Archives of General Psychiatry
January 1, 2009
Paolo Fusar‐poli, José A. Crippa, Sagnik Bhattacharyya et al.
461 citations
In healthy men with minimal prior cannabis use, the two main psychoactive compounds in cannabis had opposite effects on anxiety and brain activity. Delta9-tetrahydrocannabinol (THC) increased anxiety, intoxication, sedation, and psychotic symptoms, while cannabidiol (CBD) showed a trend toward reducing anxiety. When participants viewed intensely fearful faces, THC increased skin conductance fluctuations (a measure of autonomic arousal), whereas CBD decreased them. CBD also dampened brain activation in the amygdala and anterior and posterior cingulate cortex, and this suppression correlated with reduced arousal. THC mainly altered activation in frontal and parietal areas. These distinct neural effects may explain why cannabis can both relieve and provoke anxiety.
Biological Psychiatry
November 29, 2014
Yasmin Schmid, Florian Enzler, Peter Gasser et al.
425 citations
In a double-blind, placebo-controlled crossover study, 200 μg of lysergic acid diethylamide (LSD) given to 16 healthy subjects produced pronounced alterations in consciousness lasting 12 hours, including visual hallucinations, audiovisual synesthesia, and positively experienced derealization and depersonalization. LSD increased subjective well-being, happiness, closeness to others, openness, and trust, and decreased prepulse inhibition (PPI) of the acoustic startle response, a measure of sensorimotor gating. It also significantly increased blood pressure, heart rate, body temperature, pupil size, and plasma levels of cortisol, prolactin, oxytocin, and epinephrine. All adverse effects subsided within 72 hours, with no severe acute adverse effects observed. LSD produces empathogenic mood effects similar to methylenedioxymethamphetamine and alters sensorimotor gating in a human model of psychosis, supporting its potential use in psychotherapy and translational psychiatric research.
Current Pharmaceutical Design
September 12, 2012
Rocío Martín‐Santos, José Alexandre S. Crippa, Albert Batalla et al.
288 citations
Delta-9-tetrahydrocannabinol (THC), but not cannabidiol (CBD), produces marked acute behavioral and physiological effects. In a randomized, double-blind, placebo-controlled trial with 16 healthy male volunteers, oral THC (10 mg) caused anxiety, dysphoria, positive psychotic symptoms, physical and mental sedation, subjective intoxication, and increased heart rate relative to placebo and CBD. CBD (600 mg) showed no differences from placebo on any symptomatic or physiological measure, indicating it is safe and well tolerated. The two main cannabis constituents thus have quite different acute effects.
Neuropsychopharmacology
November 16, 2019
Friederike Holze, Patrick Vizeli, Felix Müller et al.
250 citations
LSD, MDMA, and d-amphetamine all increased heart rate, blood pressure, body temperature, and pupil size, but LSD produced the strongest alterations in consciousness, mystical experiences, ego dissolution, and emotional excitation. MDMA increased feelings of good drug effects, liking, and high more than d-amphetamine, and only MDMA raised oxytocin levels. d-Amphetamine boosted activity and concentration relative to LSD. None of the substances changed brain-derived neurotrophic factor. The findings highlight distinct subjective and endocrine profiles that may inform dosing in psychedelic-assisted therapy.
Archives of General Psychiatry
April 1, 2009
Sagnik Bhattacharyya, Paolo Fusar‐poli, Stefan Borgwardt et al.
250 citations
Delta9-tetrahydrocannabinol (THC), a psychoactive constituent of cannabis, increased psychotic symptoms, anxiety, intoxication, and sedation in healthy men with minimal prior cannabis use, while cannabidiol had no significant effect on these measures. Verbal learning performance was not significantly affected by either drug. THC altered brain activation in the parahippocampal gyrus during encoding and in the ventrostriatum during retrieval, with the ventrostriatal change directly correlating with induced psychotic symptoms. These findings suggest THC modulates mediotemporal and ventrostriatal function, potentially underlying cannabis's effects on verbal learning and psychosis.
Neuropsychopharmacology
June 1, 2016
Patrick C. Dolder, Yasmin Schmid, Felix Müller et al.
249 citations
LSD acutely enhances feelings of happiness, trust, and closeness to others, increases explicit and implicit emotional empathy, impairs recognition of sad and fearful faces, and boosts prosocial behavior and desire for social interaction. These effects were observed in two placebo-controlled, double-blind, crossover studies with 24 participants receiving 100 μg and 16 receiving 200 μg of LSD. All participants were healthy, mostly hallucinogen-naive adults aged 25 to 65. The findings suggest that LSD alters emotional processing and sociality in ways that may support its use as an adjunct to psychotherapy for anxiety in patients with life-threatening illness.
Neuropsychopharmacology
October 15, 2020
Friederike Holze, Patrick Vizeli, Laura Ley et al.
243 citations
Lysergic acid diethylamide (LSD) produces dose-dependent subjective effects starting at 25 µg, with a ceiling for good drug effects at 100 µg, while ego dissolution and anxiety increase further at 200 µg. The average duration of subjective effects lengthens from 6.7 to 11 hours across the 25–200 µg range. LSD moderately raises blood pressure and heart rate. The serotonin 5-HT2A receptor antagonist ketanserin (40 mg) given before 200 µg LSD prevents the response, indicating that LSD's full psychedelic effects are primarily mediated by 5-HT2A receptor activation. These results assist dose finding for future LSD research.
Psychological Medicine
July 23, 2009
R. Martín-Santos, Ana B. Fagundo, José Alexandre S. Crippa et al.
207 citations
A systematic review of neuroimaging studies published up to January 2009 assessed evidence for cannabis effects on brain structure and function. Among 41 included studies, functional imaging indicated that resting global and prefrontal blood flow are lower in cannabis users than in controls. Activation studies during cognitive tasks produced inconsistent results. Acute administration of THC or marijuana increased resting activity and activation of the frontal and anterior cingulate cortex during cognitive tasks. Only three of eight structural imaging studies found differences between users and controls, providing minimal evidence of major effects of cannabis on brain structure.
The International Journal of Neuropsychopharmacology
September 24, 2009
Paolo Fusar‐poli, Paul Allen, Sagnik Bhattacharyya et al.
165 citations
Cannabidiol (CBD), but not delta-9-tetrahydrocannabinol (THC), disrupts forward connectivity between the amygdala and the anterior cingulate cortex during the neural response to fearful faces. This disruption may represent a neurophysiological correlate of CBD's anxiolytic properties. The study used dynamic causal modelling and Bayesian model selection to analyze effective connectivity in 15 healthy subjects under a double-blind, randomized, placebo-controlled fMRI paradigm while they viewed faces eliciting different levels of anxiety.
Acta Psychiatrica Scandinavica
September 21, 2017
Felix Müller, Claudia Lenz, Patrick C. Dolder et al.
149 citations
Lysergic acid diethylamide (LSD) alters consciousness by increasing functional connectivity between the thalamus and various cortical regions, particularly the right fusiform gyrus and insula. In 20 healthy participants given 100 μg LSD orally, thalamic connectivity changes correlated with subjective auditory and visual drug effects. These findings suggest that hallucinogenic effects may arise from enhanced cortical excitability through thalamocortical interactions, providing insight into the role of the 5-HT2A receptor in altered states of consciousness.
Translational Psychiatry
April 4, 2017
Felix Mueller, Claudia Lenz, Patrick C. Dolder et al.
124 citations
Lysergic acid diethylamide (LSD) reduces reactivity in the left amygdala and right medial prefrontal cortex when processing fearful faces, compared to a placebo. In a double-blind, randomized, crossover study, 20 healthy adults received either 100 μg of LSD or a placebo before undergoing functional magnetic resonance imaging (fMRI). Plasma LSD levels were measured before and after the scan. A significant negative correlation emerged between the reduced amygdala response to fearful stimuli and the subjective drug effects reported by participants. These findings indicate that LSD alters the engagement of brain regions involved in emotional processing.
Psychopharmacology
May 27, 2017
Patrick C. Dolder, Felix Müller, Yasmin Schmid et al.
118 citations
At equally cardiostimulant doses, MDMA (125 mg) produced distinct subjective, emotional, sexual, and endocrine effects compared to methylphenidate (60 mg) and modafinil (600 mg) in healthy participants. MDMA increased pupil dilation, subjective good drug effects, drug liking, happiness, trust, well-being, and alterations in consciousness, while reducing anxiety and impairing fear recognition, leading to misclassifications of emotions as happy. It also induced sexual arousal-like effects and marked increases in cortisol, prolactin, and oxytocin. Methylphenidate increased anxiety and, along with modafinil, increased misclassifications of emotions as angry. Modafinil had no significant subjective effects but produced sympathomimetic and adverse effects.
Current Pharmaceutical Design
May 10, 2014
Johannes Wrege, André Schmidt, Anna Walter et al.
96 citations
A systematic review of 17 studies (13 meeting inclusion criteria) examined cannabis's effects on impulsivity, disinhibition, and motor control, with a focus on neuroimaging findings from acute and chronic use up to May 2012. Functional imaging studies indicate that chronic cannabis users have lower prefrontal blood flow than controls, while acute administration of THC or marijuana increases brain metabolism in several regions during impulsivity tasks. Structural imaging studies found reduced prefrontal volumes and white matter integrity in cannabis users, which may mediate abnormal impulsivity and mood. The review concludes that more longitudinal studies are needed to determine whether impulsivity precedes cannabis use or cannabis aggravates impulsivity and discontinuation.
British Journal of Clinical Pharmacology
March 19, 2019
Friederike Holze, Urs Duthaler, Patrick Vizeli et al.
72 citations
After a 100 μg oral dose of LSD, plasma levels peak at about 1.7 hours and decline with a half-life of 3.6 hours. The main metabolite O-H-LSD peaks later, around 5 hours, and has a longer half-life of 5.2 hours. No sex differences in pharmacokinetics were observed. Subjective effects last an average of 8.5 hours, peaking at 2.5 hours. The concentration needed to produce half-maximal effects is 1.0 ng/mL for good effects and 1.9 ng/mL for bad effects, showing that subjective experiences closely track plasma concentrations over time.
Neuroscience & Biobehavioral Reviews
December 30, 2015
Felix Mueller, Claudia Lenz, Markus Steiner et al.
68 citations
Moderate use of MDMA (ecstasy) shows no convincing evidence of structural or functional brain alterations in neuroimaging studies. A review of 19 studies, each involving subjects with fewer than 50 lifetime episodes or under 100 tablets consumed, found no significant harmful effects. However, the lack of results is linked to high methodological variability in dosages and co-consumption of other drugs, low study quality, and small sample sizes.
Psychopharmacology
January 25, 2022
Felix Müller, Elias Kraus, Friederike Holze et al.
64 citations
Up to 9.2% of healthy volunteers reported reoccurring drug-like experiences after taking LSD or psilocybin in controlled studies, but none met the criteria for hallucinogen-persisting perception disorder (HPPD). The experiences were mostly mild, visual, brief, and perceived as neutral or pleasant, with no impairment in daily life. Distressing experiences occurred in two subjects but subsided spontaneously. The findings suggest that flashbacks are not a clinically relevant problem in controlled settings with healthy participants.
Psychological Medicine
October 2, 2017
André Schmidt, Felix Müller, Claudia Lenz et al.
62 citations
Activating the serotonin 2A receptor with LSD impairs the brain's ability to stop or inhibit responses, and this breakdown is linked to visual hallucinations. In a double-blind, placebo-controlled experiment with 18 healthy adults, LSD reduced brain activity in regions including the frontal and cingulate cortex, middle temporal gyrus, and cerebellum during a response-inhibition task. Parahippocampal activation related differently to performance under LSD versus placebo. Less activation in the left superior frontal gyrus during LSD exposure was associated with greater cognitive impairment and visual imagery. The findings suggest that 5-HT2A receptor activation disrupts hippocampal-prefrontal circuits, which may promote visual hallucinations.
Psychological Medicine
October 1, 2012
Zerrin Atakan, Sagnik Bhattacharyya, Paul Allen et al.
54 citations
A double-blind, placebo-controlled study of 21 healthy men with minimal cannabis experience found that oral administration of 10 mg THC induced transient psychotic symptoms in 11 participants but not in the other 10. Those who became transiently psychotic made more inhibition errors and showed opposite patterns of brain activation in the left parahippocampal gyrus, left and right middle temporal gyri, and right cerebellum compared to the non-psychotic group. The findings suggest that variability in sensitivity to THC's psychotogenic effects is linked to differential activation in ventral and medial temporal cortex and cerebellum.
Neuroscience & Biobehavioral Reviews
November 12, 2018
Felix Müller, Raphael Brändle, Matthias E. Liechti et al.
52 citations
A meta-analysis of neuroimaging studies found that people who use MDMA (ecstasy) have significantly lower serotonin transporter (SERT) density in eight out of thirteen brain regions examined, compared to non-users. The reduction in SERT density was positively associated with the duration of abstinence, suggesting that these brain changes may be partially reversible with sustained abstinence. No significant differences were found between users and controls in neurochemical ratios in the frontal and occipital lobes or in blood flow in the basal ganglia. The analysis included 356 MDMA users and 311 controls from sixteen studies, but the user groups showed heavy use patterns and the overall study quality was poor.
Neurosignals
January 1, 2017
Davide Zanchi, Marie‐Louise Montandon, Indrit Sinanaj et al.
46 citations
Brain functional changes in the fronto-parietal network and default mode network precede observable cognitive decline in healthy older adults. In a study of 62 elderly individuals, those with stable cognition, those who later deteriorated, and those with mild cognitive impairment showed distinct brain activation patterns during a working memory task. Compared to stable controls, individuals with mild cognitive impairment and those who later declined had lower activation in frontal regions but higher activation in the anterior and posterior cingulate cortex and insula. These neural differences appeared before performance differences on cognitive tests, suggesting they may serve as early markers of cognitive decline.
Neuropsychopharmacology
April 25, 2023
Peter Bedford, Daniel J. Hauke, Zheng Wang et al.
43 citations
Lysergic acid diethylamide (LSD) predominantly strengthens interregional connections and reduces self-inhibition across the brain, except in occipital and subcortical regions where connections weaken and self-inhibition increases. These patterns suggest LSD perturbs the brain's excitation/inhibition balance. Whole-brain effective connectivity, assessed via regression dynamic causal modelling of resting-state fMRI data from 45 participants in two placebo-controlled trials, discriminated LSD from placebo with 91.11% accuracy and correlated with global subjective effects, indicating potential for decoding subjective experiences.
Biological Psychiatry Cognitive Neuroscience and Neuroimaging
April 29, 2022
Mihai Avram, Felix Müller, Helena Rogg et al.
43 citations
Psychedelics, empathogens, and psychostimulants produce increased connectivity between the thalamus and sensorimotor areas of the brain, a pattern similar to that observed in individuals with psychotic disorders. This suggests a shared neural mechanism across these substances and certain psychiatric conditions, linking altered thalamocortical communication to changes in perception and behavior.
Frontiers in Psychiatry
October 13, 2021
Mihai Avram, Helena Rogg, Αλεξάνδρα Κορδά et al.
43 citations
Classic psychedelics and acute psychosis share overlapping disruptions in brain connectivity, particularly involving the thalamus and its connections to cortical regions. Both states exhibit hyperconnectivity between the thalamus and sensorimotor cortices, linked to altered perceptions and hallucinations. Psychosis also shows hypoconnectivity between the thalamus and prefrontal cortices, associated with cognitive disturbances. These patterns of thalamocortical dysconnectivity extend to cortico-striato-pallido-thalamo-cortical circuitry. The review synthesizes neuroimaging and neuropharmacological evidence to highlight shared and distinct neurophysiological changes, suggesting clinically relevant parallels that may inform future research on perception and cognition.
Neuropsychopharmacology
November 20, 2020
Felix Müller, Friederike Holze, Patrick C. Dolder et al.
43 citations
The non-hallucinogenic drug MDMA reduces functional connectivity within several resting-state brain networks, including the default mode network, visual networks, and the sensorimotor network. These decreases closely match those previously reported for hallucinogenic drugs like LSD. The findings suggest that such connectivity changes are not specific to serotonergic hallucinogens but can be induced by monoaminergic stimulation without marked subjective drug effects. However, alterations within the default mode network may help explain the antidepressant effects of some of these substances.
The International Journal of Neuropsychopharmacology
May 16, 2017
André Schmidt, Felix Müller, Patrick C. Dolder et al.
41 citations
Methylphenidate and modafinil, but not MDMA (ecstasy), improved the ability to stop a motor response in healthy adults. Using brain imaging, methylphenidate broadly activated frontal, temporal, and parietal regions, including the anterior cingulate cortex and presupplementary motor area, more than modafinil did. Modafinil increased activation in the right middle frontal gyrus and parietal lobule, while MDMA activated the right middle/inferior frontal gyrus and superior parietal lobule without improving performance. The findings suggest that methylphenidate may be superior to modafinil and MDMA for enhancing cognitive performance related to response inhibition in healthy people.