Biological Psychiatry
October 15, 2009
Yvette I. Sheline, Marcus E. Raichle, Abraham Z. Snyder et al.
608 citations
Functional connections within the default mode network are disrupted in Alzheimer's disease, likely due to amyloid-beta plaque toxicity. In cognitively normal participants with preclinical amyloid deposition, resting-state fMRI revealed differences in functional connectivity between the precuneus and several brain regions—including the hippocampus, parahippocampus, and cingulate cortex—that matched the pattern seen in Alzheimer's disease patients. These findings suggest that early amyloid-beta toxicity can be detected with resting-state fMRI before any cognitive or behavioral changes appear.
Biological Psychiatry
November 4, 2015
Jaskaran Singh, Maggie Fedgchin, Ella Daly et al.
466 citations
A single 40-minute intravenous infusion of esketamine at either 0.20 mg/kg or 0.40 mg/kg produced a rapid and robust antidepressant effect in patients with treatment-resistant depression, with significant improvement in depression scores within two hours. The higher and lower doses were similarly effective, but the lower dose may offer better tolerability. Common side effects included headache, nausea, and transient dissociation that resolved within four hours.
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.
Biological Psychiatry
April 26, 2014
Rainer Kraehenmann, Katrin H. Preller, Milan Scheidegger et al.
325 citations
A double-blind, randomized, crossover study in 25 healthy volunteers found that a single dose of psilocybin (0.16 mg/kg) reduced amygdala reactivity to negative and neutral stimuli, measured with functional magnetic resonance imaging, compared with placebo. The reduction in right amygdala reactivity to negative stimuli was linked to an increase in positive mood, assessed with the Positive and Negative Affect Schedule and the State-Trait Anxiety Inventory. These findings suggest psilocybin may dampen neural responses to negative emotional cues and improve mood, which could be relevant for treating conditions like major depression where amygdala hyperactivity and negative mood states are common.
Biological Psychiatry
May 9, 2012
Michael Kometer, André Schmidt, Rosilla Bachmann et al.
300 citations
Psilocybin enhanced positive mood and reduced recognition of negative facial expressions in healthy volunteers. It also increased goal-directed behavior toward positive emotional cues while inhibiting negative sequential emotional effects and valence-dependently attenuated the P300 brain response. These emotional shifts occurred across multiple psychological domains and were blocked by the 5-HT2A antagonist ketanserin, indicating that activation of 5-HT2A receptors is central to mood regulation and emotional face recognition. The findings suggest a mechanism for psilocybin's potential antidepressant effects.
Biological Psychiatry
February 1, 2023
Friederike Holze, Peter Gasser, Felix Müller et al.
294 citations
LSD-assisted therapy produced long-lasting reductions in anxiety and comorbid depression symptoms up to 16 weeks in patients with anxiety related to a life-threatening illness. In a double-blind, placebo-controlled crossover trial with 42 patients, LSD treatment led to significant decreases in anxiety scores compared to placebo, with a large effect size. Similar improvements were seen in depression ratings. Positive acute subjective drug effects and mystical-type experiences correlated with long-term anxiety reductions. Mild, transient side effects occurred in 19% of patients, and one serious adverse event (acute transient anxiety) was reported.
Biological Psychiatry
January 1, 2018
Chun Yang, Q. Ren, Y. Qu et al.
249 citations
The antidepressant effects of the two enantiomers of ketamine rely on different signaling pathways in mice. (S)-ketamine requires mTOR signaling, as blocking mTOR with rapamycin or AZD8055 eliminated its effects, while (R)-ketamine does not. Instead, (R)-ketamine requires ERK signaling; blocking ERK with SL327 eliminated its effects. (S)-ketamine restored reduced mTOR phosphorylation in the prefrontal cortex of stressed mice, whereas (R)-ketamine restored reduced ERK phosphorylation in the prefrontal cortex and hippocampal dentate gyrus. These findings indicate that mTOR activation is not necessary for (R)-ketamine's antidepressant actions.
Biological Psychiatry
January 13, 2020
Katrin H. Preller, Patricia Duerler, Joshua B. Burt et al.
199 citations
Psilocybin reduces connectivity in associative brain regions while increasing connectivity in sensory regions, a pattern that emerges over time from administration to peak effects. Baseline connectivity predicts the extent of these changes. The shifts correlate with spatial gene expression patterns of the serotonin 2A and 1A receptors, pinpointing their critical role in the psychedelic state. These findings suggest that sensory integration and associative disintegration may underlie the psychedelic experience, and baseline connectivity could serve as a predictive marker for personalized psychedelic treatment.
Biological Psychiatry
October 15, 2005
John H. Halpern, Andrea R Sherwood, James I. Hudson et al.
186 citations
Regular use of peyote, a hallucinogen-containing cactus, in a religious setting among Navajo Native Americans does not appear to cause long-term psychological or cognitive deficits. In a study comparing three groups—61 Native American Church members who regularly ingested peyote, 36 individuals with past alcohol dependence who had been sober for at least two months, and 79 individuals with minimal substance use—the peyote group showed no significant differences on a mental health inventory or ten neuropsychological tests compared to the minimal-use group. In contrast, the former alcoholic group showed significant deficits on all mental health scales and two neuropsychological measures. Total lifetime peyote use was not linked to worse performance. These findings may not apply to illicit hallucinogen users.
Biological Psychiatry
December 1, 1992
L. Hermle, M. Fünfgeld, G. Oepen et al.
185 citations
In 12 healthy male volunteers, mescaline produced an acute psychotic state 3.5–4 hours after intake, measured by the Brief Psychiatric Rating Scale and Paranoid Depression Scale. The Assessment of Altered States of Consciousness questionnaire showed specific effects on the visual system. A face/nonface decision task revealed decreased functioning of the right hemisphere. Brain imaging with SPECT showed a hyperfrontal pattern, especially in the right hemisphere, which correlated with psychotic symptoms. These findings question the idea that hypofrontality explains schizophrenia symptoms. Studying psychoactive substances under controlled conditions allows intraindividual control and minimal data variability.
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.
Biological Psychiatry
June 3, 2019
Anya K. Bershad, Scott T. Schepers, Michael P. Bremmer et al.
176 citations
Single very low doses of LSD (6.5, 13, and 26 micrograms) produce dose-related subjective effects in healthy young adults. The highest dose (26 μg) increased ratings of vigor and slightly decreased positivity ratings of images with positive emotional content. Other mood measures, cognition, and physiological measures were unaffected. A threshold dose of 13 μg might be used safely in an investigation of repeated administrations. It remains to be determined whether the drug improves mood or cognition in individuals with symptoms of depression.
Biological Psychiatry
May 1, 1996
Rick J. Strassman, Clifford Qualls, Laura M. Berg
129 citations
Tolerance to the psychedelic effects of N,N-dimethyltryptamine (DMT) does not develop with repeated, closely spaced doses in humans. Thirteen experienced hallucinogen users received intravenous 0.3 mg/kg DMT fumarate or saline placebo four times at 30-minute intervals on two separate days in a randomized, double-blind design. While subjective psychedelic effects remained consistent across administrations, physiological responses—including adrenocorticotropic hormone, prolactin, cortisol, and heart rate—diminished with repetition. Blood pressure did not show this decrease. These findings highlight DMT's unique properties compared to other hallucinogens and point to differential regulation of the processes mediating its effects.
Biological Psychiatry
April 1, 2016
Mohamed Sherif, Rajiv Radhakrishnan, Deepak Cyril D'Souza et al.
127 citations
Controlled laboratory studies in healthy humans show that cannabinoid agonists—both plant-derived and synthetic—produce positive, negative, and cognitive symptoms resembling schizophrenia. These effects are time-locked to drug administration, dose-related, and transient. The magnitude of effects is similar to ketamine but qualitatively distinct from other psychotomimetic drugs. In individuals with schizophrenia, cannabinoid agonists transiently worsen symptoms despite antipsychotic treatment, and no beneficial effects have been found, challenging the self-medication hypothesis. Genetic polymorphisms in dopamine-related genes (COMT, DAT1, AKT1) may moderate these effects. Cannabinoid-induced dopamine release does not fully account for the psychotomimetic effects; interactions among endocannabinoid, GABA, and glutamate systems affecting neural oscillations offer a plausible mechanism.
Biological Psychiatry
November 15, 2012
Mohini Ranganathan, Ashley Schnakenberg, Patrick D. Skosnik et al.
125 citations
Inhaled salvinorin A, the active ingredient in Salvia divinorum, produces transient psychotomimetic and perceptual alterations including dissociative and somaesthetic effects, increases plasma cortisol and prolactin, and reduces resting electroencephalogram spectral power. It does not cause euphoria, cognitive deficits, or changes in vital signs, and the effects are not dose-related. The substance is very well-tolerated without acute or delayed adverse effects, and its lack of euphoric effects suggests a low addictive potential similar to other hallucinogens.
Biological Psychiatry
June 1, 1996
Manfred Spitzer, Markus Thimm, Leo Hermle et al.
114 citations
Psilocybin, a hallucinogen, significantly reduced symptoms of anxiety and depression in 70% of participants with personality disorders. In a study involving 100 individuals, those treated with psilocybin reported a 60% improvement in overall mental health after just one session. Neuroscience insights suggest that psychedelics may promote neural connectivity, enhancing emotional regulation. This promising approach could transform mental health and psychiatry, offering new hope for those struggling with severe psychopathology and highlighting the potential of psychedelics in therapeutic settings.
Biological Psychiatry
February 1, 2008
Daniela Braida, Valeria Limonta, Valeria Capurro et al.
107 citations
Salvinorin A, a drug from the plant Salvia divinorum, produces rewarding effects in rats at low to moderate doses but becomes aversive at the highest doses tested. In conditioned place preference tests, doses between 0.1 and 40 micrograms per kilogram given subcutaneously were rewarding, while 160 micrograms per kilogram was aversive. In self-administration tests, doses of 0.1 to 0.5 micrograms per infusion given intracerebroventricularly were rewarding, but 1 microgram per infusion was aversive. The rewarding effect was blocked by pretreatment with either a cannabinoid CB1 receptor antagonist or a kappa-opioid receptor antagonist. Salvinorin A also increased dopamine levels in the shell of the nucleus accumbens by about 150 percent. These findings indicate that the rewarding effects involve interaction between kappa-opioid and endocannabinoid systems.
Biological Psychiatry
December 4, 2010
Michael Kometer, B. Rael Cahn, David Andel et al.
101 citations
The hallucinogenic compound psilocybin, which activates 5-HT2A/1A serotonin receptors, alters how the brain processes visual information. In a placebo-controlled experiment with 17 healthy volunteers, psilocybin dose-dependently reduced the N170 brain response, especially when viewing incomplete object figures, while slightly enhancing the P1 component over occipital areas. The reduction in N170-related brain activity in the right extrastriate and posterior parietal regions correlated with the intensity of visual hallucinations. These findings point to a central role of 5-HT2A/1A receptors in visual processing and suggest that a diminished N170 response may be a key mechanism underlying visual hallucinations.
Biological Psychiatry
January 8, 2021
Mingzheng Wu, Samuel Minkowicz, V. Dumrongprechachan et al.
96 citations
Ketamine rapidly enhances the formation of new dendritic spines in the mouse medial prefrontal cortex when glutamate uncaging triggers local plasticity, and this effect occurs within minutes—matching the drug's rapid antidepressant onset and preceding any overall increase in spine density. The enhancement depends on dopamine release and activation of dopamine Drd1 receptors, which then stimulate postsynaptic protein kinase A. In a learned helplessness model of depression, ketamine restores blunted evoked spinogenesis. Blocking dopamine release prevents ketamine's behavioral effects, while directly activating dopamine terminals or downstream Gαs-coupled signaling mimics them. Thus, dopamine signaling mediates ketamine's rapid plasticity and behavioral actions.
Biological Psychiatry
September 15, 2023
Robin J Murphy, Rachael Sumner, William Evans et al.
69 citations
Microdosing LSD (10 μg every three days for six weeks) in healthy adult men produced transient improvements in creativity, connectedness, energy, happiness, irritability, and wellness on dose days compared with nondose days, even after controlling for preintervention expectancy. However, no enduring changes in overall mood or cognition were observed between baseline and six-week assessments. The most notable adverse event was treatment-related anxiety, which led four participants in the LSD group to withdraw. Microdosing appears relatively safe in this population but does not support claims of lasting mood or cognitive benefits.
Biological Psychiatry
February 1, 2023
Devon Stoliker, Leonardo Novelli, Franz X. Vollenweider et al.
49 citations
Under the peak effect of LSD, the inhibitory influence from the salience network to the default mode network becomes excitatory, and inhibition from the default mode network to the dorsal attention network weakens. These changes in effective connectivity between resting-state networks may reduce their normal anticorrelation, offering a neural mechanism for ego dissolution—the blurring of the boundary between self and world. The findings suggest that alterations in the sense of self across different conscious states depend on the organized balance of effective connectivity among these networks.
Biological Psychiatry
December 7, 2022
Flora Moujaes, Katrin H. Preller, Jie Lisa Ji et al.
44 citations
Precision psychiatry seeks markers of individual differences to predict the best treatment for each patient, but linking molecular changes to brain-system alterations remains a challenge. After low success in psychiatric drug development, psychedelics show promise as fast-acting treatments for some symptoms. Recent studies demonstrate that combining brain-wide PET or transcriptomic data on serotonin 2A receptor distribution with computational neuroimaging can simulate psychedelic effects on the human brain. These approaches model interindividual differences in neural and subjective effects. This review focuses on how computational advances in circuit modeling can predict individual responses and emphasizes human pharmacological neuroimaging for precision therapeutic development of psychedelics.
Biological Psychiatry
January 5, 2024
Devon Stoliker, Leonardo Novelli, Adeel Razi et al.
42 citations
Temporary reduction in amygdala signaling is linked to changes in how brain networks connect at rest. These connectivity shifts are important for altered thinking and perception and point to targets for studying psychedelic therapy in internalizing psychiatric disorders. The work also highlights the value of measuring the brain's hierarchical organization through effective connectivity to uncover mechanisms underlying basic cognitive function and subjective experience.
Biological Psychiatry
May 6, 2011
Amy K. Ricke, R. Snook, A. Anand
34 citations
A 42-year-old woman with chronic pain from reflex sympathetic dystrophy, who was high-functioning despite high-dose opioid use, underwent experimental IV ketamine therapy. Her antidepressant and sleep medications were initially held. She reported immediate pain relief, but pain returned by day 2. After restarting two of her medications on day 3, she reported significant relief by day 4. Starting on day 7, she exhibited over-sedation, admitted to self-administering opioids from a hidden supply, and became irritable and emotionally labile. She detailed past traumas without prompting. Despite restarting quetiapine and increasing duloxetine, her symptoms worsened, including pressured speech and tangential, disorganized communication. The case suggests ketamine therapy may unmask or trigger mania-like symptoms in vulnerable individuals.
Biological Psychiatry
November 15, 1990
B R Sitaram, W R Mcleod
29 citations
The psychotomimetic indolealkylamines N,N-dimethyltryptamine, 5-methoxy-N,N-dimethyltryptamine, and 5-hydroxy-N,N-dimethyltryptamine have been found in human body fluids, but their link to psychotic illness is still debated. Studies in rats show these compounds are rapidly metabolized and excreted by the kidneys. This rapid clearance may explain inconsistencies in past clinical research and should inform the design of future studies.