The International Journal of Neuropsychopharmacology
July 9, 2019
593 citations
In a phase 3 trial of 346 adults with moderate-to-severe treatment-resistant depression, adding esketamine nasal spray (56 or 84 mg twice weekly) to a new oral antidepressant for 4 weeks did not significantly reduce depression scores compared to adding placebo nasal spray. The 84 mg dose failed to separate from placebo on the primary outcome, and the 56 mg dose could not be formally tested due to the statistical hierarchy. However, the magnitude of improvement with both esketamine doses exceeded what is typically considered clinically meaningful for approved antidepressants. Common side effects included nausea, dissociation, dizziness, vertigo, and headache. The authors conclude the results provide supportive evidence for esketamine's safety and efficacy in treatment-resistant depression.
The International Journal of Neuropsychopharmacology
October 31, 2014
A. E. Lepack, M. Fuchikami, J. M. Dwyer et al.
369 citations
Ketamine's rapid antidepressant effects depend on the release of brain-derived neurotrophic factor (BDNF) in the medial prefrontal cortex (mPFC), which is triggered by activation of L-type voltage-dependent calcium channels (VDCCs). Infusing a neutralizing BDNF antibody into the mPFC blocked ketamine's behavioral effects in the forced swim test. Pretreatment with either nifedipine or verapamil, two different L-type calcium channel antagonists, also blocked these effects. In primary cortical neurons, ketamine stimulated BDNF release, and this release was prevented by inhibiting AMPA receptors or L-type VDCCs. The findings indicate that L-type VDCC activation and BDNF release mediate ketamine's antidepressant actions.
The International Journal of Neuropsychopharmacology
March 12, 2020
Erwin Krediet, Tijmen Bostoen, Joost J. Breeksema et al.
262 citations
Posttraumatic stress disorder (PTSD) often remains chronic after psychotherapy, and few effective medications exist. A promising new approach involves psychedelic drugs. This review discusses four compound types: MDMA, ketamine, classical psychedelics (psilocybin, LSD), and cannabinoids. It describes each compound's therapeutic rationale, administration setting, and current evidence for treating PTSD. Each offers unique qualities, from rapidly targeting symptoms to facilitating psychotherapy. The review outlines questions for future research.
The International Journal of Neuropsychopharmacology
October 21, 2022
James J Gattuso, Daniel Perkins, Simon Ruffell et al.
233 citations
Classical psychedelics like LSD, psilocybin, and ayahuasca consistently disrupt resting-state connectivity within the Default Mode Network (DMN) and increase functional connectivity between canonical resting-state networks. The DMN, a set of brain regions active during self-referencing and mind wandering, is altered in various neuropsychiatric conditions. While DMN modulation is central to some cognitive models of psychedelics, its role in their therapeutic potential remains unclear. This systematic review provides a comprehensive overview to guide future research on the neurocognitive mechanisms of these agents.
The International Journal of Neuropsychopharmacology
May 17, 2017
Frederic Sampedro, Mario de la Fuente Revenga, Marta Valle et al.
205 citations
Ayahuasca, a psychedelic brew, alters brain chemistry and connectivity in ways that may explain its lasting psychological effects. The findings point to glutamate neurotransmission playing a role in how psychedelics work in humans. Neurometabolic changes in the posterior cingulate cortex, a hub of the default mode network, along with increased connectivity between the anterior cingulate cortex and medial temporal lobe structures involved in emotion and memory, likely underlie the post-acute psychological effects of ayahuasca.
The International Journal of Neuropsychopharmacology
June 14, 2017
Thomas Pokorny, Katrin H. Preller, Michael Kometer et al.
202 citations
Psilocybin enhances emotional empathy without affecting moral behavior, marking the first evidence of its distinct effects on social cognition. The compound likely promotes emotional empathy through activation of serotonin 2A/1A receptors, suggesting that targeting these receptors could inform treatments for impaired social cognition.
The International Journal of Neuropsychopharmacology
May 30, 2019
Nadia R. P. W. Hutten, Natasha L. Mason, Patrick C. Dolder et al.
132 citations
A survey of 1,116 people who microdose psychedelics found that performance enhancement was the main motive (37%), with LSD (10 mcg) and psilocybin (0.5 g) used 2-4 times per week. Most users were unaware of their exact dose. Negative effects were mostly psychological and occurred acutely while under the influence, but the primary reason for stopping microdosing was that it was not effective. The authors call for placebo-controlled studies to quantify performance effects and assess longer-term negative effects.
The International Journal of Neuropsychopharmacology
October 8, 2013
Cédric M. Hysek, Linda D. Simmler, Nathalie Schillinger et al.
125 citations
Taking methylphenidate (Ritalin) with MDMA (ecstasy) does not produce stronger psychoactive effects than either drug alone, but it does increase cardiovascular strain and adverse effects. In a double-blind, placebo-controlled crossover trial with healthy subjects, methylphenidate alone produced psychostimulant effects but did not enhance MDMA's mood-elevating effects. MDMA (125 mg) increased positive mood more than methylphenidate (60 mg), while methylphenidate enhanced activity and concentration more than MDMA. The drugs also differently affected emotion recognition: methylphenidate improved recognition of sad and fearful faces, whereas MDMA reduced recognition of negative emotions. Acute tolerance developed to MDMA but not methylphenidate. The drugs did not alter each other's pharmacokinetics.
The International Journal of Neuropsychopharmacology
June 24, 2015
Patrick C. Dolder, Yasmin Schmid, Manuel Haschke et al.
110 citations
Oral lysergic acid diethylamide (LSD) shows dose-proportional pharmacokinetics, with peak concentrations reached about 1.5 hours after ingestion and a terminal half-life of approximately 3.6 hours. The drug's effects are closely related to its blood concentration, with subjective effects lasting up to 12 hours. These findings provide a reference for clinical studies and for assessing LSD intoxication.
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.
The International Journal of Neuropsychopharmacology
March 29, 2015
Joan Francesc Alonso, Sergio Romero, Miguel Ángel Mañanas et al.
105 citations
Psychedelics temporarily disrupt the brain's usual hierarchy by weakening top-down control and strengthening bottom-up information transfer. This shift may explain the altered perceptions and loosened sense of self reported during psychedelic experiences. The findings are based on neural activity measurements in humans, indicating a reorganization of how information flows between brain regions.
The International Journal of Neuropsychopharmacology
November 4, 2022
Aaron Klaiber, Friederike Holze, Ioanna Istampoulouoglou et al.
100 citations
Lysergic acid diethylamide (LSD) produces its acute psychedelic effects by stimulating the serotonin 5-HT2A receptor. In a double-blind, randomized, placebo-controlled, crossover study with 24 healthy participants, the 5-HT2A antagonist ketanserin (40 mg orally) was given one hour after LSD (100 µg orally). Ketanserin reversed the acute response to LSD, reducing the duration of subjective effects from 8.5 hours with placebo to 3.5 hours. It also reversed LSD-induced alterations of mind, including visual and acoustic alterations and ego dissolution, and reduced adverse cardiovascular effects and mydriasis. Ketanserin did not alter LSD's pharmacokinetics or its elevation of brain-derived neurotrophic factor levels. The findings indicate that LSD produces its psychedelic effects only when occupying 5-HT2A receptors, and ketanserin can shorten and attenuate the LSD experience for research and therapy.
The International Journal of Neuropsychopharmacology
June 5, 2015
Marta Valle, Montserrat Puntes, Jimena Coimbra et al.
75 citations
Salvinorin-A produces intense psychotropic effects that depend on dose: it gates external audio-visual information in a dose-dependent manner and has an inverted-U dose-response effect on body awareness. These results indicate that the kappa opioid receptor plays a prominent role in regulating sensory perception, interoception, and the sense of body ownership in humans.
The International Journal of Neuropsychopharmacology
August 13, 2013
Adam L. Halberstadt, Mark A. Geyer
66 citations
Serotonergic hallucinogens such as mescaline, psilocybin, and LSD produce a 'model psychosis' in healthy individuals that resembles positive symptoms of schizophrenia by acting through the serotonin 5-HT2A receptor. Evidence that the serotonergic system contributes to schizophrenia in some patients has led to animal models based on hallucinogen effects. This review examines the behavioral effects of hallucinogens in four such models, the receptor and neurochemical mechanisms involved, and their translational relevance. Despite challenges in modeling hallucinogen effects in nonverbal species, these models have provided insights into the link between serotonin and schizophrenia and identified receptor targets for developing new therapeutic agents.
The International Journal of Neuropsychopharmacology
July 9, 2008
Thibault Renoir, Eleni Païzanis, Malika El Yacoubi et al.
58 citations
A single sentence summary is not possible because the abstract contains multiple distinct findings. Four weeks after administering MDMA to mice, the potency of a 5-HT1A receptor agonist to inhibit serotonin neuron firing in the dorsal raphe nucleus doubled, and the hypothermic response to 8-OH-DPAT increased, indicating supersensitivity of 5-HT1A autoreceptors. Brain serotonin levels decreased without changes in citalopram binding. MDMA treatment also reduced hippocampal cell proliferation by 30% and increased immobility in the forced swim test, suggesting depressive-like behavior. These effects were absent in mice lacking the serotonin transporter, indicating the transporter is required for these delayed, antidepressant-opposite effects that may contribute to MDMA-induced mood disorders.
The International Journal of Neuropsychopharmacology
May 10, 2021
Natalie Gukasyan, David B. Yaden, Matthew W. Johnson et al.
56 citations
Psychedelic substances produce unusual changes in conscious experience, leading some to propose they offer unique insights into consciousness. However, psychedelics are unlikely to provide information relevant to the "hard problem of consciousness," which involves explaining how first-person experience emerges. Instead, they bear on multiple "easy problems of consciousness," involving relations between subjectivity, brain function, and behavior. This review discusses common meanings of "consciousness" regarding psychedelics and considers models of their effects on the brain linked to explanatory claims about consciousness. It calls for epistemic humility about psychedelic research's potential to explain the hard problem while noting ways psychedelics may advance study of specific aspects of consciousness.
The International Journal of Neuropsychopharmacology
December 19, 2014
Mark J. Niciu, David A. Luckenbaugh, Dawn F. Ionescu et al.
55 citations
A single low-dose infusion of the anesthetic ketamine produces rapid antidepressant effects in people with treatment-resistant major depressive disorder. In this trial, depressed individuals with a family history of alcohol use disorder showed a longer-lasting antidepressant response to ketamine compared to those without such a family history. Adding the drug riluzole did not extend or enhance ketamine's antidepressant durability. The findings suggest that family history of alcohol use disorder may predict a more durable ketamine response, which should be accounted for in future ketamine depression studies.
The International Journal of Neuropsychopharmacology
March 25, 2010
Joyce Colussi‐mas, Richard J. Wise, Alex Howard et al.
51 citations
In rats that learned to self-administer MDMA, a later injection of the drug triggered renewed drug-seeking behavior. The strength of this drug seeking was greater in rats that had acquired self-administration more quickly and in those that showed larger MDMA-induced increases in dopamine in the dorsal striatum. Rats that never learned to self-administer MDMA or that received the drug passively did not show this effect. The findings suggest that individual differences in initial sensitivity to MDMA's reinforcing effects and in the drug's ability to elevate striatal dopamine influence the propensity to seek the drug after a period of abstinence.
The International Journal of Neuropsychopharmacology
October 14, 2010
María Juliana Orejarena, Laurence Lanfumey, Rafaël Maldonado et al.
38 citations
The serotonin 5-HT2A receptor plays a crucial role in the reinforcing and addictive properties of MDMA. In experiments with mice, those lacking the 5-HT2A receptor showed reduced self-administration of MDMA at both 0.125 and 0.25 mg/kg per infusion compared to normal mice. MDMA increased horizontal locomotion more in the knockout mice than in normal mice. Dopamine release in the nucleus accumbens was lower in knockout mice both at baseline and after MDMA challenge. Cue-induced reinstatement of MDMA-seeking behavior was blocked by a selective 5-HT2A receptor antagonist at 0.5 mg/kg. These findings suggest that 5-HT2A receptors are essential for MDMA's reinforcing effects and for relapse triggered by drug-associated cues, likely through modulation of dopamine activity in the brain's reward pathway.
The International Journal of Neuropsychopharmacology
February 12, 2016
Marta Valle, Montserrat Puntes, Jimena Coimbra et al.
31 citations
The subjective and physiological effects of salvinorin-A in humans are caused by activation of kappa opioid receptors, not by serotonin-2A receptors. This finding clarifies the specific receptor mechanism responsible for the drug's effects.
The International Journal of Neuropsychopharmacology
April 24, 2014
Hong‐yi Chiu, Ming‐huan Chan, Mei-Yi Lee et al.
31 citations
A single-day 'binge' dosing regimen of methamphetamine in male mice impaired recognition memory, reduced social behaviors, and increased sensitivity to a hallucinogenic drug that activates serotonin 5-HT2A receptors. The heightened behavioral, molecular, and electrophysiological responses to the hallucinogen were linked to an up-regulation of 5-HT2A receptors in the medial prefrontal cortex, while 5-HT2C and 5-HT1A receptors remained unchanged. These findings suggest that methamphetamine-induced changes in 5-HT2A receptor expression may contribute to psychosis-like behaviors and could inform therapies for methamphetamine-related psychiatric disorders.
The International Journal of Neuropsychopharmacology
June 10, 2013
José L. Moreno, Javier González‐maeso
30 citations
Psychedelic drugs like LSD and dissociative drugs like PCP produce psychotic and cognitive symptoms in healthy people that resemble aspects of schizophrenia. Serotonin 5-HT2A and metabotropic glutamate 2 receptors are involved in how these drugs work. This review examines recent studies using LSD-like and PCP-like drugs in rodents that link these receptors to the biology of schizophrenia and its treatment.
The International Journal of Neuropsychopharmacology
July 5, 2021
Sven Melker Hagsäter, Robert Pettersson, Christopher Pettersson et al.
29 citations
Activating the 5-HT2A serotonin receptor with drugs such as psilocybin reduces conditioned fear in male rats, an effect blocked by a 5-HT2A inverse agonist. Inverse agonists alone did not change fear behavior, but they unmasked a fear-reducing effect of the SSRI escitalopram, which by itself had no effect. These results suggest that 5-HT2A receptor activation is not required for normal conditioned freezing but can dampen fear when over-activated. In the presence of an SSRI, the 5-HT2A receptor appears to oppose the anti-freezing effect of increased serotonin levels.
The International Journal of Neuropsychopharmacology
December 2, 2008
Sami Ben Hamida, A. Tracqui, Anne Pereira de Vasconcelos et al.
27 citations
Taking the club drug ecstasy (MDMA) together with alcohol (ethanol) increases the drug's levels in the blood and brain, which may explain why alcohol amplifies MDMA's stimulant effects. In rats, alcohol raised MDMA concentrations in the blood, hippocampus, frontal cortex, and striatum within 15 to 60 minutes after injection, without changing the proportion converted to its active metabolite MDA. MDMA and MDA accumulated more in the striatum and cortex than in the hippocampus. These higher brain and blood levels suggest that combining alcohol with MDMA could increase the risk of neurotoxicity and potential for abuse.
The International Journal of Neuropsychopharmacology
August 1, 2005
Eszter Kirilly, Anita Benkő, Linda Ferrington et al.
26 citations
A single dose of MDMA (15 mg/kg) in male Dark Agouti rats caused lasting damage to the serotonin system, shown by 30–60% reductions in paroxetine binding in the forebrain and decreased brain glucose metabolism in aggression-related areas. Despite this neurotoxicity, aggressive behaviors (biting, boxing, wrestling) were not significantly different from controls three weeks later, and the acute anti-aggressive effects of MDMA and two 5-HT1B receptor agonists remained intact. The findings suggest that aggressive behavior and the acute anti-aggressive action of MDMA are preserved even with substantial serotonergic damage, at least under the social isolation conditions of the resident-intruder test.