Sci Rep
October 13, 2017
Robin Carhart-Harris, Leor Roseman, Mark Bolstridge et al.
590 citations
In patients with treatment-resistant depression, a single dose of psilocybin combined with psychological support reduced depressive symptoms and altered brain activity and connectivity. Functional MRI scans before and after treatment showed decreased blood flow in the temporal cortex, including the amygdala, and increased resting-state functional connectivity within the default-mode network. Reduced amygdala blood flow correlated with fewer depressive symptoms. Changes in connectivity between the ventromedial prefrontal cortex and inferior lateral parietal cortex, as well as between the parahippocampus and prefrontal cortex, predicted treatment response at five weeks. These brain changes differ from the drug's acute effects and suggest a 'reset' of neural circuits.
Nat Med
April 11, 2022
Richard E. Daws, Christopher Timmermann, Bruna Giribaldi et al.
432 citations
Psilocybin therapy produces rapid and sustained antidepressant effects that correlate with a global increase in brain network integration. In two clinical trials, one open-label in treatment-resistant depression and one double-blind randomized controlled trial comparing psilocybin with escitalopram in major depressive disorder, functional MRI showed that psilocybin reduced brain network modularity, making higher-order functional networks more interconnected and flexible. The antidepressant response to escitalopram was milder, with no changes in brain network organization. These consistent efficacy-related brain changes across both studies suggest that psilocybin's antidepressant mechanism involves global increases in brain network integration.
Neuropharmacology
December 27, 2017
Leor Roseman, Lysia Demetriou, Matthew B. Wall et al.
239 citations
In an open-label study, 20 individuals with moderate to severe, treatment-resistant depression received two doses of psilocybin with psychological support. Nineteen completed fMRI scans before and after treatment. Depressive symptoms improved rapidly and enduringly. Right amygdala responses to fearful and happy faces increased after psilocybin, and increased responses to fearful versus neutral faces predicted clinical improvement at one week. This contrasts with SSRIs, which typically reduce amygdala responses, suggesting psilocybin may help patients confront and work through emotions rather than dampen them. The authors propose psilocybin with psychological support revives emotional responsiveness in depression.
Pharmacology & Therapeutics
October 20, 2018
Michael Bloomfield, Chandni Hindocha, Sebastian F Green et al.
236 citations
Cannabis and its primary psychoactive component, THC, acutely alter executive, emotional, reward, and memory processing by directly interacting with the endocannabinoid system and indirectly affecting glutamatergic, GABAergic, and dopaminergic systems. Cannabidiol, a non-intoxicating cannabinoid, may offset some of these acute effects. Heavy repeated cannabis use, especially during adolescence, is associated with adverse effects that increase the risk of mental illnesses such as addiction and psychosis. This review synthesizes human neuroimaging research on the acute and chronic neuropsychopharmacology of cannabis, covering effects during development, implications for psychosis and cannabis use disorder, and methodological considerations.
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.
Psychopharmacology
September 2, 2016
Will Lawn, Tom P. Freeman, Rebecca Pope et al.
177 citations
Cannabis containing only THC reduced the likelihood of choosing high-effort rewards compared to placebo, indicating a transient amotivational state, while adding CBD altered the effect of THC on expected value. Cannabis-dependent individuals showed preserved motivation but impaired reward learning compared to non-dependent controls, though depression may have influenced results.
Eur Neuropsychopharmacol
April 12, 2016
Mendel Kaelen, Leor Roseman, Joshua Kahan et al.
143 citations
Psychedelic drugs like LSD are being re-examined for therapeutic use, often combined with music during psychotherapy. In a placebo-controlled fMRI study with 12 healthy volunteers, researchers investigated how LSD and music together affect mental imagery. They found that the combination of LSD and music increased functional connectivity and information flow from the parahippocampal cortex to the visual cortex. This enhanced connectivity correlated with stronger eyes-closed visual imagery, including autobiographical imagery. The findings suggest a neural mechanism by which music and LSD synergistically enhance subjective experiences that may be valuable in therapeutic settings.
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
April 23, 2019
Matthew B. Wall, Rebecca Pope, Tom P. Freeman et al.
89 citations
Two strains of cannabis—one containing only THC (8 mg) and another containing THC plus CBD (8 mg THC + 10 mg CBD)—were compared with placebo in seventeen healthy, experienced but non-regular cannabis users. Using resting-state fMRI, both strains reduced functional connectivity in the default mode and salience networks relative to placebo, but with distinct spatial patterns. The THC-only strain specifically disrupted the posterior cingulate cortex within the default mode network, and this disruption correlated with subjective feelings of being 'stoned' and 'high'. The THC-plus-CBD strain produced less disruption of the salience network, suggesting CBD may buffer THC's effects on salience processing, which could underlie its potential therapeutic role in disorders like psychosis and addiction.
The International Journal of Neuropsychopharmacology
August 30, 2017
Tom P. Freeman, Rebecca Pope, Matthew B. Wall et al.
67 citations
Cannabis dampens the brain's response to music in regions involved in reward and emotion, including the auditory cortex, hippocampus, amygdala, and ventral striatum. However, when cannabis also contains cannabidiol, these dampening effects are offset, and brain activity does not differ from placebo. Despite reduced neural responses, both types of cannabis increased participants' self-reported desire to listen to music and enhanced sound perception. The findings suggest that cannabidiol may mitigate some of cannabis's effects on brain reward systems.
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.
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.
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.
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.
Addiction
February 8, 2023
Will Lawn, Katie Trinci, Claire Mokrysz et al.
36 citations
Adolescent cannabis users are neither more resilient nor more vulnerable than adult cannabis users to the acute psychotomimetic, verbal memory-impairing, or subjective effects of cannabis. In a randomized, double-blind, placebo-controlled crossover experiment with 24 adolescents (16-17 years old) and 24 adults (26-29 years old) who used cannabis 0.5-3 days per week, vaporized THC (8 mg for a 75 kg person) and THC plus CBD (24 mg) both significantly increased subjective drug effect, impaired verbal episodic memory, and increased psychotomimetic effects compared to placebo. There was no evidence that adolescents differed from adults in their responses, and CBD did not modulate the acute effects of THC.
Journal of Psychopharmacology
August 13, 2014
LH Stewart, B. Ferguson, CJA Morgan et al.
28 citations
Acute recreational use of MDMA (ecstasy) increases perceived trustworthiness of faces and cooperative behavior in economic games. In a study comparing 17 ecstasy users tested on the night of drug use and again three days later with 22 controls, users rated faces as more trustworthy and showed more cooperation on dictator and ultimatum games while intoxicated. By day three, no group differences remained on these tasks. Self-ratings showed typical acute effects such as euphoria and energy, with negative effects like reduced empathy and increased distrust emerging on day three. The findings suggest a single dose enhances aspects of empathy, which may contribute to its recreational popularity and potential therapeutic use.
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.
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.
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.
Neuropsychopharmacology
May 28, 2024
Natalie Ertl, Tom P. Freeman, Claire Mokrysz et al.
19 citations
Cannabis use disrupts resting-state functional connectivity in key brain networks—default mode, executive control, salience, hippocampal, and limbic striatal—similarly in adolescents (16–17 years) and young adults (26–29 years). Cannabidiol (CBD) did not counteract the effects of delta-9-tetrahydrocannabinol (THC) and, in some cases, further reduced connectivity both within networks and across the whole brain. These findings challenge the assumption that CBD makes cannabis safer and indicate that the adolescent brain is not more vulnerable to cannabis-induced connectivity disruptions than the adult brain.
Journal of Psychopharmacology
July 29, 2023
Natalie Ertl, Will Lawn, Claire Mokrysz et al.
17 citations
Regular cannabis use is associated with localized increases in connectivity of the executive control network (ECN), which may reflect adaptive or compensatory changes in response to regular intoxication. Adolescents generally showed weaker connectivity than adults across multiple brain networks, consistent with normal developmental effects. However, there were no significant interactions between age group and cannabis user group, meaning the connectivity changes linked to cannabis use did not differ between adolescents and adults. No associations were found between cannabis use frequency and any connectivity measures.
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.