Neuropsychopharmacology
April 26, 2017
Robin L Carhart-Harris, Guy M Goodwin
680 citations
Plant-based psychedelics like psilocybin have ancient medicinal roots. After LSD's first English-language report in 1950, psychedelics briefly aided psychotherapy for mood disorders and alcohol dependence before prohibitive legislation in the mid-1960s halted major research. Since the early 1990s, human psychedelic research has revived, with recent reports including the first modern brain imaging study with LSD and three clinical trials of psilocybin for depressive symptoms. The authors offer opinions on the promises and pitfalls of renewed research, focusing on developing psilocybin as a depression treatment.
Neuropsychopharmacology
January 26, 2019
M. Madsen, Patrick M. Fisher, Daniel Burmester et al.
505 citations
Psilocybin, the main psychedelic component of magic mushrooms, produces its effects by activating serotonin 2A receptors in the brain. In eight healthy volunteers who received a single oral dose of psilocybin (3–30 mg), PET scans showed dose-related occupancy of these receptors up to 72%. Plasma levels of psilocin, the active metabolite, and receptor occupancy both closely matched subjective ratings of psychedelic intensity, supporting that stimulation of serotonin 2A receptors is a key determinant of the psychedelic experience. Although psilocin levels in the blood varied over time, they were strongly linked to the intensity of the experience, which is important for designing clinical studies.
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.
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.
Neuropsychopharmacology
September 28, 2011
Boris B. Quednow, Michael Kometer, Mark A. Geyer et al.
241 citations
The hallucinogen psilocybin disrupts automatic and controlled inhibition processes in healthy humans by stimulating the serotonin-2A receptor (5-HT(2A)R). In a double-blind, randomized study with 16 participants, psilocybin (260 μg/kg) reduced prepulse inhibition of the acoustic startle response at short lead intervals, increased scores on the altered states of consciousness questionnaire, and increased errors and response latencies in the interference condition of the Stroop Test. These effects were attenuated by pretreatment with the 5-HT(2A/2C)R antagonist ketanserin (40 mg), which alone had no significant effects. The findings indicate that sensorimotor gating and attentional control deficits in schizophrenia may involve changes in the 5-HT(2A)R system.
Neuropsychopharmacology
April 27, 2017
Matthias E Liechti
230 citations
Over the past 25 years, six clinical studies have examined the classic hallucinogen LSD in healthy subjects and patients. In controlled settings, LSD acutely produces bliss, audiovisual synesthesia, altered meaning of perceptions, derealization, depersonalization, and mystical experiences, mediated by the 5-HT2A receptor. It increases feelings of closeness, openness, trust, and suggestibility, impairs recognition of sad and fearful faces, reduces left amygdala reactivity to fearful faces, enhances emotional empathy, and increases emotional response to music. LSD also causes sensorimotor gating deficits, weak autonomic stimulation, and elevated cortisol, prolactin, and oxytocin.
Neuropsychopharmacology
July 24, 2023
J. Krystal, E. Kavalali, L. Monteggia
229 citations
Ketamine, a drug that blocks NMDA receptors in the brain, produces rapid antidepressant effects in people with depression and treatment-resistant depression. This finding has led to new treatments for mood disorders and has advanced understanding of the brain's neurobiology and the synaptic plasticity mechanisms that make ketamine effective. This review covers the clinical aspects of ketamine's rapid antidepressant action, the synaptic and circuit mechanisms behind it, and how these insights can guide future research toward more effective treatments for neuropsychiatric disorders.
Neuropsychopharmacology
June 1, 1999
E Gouzoulis-Mayfrank
224 citations
Psilocybin (0.2 mg/kg) increased glucose metabolism in right frontotemporal cortical regions, especially the anterior cingulate, and decreased metabolism in the thalamus. Both MDE (2 mg/kg) and methamphetamine (0.2-0.4 mg/kg) caused cortical hypometabolism and cerebellar hypermetabolism. Cognitive activation-related increases in left frontocortical regions were attenuated under all three substances, but less so under MDE. The psilocybin results align with studies of acute schizophrenia showing frontal overactivity at rest but diminished capacity to activate prefrontal regions during cognitive tasks. The MDE findings support the idea that entactogens form a distinct psychoactive class intermediate between stimulants and hallucinogens.
Neuropsychopharmacology
February 25, 2022
Friederike Holze, Laura Ley, Felix Müller et al.
223 citations
In healthy volunteers, 100 and 200 micrograms of LSD and 30 milligrams of psilocybin produce comparable subjective effects, including alterations of mind that are qualitatively and quantitatively very similar. The 15 milligram psilocybin dose produces clearly weaker subjective effects. The 200 microgram dose of LSD induces higher ratings of ego-dissolution, impairments in control and cognition, and anxiety than the 100 microgram dose. LSD at both doses has clearly longer effect durations than psilocybin. Psilocybin increases blood pressure more than LSD, whereas LSD increases heart rate more than psilocybin, though both show comparable overall cardiostimulant properties. Any differences between LSD and psilocybin appear dose-dependent rather than substance-dependent, except for the differential effects on heart rate and blood pressure.
Neuropsychopharmacology
February 14, 2007
Franz X. Vollenweider, Philipp Csomor, Bernhard Knappe et al.
194 citations
Psilocybin, a hallucinogenic 5-HT(2A) receptor agonist, produces opposite effects on prepulse inhibition (PPI) of the startle response depending on the time interval between the prepulse and the startle stimulus. In healthy humans, psilocybin dose-dependently reduced PPI at short intervals (30 ms) and increased PPI at long intervals (120-2000 ms), with no effect at medium intervals (60 ms). The reduction in PPI at short intervals correlated with impaired sustained attention, consistent with PPI deficits seen in schizophrenia. Psilocybin also impaired attention and increased altered states of consciousness scores.
Neuropsychopharmacology
January 1, 2003
Daniel Umbricht, Franz X. Vollenweider, Liselotte Schmid et al.
192 citations
The NMDA receptor antagonist ketamine disrupts auditory mismatch negativity (MMN) and performance on an AX-type continuous performance test (AX-CPT), similar to deficits seen in schizophrenia. This placebo-controlled study tested the 5-HT(2A) receptor agonist psilocybin on the same measures in 18 healthy volunteers. Psilocybin caused significant performance deficits on the AX-CPT but did not significantly reduce MMN generation. These results suggest that deficient MMN generation in schizophrenia may specifically reflect NMDA receptor dysfunction, while impairments in AX-CPT performance during both psilocybin and ketamine administration may stem from shared disruption of glutamatergic neurotransmission. Comparable deficits in schizophrenia may arise from independent dysfunctions of 5-HT(2A) and NMDA receptor-related neurotransmission.
Neuropsychopharmacology
February 24, 2020
C. Abdallah, L. Averill, R. Gueorguieva et al.
181 citations
Ketamine produces rapid antidepressant effects within 24 hours, thought to involve mTORC1 activation. In a double-blind crossover trial, 20 depressed patients received either rapamycin (an mTORC1 inhibitor) or placebo before ketamine. Rapamycin did not block ketamine's 24-hour antidepressant effects. Over two weeks, rapamycin prolonged ketamine's benefits: response rates were 41% with rapamycin versus 13% with placebo, and remission rates were 29% versus 7%. These findings question whether systemic or local mTORC1 blockade matters and suggest rapamycin may extend ketamine's effects, potentially informing mechanisms of depression relapse.
Neuropsychopharmacology
May 1, 2002
C Nichols
165 citations
Lysergic acid diethylamide (LSD) produces profound effects such as hallucinations and detachment from reality, which resemble symptoms of schizophrenia. The first comprehensive analysis of gene expression after acute LSD administration in the mammalian brain identified genes involved in synaptic plasticity, glutamatergic signaling, and cytoskeletal architecture. These molecular events may provide new insights into disorders with similar behavioral symptoms and could lead to new therapies.
Neuropsychopharmacology
May 12, 2023
Naim Zaki, Li Chen, Rosanne Lane et al.
122 citations
Adults with treatment-resistant depression who continued esketamine nasal spray plus an oral antidepressant in a long-term extension study (SUSTAIN-3) showed sustained improvement in depression ratings over up to 4.5 years. Among 1148 participants, common side effects included headache, dizziness, nausea, dissociation, somnolence, and nasopharyngitis. Depression scores dropped during the initial four-week induction phase and remained low during maintenance; about 46% of participants were in remission at the maintenance phase endpoint. No new safety concerns emerged with long-term, intermittent dosing.
Neuropsychopharmacology
January 26, 2005
Olivia Carter, John D. Pettigrew, Felix Hasler et al.
122 citations
Binocular rivalry, where each eye sees a different image and perception alternates between them, is influenced by psilocybin. In 12 healthy volunteers, both low (115 µg/kg) and high (250 µg/kg) doses of psilocybin significantly reduced the rate and rhythmicity of perceptual alternations 90 minutes after administration, compared to placebo. Over time, switch rates increased, with some exceeding pretest levels at 360 minutes, though mean phase duration did not significantly differ from placebo. Drug-induced changes in rivalry phase durations corresponded to altered states of consciousness measured by the 5D-ASC scale. The findings implicate serotonergic pathways and support a brainstem oscillator's role in perceptual rivalry and psychosis symptoms.
Neuropsychopharmacology
March 17, 2022
Danilo de Gregorio, Antonio Inserra, Justine P. Enns et al.
89 citations
Lysergic acid diethylamide (LSD) is a serotonergic psychedelic being studied for potential anxiety and depression treatments, but its brain mechanisms are unclear. In male mice exposed to chronic restraint stress, acute LSD at doses of 5, 15, 30, and 60 μg/kg did not reduce anxiety or depression in non-stressed mice. However, daily 30 µg/kg LSD for 7 days prevented stress-induced anxiety-like behavior and the stress-induced loss of cortical dendritic spines. Repeated LSD increased the baseline firing rate of serotonin neurons in the dorsal raphe nucleus, which had been lowered by stress, and reduced the neurons' inhibitory response to a 5-HT1A receptor agonist. These effects suggest that repeated LSD prevents stress-induced anxiety by enhancing serotonin transmission and cortical spine density, possibly through desensitization of 5-HT1A receptors.
Neuropsychopharmacology
March 5, 2015
Sarah A. Stuart, Paul Butler, Marcus R. Munafò et al.
73 citations
Antidepressant drugs like ketamine and venlafaxine modify emotional biases in rats, but through different brain regions and at different times. In a bowl-digging task, rats learned two equal-value experiences, one under an affective manipulation and one under control conditions; their later choices revealed an affective bias. Ketamine, which acts rapidly, reduced a previously acquired negative bias when given before the preference test, and its effect depended on the medial prefrontal cortex. Venlafaxine, which acts slowly, induced a positive bias when given before learning, and its effect depended on the amygdala. Increasing the number of substrate-reinforcer associations amplified both positive and negative biases. This pattern may explain why venlafaxine has a delayed onset of action while ketamine acts quickly but lacks long-term efficacy.
Neuropsychopharmacology
February 20, 2023
Gabriela Garza, Bita Moghaddam, Alejandro Torrado Pacheco et al.
69 citations
Acute psilocybin robustly improves cognitive flexibility in male and female rats, enhancing their ability to switch between previously learned strategies in response to uncued environmental changes. Psilocybin did not affect Pavlovian reversal learning, indicating its cognitive effects are selective to strategy switching. The serotonin 5HT2A receptor antagonist ketanserin blocked psilocybin's effect on set-shifting, while a 5HT2C-selective antagonist did not; ketanserin alone also improved set-shifting performance, suggesting a complex pharmacological relationship. The psychedelic DOI impaired cognitive flexibility in the same task, showing this effect does not generalize to all serotonergic psychedelics. These findings provide a behavioral model for investigating psilocybin's neuronal effects relevant to its clinical outcomes.
Neuropsychopharmacology
July 24, 2023
Boris D. Heifets, David E. Olson
66 citations
Psychedelics and entactogens can produce rapid and lasting therapeutic effects, but there is a disconnect between how they are used in human clinics and how they are studied in animals. Human research emphasizes extra-pharmacological factors like set, setting, and integration, which are poorly modeled in animal experiments. Animal studies focus on neuronal activation and structural plasticity, which are hard to measure in humans. The paper proposes bridging this gap by focusing on the circuits these compounds modulate rather than single molecular targets, suggesting that selective circuit modulation of behavioral phenotypes may be more fruitful for identifying novel compounds with similar therapeutic effects.
Neuropsychopharmacology
May 5, 2020
Marcus W. Meinhardt, Cansu Güngör, Ivan Skorodumov et al.
66 citations
Psychedelic-assisted psychotherapy is hypothesized to restore normal brain function in people with alcohol use disorder (AUD) and reduce relapse risk after a single session. In this study, three treatment schedules with psilocybin or LSD were tested in male and female rats using the alcohol deprivation effect (ADE) model of relapse-like drinking. Neither high doses comparable to clinical studies nor chronic microdosing produced long-lasting reductions in relapse-like drinking. Only sub-chronic psilocybin had a short-lasting anti-relapse effect, but this regimen is not considered a translatable treatment. The findings do not support the hypothesis that microdosing or high-dose psychedelics reduce relapse behavior in this model, though the authors note that animal models may not fully capture psychedelics' therapeutic potential.
Neuropsychopharmacology
November 27, 2018
Hanna J. Szkudlarek, Sagar Desai, Justine Renard et al.
63 citations
Acute infusions of THC directly into the prefrontal cortex of rats produce anxiety-like effects without impairing executive function, while CBD infusions impair attentional set-shifting and spatial working memory without affecting anxiety or sociability. CBD reverses cognitive impairments caused by glutamatergic antagonism in the prefrontal cortex and blocks the anxiety-inducing properties of THC, suggesting CBD's therapeutic effects may only emerge during pathological states. These opposing effects are mediated through dissociable CB1 and 5-HT1A receptor signaling mechanisms within the prefrontal cortex.
Neuropsychopharmacology
March 9, 2005
Paul J Gresch, Randy L Smith, Robert J Barrett et al.
62 citations
Repeated administration of lysergic acid diethylamide (LSD) leads to tolerance, a decreased responsiveness to the drug. In rats trained to discriminate LSD from saline, five daily injections of a higher LSD dose caused a 44% reduction in their ability to recognize the drug. This behavioral tolerance was linked to reduced signaling through serotonin 5-HT2A receptors in the medial prefrontal cortex and anterior cingulate cortex, as shown by decreased G-protein coupling and lower receptor density. The findings suggest that adaptive changes in serotonin receptor signaling underlie tolerance to LSD's subjective effects.
Neuropsychopharmacology
June 21, 2022
Gitte M. Knudsen
56 citations
A single dose of serotonergic classical psychedelics like LSD, psilocybin, or DMT can produce long-lasting effects on personality, such as increased openness, and reduce depressive symptoms. This review synthesizes behavioral, biochemical, neuroimaging, and electrophysiological evidence suggesting that these enduring effects are rooted in neural plasticity. The authors highlight that while the acute emotional effects of these compounds are well understood, the mechanisms behind their sustained benefits remain understudied, and they propose future research directions to clarify how a single psychedelic dose can lead to prolonged therapeutic changes in the brain and mind.
Neuropsychopharmacology
August 1, 1999
J Backstrom
55 citations
Lysergic acid diethylamide (LSD) modifies serotonin neurotransmission, and new molecular techniques reveal that its signaling at serotonin 5-HT2C receptors differs from that of the endogenous agonist serotonin. RNA editing of the 5-HT2C receptor dramatically alters LSD's ability to stimulate phosphatidylinositol signaling, offering insight into the mechanisms of partial agonism.