after receiving MDMA in a clinical setting, contrary to the 'Blue Monday' crash reported by recreational users. Self-reported sleep quality improved at 3- and 6-month follow-ups compared to baseline. No participants used or desired to use illicit MDMA, and anecdotal reports were favorable. The findings suggest that negative after-effects previously associated with MDMA may stem from confounds such as illicit drug sourcing and recreational settings, rather than the drug itself.
Comprehensive Psychiatry
July 1, 2025
Luca Pellegrini, Naomi A Fineberg, Sorcha O'Connor et al.
17 citations
A 10 mg dose of psilocybin produced a rapid, moderate-to-large reduction in compulsive symptoms in people with obsessive-compulsive disorder (OCD), lasting up to one week after dosing. In a blinded pharmacological challenge study, 18 adults with at least moderate OCD received a 1 mg and then a 10 mg dose of oral psilocybin, separated by four weeks. One week after the 10 mg dose, scores on the compulsion subscale of the Yale-Brown Obsessive Compulsive Scale showed a significant improvement compared to the 1 mg dose (Cohen's d = 0.74). No effect on depression was detected. The drug was well tolerated with no serious adverse events.
Psychopharmacology (Berl)
February 1, 2018
H. Valerie Curran, David Nutt, Harriet de Wit
17 citations
Psychedelics and related drugs show therapeutic possibilities for mental health conditions, with research exploring their mechanisms, including brain modulation and neuroplasticity. The work discusses how these compounds may alter brain pathways and states of consciousness to produce therapeutic benefits. It also addresses the regulatory landscape for these substances in medical research and mental healthcare. The authors suggest that understanding the neurobiology and therapeutic mechanisms is crucial for advancing treatment research and medical innovation.
American Journal of Psychiatry
May 7, 2025
Matthew B. Wall, Lysia Demetriou, Bruna Giribaldi et al.
16 citations
Psilocybin therapy greatly improved depressive symptoms but had only a small effect on how the brain responds to emotional stimuli. This contrasts with SSRIs, which often reduce emotional responsiveness alongside their antidepressant action. The findings suggest that psychedelic therapy may work through different neural mechanisms than conventional antidepressants.
Journal of psychopharmacology (Oxford, England)
October 1, 2024
Valerie Bonnelle, Amanda Feilding, Fernando E. Rosas et al.
16 citations
The joint influence of the sympathetic and parasympathetic nervous systems over cardiac activity, known as sympathovagal coactivation, is positively related to ratings of spiritual experience and insightfulness during the DMT-induced peak experience, and also to improved well-being two weeks later. The balance between the two autonomic branches before DMT injection predicted insightfulness scores and subsequent coactivation. These findings demonstrate the autonomic nervous system's involvement in psychedelic-induced peak experiences.
Journal of Psychopharmacology
November 14, 2022
Meg J. Spriggs, Bruna Giribaldi, Taylor Lyons et al.
15 citations
A fixed 25 mg dose of psilocybin produces similar acute psychedelic effects and improvements in well-being regardless of body mass index (BMI). Pooling data from three therapeutic studies, results support the null hypothesis that BMI does not predict overall intensity of the altered state, mystical experiences, perceptual changes, or emotional breakthroughs. There was weak evidence that lower BMI participants reported greater 'dread of ego dissolution,' but BMI did not meaningfully add to predictions beyond age, sex, and study. Mystical-type experiences and emotional breakthroughs strongly predicted well-being improvements, but BMI did not. These findings suggest body weight-adjusted dosing may be unnecessary, supporting fixed dosing to reduce practical and financial burdens on psychedelic therapy scalability.
Psychedelic Medicine
October 28, 2022
Bruna Giribaldi, Sandeep M. Nayak, Bilal A. Bari et al.
15 citations
A Bayesian reanalysis of a trial comparing psilocybin (25 mg) to escitalopram (20 mg) over 6 weeks in 59 patients with major depressive disorder found that psilocybin outperformed escitalopram on three of four depression scales, though evidence was not uniformly clinically meaningful. Using skeptical priors that bias results toward zero, the analysis showed strong to extremely strong evidence favoring psilocybin on the BDI-1A, MADRS, and HAMD-17, while evidence on the primary outcome (QIDS SR-16) was indeterminate. For clinically meaningful superiority, evidence was moderate against it for the QIDS SR-16 but moderate to strong for the MADRS and HAMD-17. Psilocybin showed extremely strong evidence of noninferiority to escitalopram across all scales. The findings support further research on psilocybin's relative efficacy.
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.
National Science Review
May 1, 2024
Jakub Vohryzek, Joana Cabral, Christopher Timmermann et al.
13 citations
The human brain's activity constantly reorganizes across space and time, and decomposing whole-brain recordings into harmonic modes reveals gradient-like patterns linked to different functions. Using the HADES framework, researchers analyzed brain activity in healthy participants after taking the serotonergic psychedelic DMT. They found significant decreases in contributions across most low-frequency harmonic modes during the DMT state. Specifically, the second functional harmonic, which represents the uni- to transmodal functional hierarchy, decreased, supporting the hypothesis that psychedelics alter this hierarchy. Dynamic measures of fractional occupancy, lifetime, and latent space precisely described the changes in the brain's spacetime hierarchical organization during the psychedelic state.
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.