Behavioural Pharmacology
September 1, 2005
A. B. Ilan, Alan Gevins, Michael J. Coleman et al.
165 citations
Smoking marijuana with delta9-tetrahydrocannabinol (THC) produces expected effects on mood, behavior, and brain activity, but varying the concentrations of other cannabinoids like cannabichromene (CBC) and cannabidiol (CBD) does not change responses. Twenty-three healthy marijuana users (12 men, 11 women) participated in four sessions, randomly assigned to low or high THC groups (1.8% versus 3.6%). Under blinded conditions, they smoked placebo or THC cigarettes with low or high levels of CBC (0.1% versus 0.5%) and CBD (0.2% versus 1.0%). Active THC cigarettes decreased performance, reduced EEG power, and attenuated ERP components reflecting attentional processes during working and episodic memory tests, mostly without dose dependence. CBC and CBD concentrations did not alter any outcomes, consistent with THC being the primary active constituent.
Behavioural Pharmacology
March 1, 2004
William E Fantegrossi, J H Woods, Gail Winger
99 citations
Hallucinogenic compounds such as DMT, mescaline, and psilocybin can produce weak and transient self-administration in rhesus monkeys previously trained to self-administer MDMA. No compound generated reliable responding, and no subject self-administered DOI at rates above those for saline. In some sessions, 3 out of 4 subjects responded at rates between 0.75 and 3.0 responses per second when DMT, mescaline, or psilocybin were available, earning a majority of infusions and appearing intoxicated. This pattern suggests these hallucinogens may have weak reinforcing effects or mixed reinforcing and aversive properties.
Behavioural Pharmacology
October 13, 2015
Filip Tylš, Tomáš Páleníček, L. Kadeřábek et al.
86 citations
Psilocin, the active metabolite of psilocybin, produces dose-dependent inhibition of movement and suppression of normal behavior in rats, including behavioral serotonin syndrome and impaired prepulse inhibition. These effects are more pronounced in male rats than in females. The inhibition of locomotion is normalized by 5-HT 1A and 5-HT 2B/C receptor antagonists, but prepulse inhibition is not significantly affected by these antagonists. The findings highlight sex-specific reactions to psilocin and indicate that, in addition to 5-HT 2A-mediated effects, 5-HT 1A and 5-HT 2C/B receptors also play an important role, with implications for clinical trials.
Behavioural Pharmacology
April 1, 2019
Kevin Sean Murnane
84 citations
Serotonin is an ancient neurotransmitter found throughout the brain, but its specific functions remain debated. This review argues that stress, especially from danger or existential threats, increases the activity of the 5-HT2A serotonin receptor subtype. This upregulation is proposed as an adaptive mechanism to enhance learning and avoidance of danger by forming associations with environmental cues signaling threat. The system may contribute to PTSD symptoms during life-threatening situations. The drug MDMA, which activates 5-HT2A receptors, has shown success in treating PTSD and is suggested to paradoxically work through these same receptors to alleviate symptoms. The central claim is that serotonin acts as a stress detection and response system.
Behavioural Pharmacology
December 1, 2005
William E Fantegrossi, Kelly M Kugle, Leander J. Valdés et al.
80 citations
Salvinorin A, a natural compound from the Mexican mint Salvia divinorum, is the first known naturally occurring kappa-opioid receptor agonist with a novel chemical structure distinct from other opioids. In mice, salvinorin A caused rapid but short-lived sedation and motor incoordination, similar to the effects of the mu-agonist remifentanil and the synthetic kappa-agonist U69,593. Using selective antagonists, the motor effects of salvinorin A and U69,593 were shown to be mediated by kappa-opioid receptors, while remifentanil's effects involved mu-receptors. Salvinorin A and U69,593 differed in their susceptibility to antagonism by nor-binaltorphamine, suggesting salvinorin A may bind to the kappa-receptor differently than traditional kappa-agonists. This raises the possibility that developing other diterpene-based opioids could yield therapeutic compounds.
Behavioural Pharmacology
November 1, 1998
Euphrosyne Gouzoulis‐mayfrank, Karsten Heekeren, B. Thelen et al.
79 citations
In a small double-blind, placebo-controlled study with 12 healthy subjects, the hallucinogen psilocybin increased prepulse inhibition (PPI) of the startle reflex, contrary to findings from animal models where hallucinogens disrupt PPI. Psilocybin had no clear effect on habituation of the startle reflex. These preliminary results suggest that the effects of hallucinogens on sensorimotor gating may differ between humans and animals, possibly due to differences in dose regimens or experimental parameters. Further research is needed to understand the relationship between hallucinogen-induced states and naturally occurring psychoses.
Behavioural Pharmacology
April 8, 2011
Adam Stewart, Russell Riehl, Keith Wong et al.
66 citations
Acute exposure to high doses of MDMA (40-120 mg/l) reduces bottom swimming and immobility in zebrafish and impairs intrasession habituation at doses as low as 10 mg/l, while lower doses (0.25-10 mg/l) show no behavioral effects. MDMA also increases brain c-fos expression. These findings support the use of zebrafish as a model for screening hallucinogenic compounds.
Behavioural Pharmacology
March 13, 2018
Rachel R. Horsley, Tomáš Páleníček, Jan Kolin et al.
52 citations
Microdosing with hallucinogens such as ketamine and psilocin may produce mild anxiety-like effects rather than relief, according to a rat study. Over six days, rats received low or moderate doses of ketamine, psilocin, or saline on three occasions. Forty-eight hours after the final treatment, an elevated plus-maze test measured anxiety-related behaviors. Statistical effects were modest or borderline, but the pattern was most consistent with a mildly anxiogenic profile, significant at lower doses. Lower doses of both drugs produced comparable effects, as did higher doses, suggesting a possible common mechanism. The authors conclude that microdosing for therapeutic purposes might be counter-productive, though more research is needed.
Behavioural Pharmacology
April 1, 1995
Lisa E Baker, Jonathan M. Broadbent, E. K. Michael et al.
52 citations
In rats trained to distinguish either the (+)- or (-)-isomer of MDMA from saline, both isomers of MDMA and MDA fully substituted for the training drugs. Stimulants like amphetamine and cocaine did not substitute. Hallucinogens such as DOM, LSD, and mescaline did not fully substitute for (+)-MDMA; LSD substituted for (-)-MDMA only at a specific dose. The serotonin-releasing agents fenfluramine and p-chloroamphetamine substituted partially or fully for both isomers. Serotonin receptor antagonists pirenpirone and metergoline did not consistently block MDMA's effects. The findings suggest that serotonin release, but not action at 5-HT(2) receptors, is important for the discriminative stimulus effects of MDMA isomers.
Behavioural Pharmacology
March 1, 2005
V. Buben Kov, Martin Votava, J. Hora Ek et al.
38 citations
MDMA (ecstasy) dose-dependently reduces prepulse inhibition (PPI), a measure of sensorimotor gating, in both male and female Wistar rats. Male rats show a greater increase in the acoustic startle response (ASR) than females after MDMA. Among females, sensitivity to MDMA’s PPI-disrupting effect varies across the estrous cycle: rats in diestrous and metestrous phases exhibit larger PPI deficits, while those in proestrous and estrous phases are less affected.
Behavioural Pharmacology
October 1, 2012
Mitchell T Harden, Staci E Smith, Jennifer A Niehoff et al.
37 citations
Salvinorin A (SalvA), a compound from the plant Salvia divinorum that activates κ-opioid receptors, may have antidepressant effects. In a study using male and female Long-Evans rats, chronic mild stress (CMS) for three weeks reduced their preference for sucrose water, indicating anhedonia, a key symptom of depression. After three more weeks of CMS, rats given daily injections of 1 mg SalvA per kilogram of body weight showed a reversal of this anhedonia, while control rats did not. Nonstressed rats given the same dose showed no change in sucrose preference. The findings suggest that chronic SalvA treatment acts as an effective antidepressant in this animal model.
Behavioural Pharmacology
July 11, 2014
A. C. Parrott, Catharine Montgomery, Mark Wetherell et al.
34 citations
Recreational use of MDMA (ecstasy) increases cortisol levels, a marker of stress, both immediately and over longer periods. In laboratory settings, acute use raises cortisol by 100-200%, while dance clubbers combining the drug with dancing experience an 800% increase. Abstinent users' three-month hair samples show cortisol levels 400% higher than controls. Chronic users exhibit heightened cortisol in stressful settings, deficits in complex cognitive tasks, and altered brain activation patterns suggesting increased mental effort. Mood deficits include more daily stress and higher depression in susceptible individuals. Changes in the hypothalamic-pituitary-adrenal (HPA) axis may explain these neuropsychobiological stress effects.
Behavioural Pharmacology
May 14, 2015
María Pilar García-pardo, Carla Escobar-Valero, Marta Rodrı́guez-arias et al.
29 citations
Blocking NMDA glutamate receptors with memantine prevents mice from learning to prefer a place associated with MDMA (ecstasy) and also prevents a single dose of MDMA from re-establishing that preference after it has been extinguished. Memantine did not block preference for a chocolate-associated place and only partly reversed MDMA's memory-impairing effects. The results suggest that NMDA receptors are critical for both the initial rewarding effect of MDMA and for relapse-like behavior, indicating memantine as a potential treatment for MDMA abuse.
Behavioural Pharmacology
September 1, 2014
María Pilar García-pardo, Marta Rodrı́guez-arias, Concepción Maldonado et al.
29 citations
Social defeat stress reduces the rewarding effects of MDMA in adult male mice, but not in adolescents. Adult mice exposed to social defeat before each MDMA conditioning session did not develop a conditioned place preference at either 1.25 or 10 mg/kg doses, indicating decreased sensitivity to MDMA reward. Social defeat did not alter the motor or anxiogenic effects of MDMA. Adult defeated mice had higher corticosterone levels than controls and adolescent mice. Social stress had no behavioral effects in adolescent mice, suggesting age-dependent vulnerability.
Behavioural Pharmacology
February 1, 1992
J. Arnt
27 citations
Sertindole, an atypical antipsychotic, blocks the effects of the hallucinogen d-LSD and the alpha-1 agonist St 587 but does not block the effects of d-amphetamine, a dopamine stimulant. Clozapine, another atypical antipsychotic, broadly blocks d-LSD, St 587, and d-amphetamine, though it increases reaction time. The typical antipsychotics haloperidol and Cis(Z)-flupentixol primarily block d-amphetamine, with haloperidol also disrupting behavior in animals trained on St 587 and d-LSD. The selective 5-HT2 antagonist ketanserin blocks only d-LSD, while the alpha-1 antagonist prazosin partially blocks St 587 but not d-LSD or d-amphetamine. Drug discrimination techniques reveal different activity profiles of typical and atypical neuroleptics.
Behavioural Pharmacology
September 1, 2011
Mary Melissa Peet, Lisa E Baker
21 citations
Two synthetic derivatives of salvinorin A, EOM-Sal B and MOM-Sal B, fully substituted for salvinorin A in rats trained to discriminate the drug, and both were more potent than the parent compound. EOM-Sal B also produced effects that lasted longer than salvinorin A. Morphine and one hallucinogen failed to substitute, but ketamine and LSD partially substituted. The findings suggest that these derivatives produce similar stimulus effects to salvinorin A, which are distinct from other drug classes, and warrant further study.
Behavioural Pharmacology
December 1, 2016
Andrew C. Parrott
19 citations
MDMA (ecstasy) affects mood and energy partly by increasing the neurohormones oxytocin and cortisol. While initial evidence linked oxytocin to enhanced sociability, that finding has not been replicated. Cortisol may amplify positive feelings from oxytocin. Chronic regular use of MDMA disrupts cortisol regulation, as shown by elevated cortisol in hair samples, altered cortisol awakening response, and higher daily stress, indicating changes to the hypothalamic–pituitary–adrenal axis. The effects of chronic use on oxytocin remain unknown. The neurohormones oxytocin and cortisol contribute to the psychobiological effects of recreational ecstasy/MDMA.
Behavioural Pharmacology
October 1, 1992
Jonathan M. Broadbent, J. B. Appel, E. K. Michael et al.
18 citations
In rats trained to distinguish either the left- or right-handed form (isomer) of the drug MDA from saline, both isomers served as reliable cues at specific doses. The two isomers substituted for each other, and both were fully substituted by the related drug MDMA. The hallucinogens LSD and DOM substituted only for the left-handed isomer, while stimulants like amphetamine and cocaine did not produce MDA-like effects. The left-handed isomer's cue was blocked by a serotonin receptor antagonist, but dopamine blockers had no effect. Neither MDA isomer fully substituted for LSD or amphetamine cues, suggesting the left-handed isomer has more hallucinogen-like and serotonin-mediated effects, while both lack strong amphetamine-like properties.
Behavioural Pharmacology
December 1, 2020
Keli A. Herr, Lisa E Baker
9 citations
In rats trained to distinguish LSD from saline, the drug's effects were largely similar between males and females, though some differences emerged with other substances. Both sexes showed comparable substitution by serotonergic hallucinogens. Partial substitution by MDMA, MDA enantiomers, and synthetic cathinones differed modestly between sexes. Dopamine antagonists did not block the LSD cue and suppressed behavior more in males. The serotonin antagonist MDL 100,907 blocked LSD discrimination in both sexes, but complete blockade occurred at lower doses in males. These findings confirm the central role of serotonin in LSD's effects and extend this to females, suggesting further research on sex differences in psychedelic effects is warranted.
Behavioural Pharmacology
August 1, 1996
Christine A. Sannerud, B. Kaminski, Roland R. Griffiths
9 citations
Intravenous self-administration of four substituted phenethylamines was evaluated in baboons trained to self-inject cocaine. High doses of MDE and N-OH-MDA maintained self-injection, while NNDMA did not reliably do so, and BDMPEA maintained self-injection in each of three baboons at one or more doses. Intermediate to high doses of all four compounds decreased food pellet intake. In some baboons, high doses of N-OH-MDA, NNDMA, and BDMPEA produced signs of behavioral toxicity similar to those of classic psychomotor stimulants, though severity and profile differed between compounds. The study documents both similarities and differences in the behavioral profiles of these phenethylamines.
Behavioural Pharmacology
August 1, 2000
C Zubaran, M Shoaib, I P Stolerman
7 citations
Ibogaine, a naturally occurring psychoactive alkaloid reported to block nicotinic receptors, was tested for its ability to alter sensitization to nicotine's locomotor stimulant effect in rats. Over 21 days, rats received daily co-administration of ibogaine (0, 5, or 10 mg/kg) with nicotine (0 or 0.4 mg/kg). Nicotine alone produced clear sensitization—enhanced locomotor activity upon repeated exposure—but co-administration of ibogaine did not affect the degree of sensitization. Ibogaine alone (5–20 mg/kg) did not influence locomotor activity and did not alter the expression of the already-sensitized response to nicotine. The results provide no evidence that ibogaine retards or suppresses sensitization to nicotine.
Behavioural Pharmacology
June 1, 2020
Michael B. Gatch, Sean B. Dolan, Michael J. Forster
6 citations
Most synthetic cathinones tested produce effects similar to the club drug MDMA in rats, but not all. In rats trained to distinguish MDMA from a placebo, six of seven cathinones—4-fluoromethcathinone, 4-methylmethcathinone, 4-methylethcathinone, 3-fluoromethcathinone, pentedrone, and ethylone—fully substituted for MDMA's discriminative stimulus effects. Methcathinone produced at most 43% MDMA-like responding, and higher doses suppressed responding. The potency of MDMA-like versus psychostimulant-like effects varied substantially among compounds, indicating that some synthetic cathinones are more MDMA-like than psychostimulant-like. This variability suggests that cathinones with MDMA-like effects may be more likely used as club drugs.
Behavioural Pharmacology
April 1, 2025
Eghbal Jasemi, Ali Razmi, Salar Vaseghi et al.
5 citations
In mice, early maternal separation caused depressive-like and anxiety-like behaviors, reduced movement, and altered hippocampal gene expression and methylation of Slc6a4 and Nr3c1. A single injection of Psilocybe cubensis extract (20 mg/kg) on postnatal day 60 reversed these behavioral and molecular changes. The extract appears to influence serotonergic signaling and stress response pathways by modifying Slc6a4 and Nr3c1 expression and methylation. These findings suggest that compounds from Psilocybe cubensis may counteract some long-term effects of early-life stress.
Behavioural Pharmacology
June 1, 2025
Ronan Depoortère, Mariusz Papp, Piotr Gruca et al.
2 citations
Ketamine rapidly reverses depression-like symptoms in rats exposed to chronic mild stress, including loss of pleasure and working memory deficits, when given systemically or directly into the prefrontal cortex. Blocking serotonin 5-HT1A receptors in the prefrontal cortex with WAY-100635 prevents these effects, showing that ketamine's rapid antidepressant and pro-cognitive actions require activation of these receptors. The findings suggest that drugs directly targeting prefrontal cortex 5-HT1A receptors could provide rapid antidepressant effects and improve cognitive deficits without ketamine's side effects or need for clinical supervision.
Behavioural Pharmacology
October 1, 2024
David R Maguire
2 citations
A 5-HT2A receptor agonist called DOM, tested in four rhesus monkeys using a choice procedure, showed neither rewarding nor punishing effects. When monkeys chose between a sucrose pellet alone or a pellet plus an intravenous infusion, fentanyl increased choice for the infusion (rewarding), while histamine decreased it (punishing). DOM, tested across doses of 3.2 to 100 µg/kg/infusion, did not systematically alter choice, whether given before or after histamine. This suggests DOM lacks both positive reinforcing and aversive properties under conditions sensitive to these effects.