Psychopharmacology
January 1, 2022
Nina Schimmers, Joost J. Breeksema, Sanne Y Smith-Apeldoorn et al.
Both classical psychedelics (DPT, LSD, psilocybin) and atypical psychedelics (MDMA, ketamine) show promise for reducing anxiety, depression, and existential distress in terminally ill patients, with recent controlled trials indicating positive effects on existential and spiritual well-being, quality of life, and acceptance while causing few adverse and no serious adverse effects. Early studies had serious methodological flaws, but newer trials are of higher quality. Larger high-quality studies are still needed for classical psychedelics and MDMA, and ketamine research should better address existential well-being and psychotherapeutic context.
Psychopharmacology
May 1, 2020
C Austin Zamarripa, Jennifer E Naylor, Sally L Huskinson et al.
Combining the kappa opioid receptor (KOR) agonists salvinorin A or nalfurafine with oxycodone reduced self-administration of oxycodone in adult male rhesus monkeys under a progressive ratio schedule. Oxycodone alone was self-administered above saline levels at sufficient doses. Adding salvinorin A reduced mean injections per session to saline levels, and nalfurafine reduced them to levels significantly lower than oxycodone alone. Pretreatment with the KOR antagonist nor-BNI reversed nalfurafine's effect, indicating the effect is KOR-dependent. The authors propose that combinations of KOR agonists with prescription opioids may have reduced abuse liability.
Psychopharmacology
May 1, 2020
Toby Lea, Nicole Amada, Henrik Jungaberle et al.
An international online survey of 1102 people who had microdosed psychedelics found that 21% did so primarily for depression, 7% for anxiety, 9% for other mental disorders, and 2% to reduce or stop substance use. Forty-four percent perceived their mental health as "much better" as a result. Perceived improvements were associated with gender, education, microdosing duration and motivations, and recent use of larger psychedelic doses. The authors call for clinical trials to determine microdosing's potential role in psychiatric treatment and for further social research on its use as a self-managed therapy.
Psychopharmacology
March 1, 2020
Arvie Abiero, Chrislean Jun Botanas, Raly James Custodio et al.
Two synthetic dissociative drugs, 4-MeO-PCP and 3-MeO-PCMo, produce rewarding and reinforcing effects in rats, indicating potential for abuse in humans. Both drugs induced conditioned place preference and self-administration, but only 4-MeO-PCP caused locomotor sensitization. Blocking dopamine D1 or D2 receptors prevented the drugs' rewarding effects. The drugs altered dopamine-related proteins and increased delta and gamma brain wave activity, effects also blocked by dopamine antagonists. These findings suggest the drugs' abuse potential is mediated through the mesolimbic dopamine system.
Psychopharmacology
September 1, 2019
Swapnil Gupta, Joao P De Aquino, Deepak C D'Souza et al.
In healthy individuals who respond to THC, pre-treatment with the antipsychotic haloperidol reduces the psychosis-like effects of THC. Among 10 THC responders, THC-induced increases in positive symptoms (measured by the PANSS) were lower after haloperidol (average increase of 1.1 points) than after placebo (average increase of 2.9 points). This suggests that dopamine signaling may play a role in the psychosis-like effects of cannabinoids.
Psychopharmacology
July 1, 2019
Shiho Ito, Satoshi Deyama, Masaki Domoto et al.
The synthetic cannabinoid 5F-AMB, when injected into the brain of mice, reduces anxiety and impairs the acquisition of recognition memory by activating CB1 receptors. Systemic injection severely reduces movement, an effect partially blocked by a CB1 antagonist. Infusion into the medial prefrontal cortex impairs memory acquisition but does not affect anxiety, suggesting other brain regions mediate the anxiolytic effect.
Psychopharmacology
March 19, 2019
L. Sayson, Chrislean Jun Botanas, Raly James Perez Custodio et al.
Three novel analogs of methoxetamine (MXE), an NMDA receptor antagonist related to ketamine, showed antidepressant-like effects in mice. The compounds—NENK, 2-MeO-NEK, and 4-MeO-NEK—reduced immobility time in the forced swimming and tail suspension tests, indicating reduced behavioral despair. Their effects were blocked by an AMPA receptor antagonist (NBQX) and a 5-HT2 receptor antagonist (ketanserin), suggesting involvement of both glutamatergic and serotonergic systems. The analogs also altered mRNA levels of AMPA receptor subunits and brain-derived neurotrophic factor in the hippocampus and prefrontal cortex. These findings suggest the compounds may offer rapid antidepressant effects, though further research is needed.
Psychopharmacology
March 1, 2019
A. Halberstadt, S. Brandt, D. Walther et al.
A class of designer drugs derived from 2-aminoindan (2-AI) interacts with monoamine transporters in ways that predict distinct psychoactive effects. 2-AI itself acts as a selective substrate for norepinephrine and dopamine transporters, suggesting (+)-amphetamine-like effects and abuse potential. Adding ring substitutions increases potency at the serotonin transporter while reducing potency at dopamine and norepinephrine transporters. Among the derivatives, MMAI is highly selective for the serotonin transporter, with 100-fold lower potency at norepinephrine and dopamine transporters, while MDAI and 5-MeO-AI show moderate serotonin selectivity. The compounds also bind to α2-adrenoceptor subtypes, with 2-AI having highest affinity for α2C receptors (Ki = 41 nM). Ring-substituted derivatives may produce MDMA-like effects with less abuse liability.
Psychopharmacology
August 1, 2018
Masaki Domoto, Hitoki Sasase, Shintaro Wada et al.
5F-AMB, a synthetic cannabinoid abused worldwide, reduces both excitatory and inhibitory signaling in layer V pyramidal neurons of the medial prefrontal cortex by activating CB1 receptors on presynaptic terminals. Bath application of 5F-AMB decreased the frequency of spontaneous and miniature excitatory and inhibitory postsynaptic currents, an effect blocked by the CB1 antagonist AM251. The suppression of excitatory transmission was greater than that of inhibitory transmission, shifting the balance toward net inhibition of these neurons. This inhibitory effect may contribute to the memory and consciousness impairments observed after inhalation of 5F-AMB.
Psychopharmacology
February 1, 2018
Liana Fattore, Alessandro Piva, Mary Tresa Zanda et al.
A review of preclinical and clinical data examines whether cannabinoids and ketamine can modulate the reconsolidation of maladaptive memories, a process that may underlie their potential therapeutic use in post-traumatic stress disorder and substance use disorders. The authors propose that memory reconsolidation modulation is a hypothetical process explaining the efficacy of these substances, and they report findings that support or do not support this working hypothesis. Metaplasticity is suggested as a common process mediating the effects of cannabinoids and ketamine on maladaptive memories.
Psychopharmacology
August 1, 2017
Amy W M Ewald, Peter J Bosch, Aimee Culverhouse et al.
Two novel analogues of salvinorin A, EOM Sal B and β-THP Sal B, were tested in rats for their ability to reduce cocaine-related behaviors and their side effects. EOM Sal B dose-dependently reduced drug-seeking behavior in a reinstatement model and, along with β-THP Sal B, attenuated cocaine-induced hyperactivity without affecting general locomotion. Neither compound produced anxiety-like or depressive-like effects in the elevated plus maze or forced swim tests. However, β-THP Sal B caused aversion in the conditioned place aversion test. EOM Sal B showed no effect on sucrose self-administration, indicating selectivity for cocaine-related behaviors. EOM Sal B was more potent than salvinorin A and β-THP Sal B with fewer side effects.
Psychopharmacology
July 1, 2017
Rainer Kraehenmann, Dan Pokorný, Leonie Vollenweider et al.
Lysergic acid diethylamide (LSD) produces waking mental imagery that resembles dreaming, an effect driven by activation of the 5-HT2A receptor. In a study with 25 healthy subjects, LSD (100 mcg orally) significantly increased cognitive bizarreness in guided mental imagery reports compared with placebo, and this increase correlated with a loss of self-boundaries and cognitive control. Both the imagery changes and altered state of consciousness were fully blocked by the 5-HT2A antagonist ketanserin (40 mg orally). The findings suggest that LSD-induced dreamlike imagery depends specifically on 5-HT2A receptor activation.
Psychopharmacology
June 1, 2016
Anna Mutti, Sonia Aroni, Paola Fadda et al.
Methoxetamine (MXE), a novel ketamine-like drug increasingly linked to emergency cases, was tested in male rats trained to self-administer ketamine. Low doses of MXE (0.125 and 0.25 mg/kg) substituted for ketamine self-administration, while the highest dose (0.5 mg/kg) did not. MXE dose-dependently increased the firing rate and burst firing of dopamine neurons in the ventral tegmental area projecting to the nucleus accumbens shell. It also raised dopamine levels in that brain region, with a 0.5 mg/kg dose having a faster onset (40 minutes) than 0.25 mg/kg (100 minutes). These findings indicate MXE has reinforcing and addiction-related properties.
Psychopharmacology
April 1, 2016
Adam L. Halberstadt, Natalia Slepak, James Hyun et al.
Methoxetamine (MXE), a ketamine analog sold online, produces behavioral effects in rats that closely resemble those of other dissociative anesthetics like phencyclidine (PCP) and ketamine. In Sprague-Dawley rats, MXE disrupted prepulse inhibition (PPI) of acoustic startle at doses of 3 and 10 mg/kg, with a potency ranking (PCP > MXE > S-(+)-ketamine > NANM > R-(-)-ketamine) that matches their affinities for the PCP binding site on NMDA receptors. In the behavioral pattern monitor, 10 mg/kg MXE caused locomotor hyperactivity, reduced rearing, increased path roughness, and perseverative locomotion—effects similar to those of PCP. These findings indicate MXE acts as a dissociative drug with abuse potential comparable to PCP and ketamine.
Psychopharmacology
March 1, 2016
Michael J Wesley, Joshua A Lile, Colleen Hanlon et al.
Long-term heavy cannabis users who are not acutely intoxicated show diminished brain responses in the medial prefrontal cortex (mPFC) when consciously evaluating emotional images, compared to non-users. Both groups judged the same stimuli as emotional and had similar activations in visual, midbrain, and middle cingulate cortices. However, controls showed additional amygdalar and inferior frontal gyrus activations, while cannabis users showed mPFC deactivations during emotional evaluation. Between-group comparisons found mPFC activity during positive and negative evaluation was significantly hypoactive in cannabis users. This abnormal neural processing of affective content extends to conscious evaluation and resembles attenuated mPFC responses found during increased non-affective cognitive load.
Psychopharmacology
March 1, 2016
HeeSeung Lee, Grace Y. Wang, Louise E. Curley et al.
A single oral dose of either TFMPP or dexamphetamine significantly reduced the P300 amplitude, a measure of brain electrical activity related to attention and information processing. A similar trend was observed with BZP alone. However, the combination of BZP and TFMPP had no effect on P300 amplitude. Neither P300 latency nor reaction time was affected by any drug treatment, nor were earlier sensory components P100 and P200. The findings suggest that BZP and TFMPP, but not their combination, affect auditory sensory-evoked P300 potential in a manner similar to dexamphetamine.
Psychopharmacology
November 1, 2015
K A L McAllister, A C Mar, D E Theobald et al.
A double-dissociation was found between two cognitive tasks in rats: dysfunction of the medial prefrontal cortex impaired learning of object-location associations but not spontaneous novel object recognition, while subchronic phencyclidine (scPCP) impaired novel object recognition but not object-location associative learning. Both scPCP and mPFC dysfunction similarly facilitated reversal learning. The pattern of impairment after scPCP raises questions about its validity as a model of cognitive impairment in schizophrenia, especially if faithfully replicating the effects of mPFC dysfunction is important.
Psychopharmacology
March 11, 2015
Amir I. A. Ahmed, G. A. H. van den Elsen, A. Colbers et al.
In a small crossover trial, ten dementia patients (mean age 77) received low doses of oral THC (0.75 mg then 1.5 mg) or placebo twice daily for three days with a four-day washout. Only 6 of 98 reported adverse events were related to THC. Most pharmacodynamic measures (feeling high, external perception, body sway with eyes open, diastolic blood pressure) did not differ significantly from placebo. After 0.75 mg, internal perception and heart rate increased slightly; after 1.5 mg, body sway with eyes closed increased. Systolic blood pressure changed in opposite directions at each dose. THC was rapidly absorbed with dose-linear pharmacokinetics but wide interindividual variability. The authors conclude that pharmacodynamic effects were minor and call for further study of higher doses in older adults with dementia.
Psychopharmacology
July 1, 2014
Kevin B Freeman, Jennifer E Naylor, Thomas E Prisinzano et al.
A kappa opioid agonist, salvinorin A, can punish self-administration of cocaine and remifentanil in monkeys. In a two-lever choice design, monkeys chose between equal doses of cocaine or remifentanil, with one option mixed with varying doses of salvinorin A. Choice for the drug combined with salvinorin A decreased as its dose increased, while operant response rates were unaffected. The findings suggest that kappa agonists may have potential to curtail drug abuse when delivered contingently, such as in combination formularies for prescription medications.
Psychopharmacology
October 1, 2013
Katja Clarissa Ward, Halima Zainab Khattak, Louise Richardson et al.
Low doses of the NMDA receptor antagonists ketamine and phencyclidine impair visual grouping in rats, requiring higher signal quality to discriminate patterns, without affecting discrimination of undistorted images. Higher doses impair task performance even with clear images, linked to stereotypic behavior and impulsivity. A new rodent task using Glass patterns differentiates perceptual effects from motor or memory effects, enabling quantification of cognitive psychosis that translates to human psychometric functions.
Psychopharmacology
March 1, 2013
Theresa M. Carbonaro, Michael J Forster, Michael B. Gatch
The hallucinogen DiPT, known for causing auditory distortions, produces discriminative stimulus effects in rats that are similar to those of other synthetic hallucinogens like LSD, DOM, and MDMA, but only partially similar to DMT and not similar to methamphetamine. Rats learned to distinguish DiPT from saline in about 60 training sessions. DiPT caused dose-dependent increases in drug-appropriate responding, reaching 99% at the highest dose. The effects began within 5 minutes and faded within 4 hours. The results suggest that DiPT's auditory effects do not make its discriminative stimulus profile distinct from other hallucinogens.
Psychopharmacology
December 1, 2012
Kevin T. Ball, Mylissa Slane
Inactivating a specific part of the prefrontal cortex in rats completely blocked cue-triggered relapse to MDMA (ecstasy) seeking. The prelimbic (PL) subregion of the medial prefrontal cortex is necessary for this relapse behavior, while the neighboring infralimbic (IL) subregion is not. This mirrors the neural mechanism seen in cocaine relapse, suggesting a common brain pathway for drug-seeking reinstatement across different substances. The effect was specific to drug-seeking and not due to general motor impairment, as food-seeking behavior remained unaffected.
Psychopharmacology
November 24, 2012
R. A. Sewell, Ashley Schnakenberg, Jacqueline Elander et al.
Intravenous THC, at doses from 0.015 to 0.05 mg/kg, produces time overestimation and underproduction in seconds-range tasks, indicating an increased internal clock speed. This effect is not dose related and is blunted in frequent cannabis smokers, who show no differences in time perception compared to infrequent or nonsmokers. Chronic cannabis use does not alter baseline time perception.
Psychopharmacology
February 1, 2011
David M Thomson, Allan McVie, Brian J Morris et al.
Cognitive problems in schizophrenia are not well treated by current drugs. The drug PCP is often used in animals to model these problems. In rats, a single dose of PCP increased impulsive, anticipatory responses 30 minutes after injection, but this effect disappeared within 24 hours. Repeated PCP treatment caused lasting delays in cognitive processing speed, which were partly improved by the antipsychotic clozapine. Clozapine also modified a measure of risk-taking versus caution (lnBeta) that was persistently altered by repeated PCP. The findings suggest that repeated PCP treatment combined with signal detection analysis provides a useful method for testing new cognitive enhancers.
Psychopharmacology
February 1, 2011
Herbert Y Meltzer, Masakuni Horiguchi, Bill W Massey
This review examines evidence that serotonin (5-HT) agents reduce the effects of NMDA receptor antagonists (NMDA-RA) like PCP, MK-801, and ketamine on locomotor activity and novel object recognition (NOR) in rats—models used to study schizophrenia and antipsychotic drug action. Selective 5-HT(2A) inverse agonists and atypical antipsychotics (e.g., clozapine, lurasidone) are more effective than selective D(2) antagonists at attenuating NMDA-RA-induced hyperactivity. 5-HT(2A) inverse agonists alone do not improve NMDA-RA-impaired NOR but augment atypical antipsychotics' effects. 5-HT(1A) partial agonists and 5-HT(6)/5-HT(7) antagonists also attenuate these behaviors. 5-HT(2C) inverse agonists block NOR in naïve rats and interfere with atypical antipsychotics' restorative effects, highlighting constitutive 5-HT(2C) receptor activity's role.