Journal of Psychopharmacology
January 16, 2020
Lea J. Mertens, Matthew B. Wall, Leor Roseman et al.
211 citations
After a single 25 mg dose of psilocybin, patients with treatment-resistant depression showed decreased functional connectivity between the ventromedial prefrontal cortex and the right amygdala while viewing faces, particularly fearful and neutral ones. This decrease was linked to lower rumination levels one week later. Increased connectivity between these regions and occipital-parietal cortices also emerged. The findings suggest psilocybin therapy may revive emotional responsiveness at both neural and psychological levels, offering a potential treatment mechanism. Placebo-controlled studies are needed to confirm these results.
Biological Psychiatry
January 10, 2014
Robin Carhart‐Harris, Kevin Murphy, Robert Leech et al.
182 citations
The medial temporal lobes (MTLs) are specifically involved in how MDMA works in the brain, though more research is needed to understand how the drug's characteristic subjective effects emerge from its modulation of spontaneous brain activity.
The International Journal of Neuropsychopharmacology
December 17, 2013
Robin Carhart‐Harris, Matthew B. Wall, David Erritzøe et al.
110 citations
MDMA (ecstasy) makes recalling favorite autobiographical memories feel more vivid, emotionally intense, and positive, while making recall of worst memories feel less negative. In a double-blind, placebo-controlled fMRI study with 19 participants who had prior MDMA experience, 100 mg of MDMA altered brain activity during memory recall: it increased activation in the fusiform gyrus and somatosensory cortex for favorite memories and decreased activation in the left anterior temporal cortex for worst memories. These neural changes suggest MDMA creates a positive emotional bias, which may explain why it helps patients revisit traumatic memories during psychotherapy for PTSD.
Frontiers in Psychiatry
June 12, 2023
Rayyan Zafar, Maxim Siegel, Rebecca Harding et al.
95 citations
Psychedelic therapy is regaining scientific and medical interest, with growing evidence for its safety and efficacy in treating psychiatric disorders, including addiction. This review charts research on these interventions for addiction, starting with the socioeconomic impact of addiction and current treatment options. It examines historical studies from the mid-late 1900s, real-world evidence from naturalistic and survey-based studies, and modern clinical trials from first-in-human to phase II. The review also covers translational neuropsychopharmacology techniques like fMRI and PET that help explain therapeutic mechanisms. A better understanding of these treatment effects can optimize psychedelic therapy development and improve patient outcomes.
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.
Journal of Psychopharmacology
August 5, 2020
Will Lawn, J. P. Hill, Chandni Hindocha et al.
23 citations
A single 600 mg oral dose of cannabidiol did not alter brain activity related to anticipating or receiving rewards in healthy adults. Using functional magnetic resonance imaging during a monetary incentive delay task, the expected reward-related brain regions—including the insula, caudate, nucleus accumbens, anterior cingulate, and orbitofrontal cortex—were activated, but no difference was observed between cannabidiol and placebo. Bayesian analyses confirmed that activity in these regions was similar under both conditions, and behavioral measures of motivation for reward also showed no significant difference. The findings suggest that acute cannabidiol does not affect the neural correlates of reward anticipation or feedback in healthy individuals.
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.
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.
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.
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.
June 30, 2022
Matthew B. Wall, Rebecca Harding, Rayyan Zafar et al.
3 citations
preprint
Psychedelic therapy shows potential for treating psychiatric disorders like depression, addiction, and PTSD. Classic serotonergic psychedelics such as psilocybin, LSD, DMT, and 5-MeO-DMT are the main focus, along with ketamine, MDMA, and ibogaine. The concurrent use of advanced neuroimaging methods, particularly PET and MRI, has allowed precise assessment of brain effects, benefiting the development of these treatments. The text identifies gaps in knowledge that future multimodal imaging studies could address, providing a stronger foundation for psychedelic therapy.
October 14, 2024
Terence J. Lyons, Merle Spriggs, Leevi Kerkelä et al.
preprint
A single high dose of psilocybin (25 mg) produced lasting functional and anatomical brain changes in healthy, psychedelic-naive adults, detected from one hour to one month later. Diffusion imaging showed decreased axial diffusivity in prefrontal-subcortical tracts, correlating with reduced brain network modularity, which in turn correlated with improved well-being. Increased cortical signal entropy shortly after dosing predicted better psychological well-being at one month, with next-day psychological insight mediating this relationship. No such effects occurred with a 1 mg placebo dose. Cognitive flexibility, psychological insight, and well-being also increased at one month.
The Biochemist
March 14, 2024
Natalie Ertl, Matthew B. Wall
Psychedelics have been used for ritual, spiritual, and medicinal purposes since prehistory across many cultures. Classic psychedelics like psilocybin act on the serotonin 5-HT2A receptor, while atypical ones like MDMA and ketamine have different mechanisms and produce less hallucination. They all induce profound shifts in consciousness, positive emotions, and feelings of connectedness. LSD, first synthesized in the early 1940s, began the first wave of Western psychedelic research. By the 1960s, thousands of patients had received LSD therapy for depression, anxiety, and addiction in the USA, UK, and Czech Republic, coinciding with the development of other psychiatric drugs like monoamine oxidase inhibitors and antipsychotics.