British Journal of Pharmacology
March 1, 2023
Antonio Inserra, Giada Giorgini, Sebastien Lacroix et al.
38 citations
Repeated doses of LSD increase social behavior in male mice and alter brain chemistry and gut bacteria. LSD raised social preference and novelty seeking. In the hippocampus, LSD lowered several endocannabinoid-like compounds, including anandamide and related N-acylethanolamines, certain monoacylglycerols, prostaglandins, thromboxane, and kynurenine. The prefrontal cortex showed fewer changes. LSD also reduced the diversity of gut bacteria, prevented a shift in the Firmicutes:Bacteroidetes ratio, and changed the abundance of specific bacterial groups such as Bifidobacterium. These findings suggest that the prosocial effects of LSD involve the hippocampal endocannabinoidome and kynurenine pathway, along with gut microbiome alterations.
British Journal of Pharmacology
November 22, 2017
Eef L. Theunissen, Nadia R. P. W. Hutten, Natasha L. Mason et al.
38 citations
A placebo-controlled crossover study gave six healthy adults with prior cannabis experience two low doses (2 mg and 3 mg) of the synthetic cannabinoid JWH-018. Serum concentrations of the drug were highest after the 2 mg dose but remained low overall. Both doses were well tolerated with no serious side effects. Participants reported feeling more 'high' at 1 and 2 hours after administration, especially after 2 mg. Despite low serum levels, behavioral impairments emerged: the 2 mg dose impaired performance on tracking, divided attention, and stop signal tasks. Higher doses are needed to obtain a more representative risk profile.
British Journal of Pharmacology
October 11, 2013
Janelle H. P. van Wel, Kim P. C. Kuypers, Eef L. Theunissen et al.
38 citations
Heavy cannabis users show broad impairments in neuropsychological function during THC intoxication, including reduced psychomotor performance and more errors on impulsivity tasks. These impairments appear less severe in psychomotor tasks than those previously seen in occasional users, suggesting some tolerance. Cocaine temporarily improves psychomotor function and speeds reaction times but increases errors, indicating a trade-off between stimulation and impulse control. The decline in impulse control may increase the risk of repeated drug use and addiction.
British Journal of Pharmacology
May 1, 1980
P. Jenner, C.d. Marsden, C.m. Thanki
38 citations
In rodents pretreated with pargyline, DMT caused a dose-dependent set of behaviors including hyperactivity, prostration, hindlimb abduction, mild tremor, Straub tail, retropulsion, and jerking. Unlike l-tryptophan or quipazine, DMT did not produce forepaw treading or head-weaving and caused only mild tremor. The hyperactivity component was potentiated by cyproheptadine, methergoline, and mianserin; inhibited by cinanserin, haloperidol, pimozide, methiothepin, and propranolol; and unaffected by 501C67-sulphate and methysergide. Other behavioral changes were mostly unaffected by these drugs, except propranolol reduced most effects and methergoline decreased prostration duration. Phenoxybenzamine and haloperidol enhanced prostration. DMT did not induce circling in mice with unilateral 6-hydroxydopamine lesions. The syndrome appears to have two components: hyperactivity, possibly mediated by dopamine, and other behaviors that are not.
British Journal of Pharmacology
November 1, 1974
Alan R. King, Ian L. Martin, Kathleen Melville
38 citations
Low doses of LSD (12.5–50 μg/kg) consistently made rats faster at learning a brightness discrimination reversal task. A similar compound, BOL-148, which has the same anti-serotonin effects outside the brain but lacks LSD's hallucinogenic properties, had no effect on learning at a comparable dose (25 μg/kg). LSD, but not BOL-148, slightly raised serotonin levels in the brain, while neither drug changed brain catecholamine levels at 25 μg/kg. These results suggest that LSD's effect on learning is tied to its specific psychoactive properties, not just its peripheral anti-serotonin activity.
British Journal of Pharmacology
April 30, 2009
Sotiria Bexis, James R. Docherty
36 citations
In conscious mice, the drug MDMA (20 mg/kg) caused a slow rise in body temperature peaking at 1.8°C above baseline about 130 minutes after injection. A low dose of the β3-adrenoceptor antagonist SR59230A (0.5 mg/kg) slightly reduced this hyperthermia. A high dose of SR59230A (5 mg/kg) instead triggered an early drop in temperature, an effect also produced by the α1-adrenoceptor blocker prazosin. Further tests showed that SR59230A also blocks α1-adrenoceptors. Thus, SR59230A alters MDMA's temperature effects mainly by blocking α1-adrenoceptors, which unmasks a hypothermic response, and to a lesser extent by possibly blocking β3-adrenoceptors to slightly reduce later hyperthermia.
British Journal of Pharmacology
October 12, 2013
Charles W. Schindler, Eric B. Thorndike, Bruce E. Blough et al.
35 citations
The cardiovascular effects of MDMA (Ecstasy) are partly caused by its metabolite HHMA. In rats, MDMA increased blood pressure, heart rate, and activity in a dose-dependent way. The metabolite MDA mimicked MDMA's effects, while HHMA increased heart rate more potently and to a greater extent than MDMA itself. The dihydroxy metabolites did not alter motor activity, and two other metabolites, HMMA and HMA, had no effects. The heart rate increases from MDMA and HHMA were blocked by the beta-blocker propranolol, suggesting a beta-adrenoceptor mechanism. HHMA may significantly contribute to MDMA's cardiovascular toxicity.
British Journal of Pharmacology
September 24, 2007
Therese Montgomery, Christophe Buon, S Eibauer et al.
33 citations
Illegal ecstasy tablets often contain compounds similar to MDMA whose effects are unknown. This study measured how well eight such compounds block the noradrenaline and serotonin transporters, key targets of MDMA in the brain. 2,3-MDMA was less potent than MDMA at the serotonin transporter but equally potent at the noradrenaline transporter. 2CB and BDB were less potent at the noradrenaline transporter but equally potent at the serotonin transporter. MBDB, DMMA, MDOH, and MDMA metabolites HMA and HMMA were all less potent than MDMA at both transporters. These results clarify how chemical structure affects the activity of MDMA-like compounds.
British Journal of Pharmacology
June 2, 2008
Andrew R. Green
30 citations
Serotonin (5-hydroxytryptamine or 5-HT) was identified as a vasoconstrictor substance by Maurice Rapport in 1949. Gaddum and colleagues soon detected 5-HT in brain and discovered that lysergic acid diethylamide (LSD) antagonized its action in peripheral tissues, leading Gaddum to propose that 5-HT might regulate mood. This review covers the first 20 years of UK scientists' contributions, including developing assays for brain 5-HT, identifying its synthesis and metabolism enzymes, and studying drug effects on brain 5-HT. It describes human LSD experiments, including Gaddum's self-administration, and investigations into 5-HT's role in psychiatric disorders and antidepressant drug effects on 5-HT levels in rodent and human brain.
British Journal of Pharmacology
March 1, 2002
Nicholas Macinnes, Sheila L. Handley
30 citations
Rats trained to distinguish the imidazoline I2-site ligand 2-BFI from saline showed that several compounds that reversibly inhibit monoamine oxidase A (MAO-A), including the anti-addictive drug ibogaine, produced similar internal cues, substituting for 2-BFI in a dose-dependent manner. In contrast, MAO-B inhibitors and other related compounds failed to substitute. The findings suggest that the subjective effects of I2-site ligands are linked to reversible MAO-A inhibition, likely through increased extracellular monoamine levels, and that ibogaine shares these subjective effects.
British Journal of Pharmacology
June 1, 1974
M J Berridge, William Prince
26 citations
LSD mimics serotonin (5-HT) in stimulating fluid secretion, changing electrical potentials, and increasing cyclic AMP in isolated salivary glands of the blowfly Calliphora. Unlike serotonin, LSD disengages slowly from the receptor, causing continued secretion even after repeated washing. Both serotonin and tryptamine prevent LSD from acting, and bound LSD is slowly displaced by agonists like tryptamine or antagonists like gramine. The ability of LSD to remain tightly bound while still functioning as an agonist may explain its profound effects in the central nervous system.
British Journal of Pharmacology
June 2, 2024
Oscar Sandoval, Quynh Nguyen, Ryan J. Rakoczy et al.
23 citations
Several tryptamines found in psilocybin-containing mushrooms—baeocystin, norbaeocystin, and aeruginascin—were compared with psilocybin to assess their pharmacological and behavioral effects. All compounds showed nearly identical rates of dephosphorylation and metabolism by monoamine oxidase. Only dephosphorylated baeocystin and norbaeocystin crossed a blood–brain barrier mimetic as effectively as psilocin. Norbaeocystin's dephosphorylated form activated the 5-HT2A receptor with similar efficacy to psilocin and norpsilocin. While only psilocybin induced head twitch responses in rats (a marker of hallucinogenic potential), norbaeocystin, like psilocybin, improved outcomes in the forced swim test. All compounds showed minimal changes to renal and hepatic health markers, suggesting safe profiles. Norbaeocystin may share therapeutic potential with psilocybin without causing hallucinations.
British Journal of Pharmacology
September 4, 2012
Kim P. C. Kuypers, Rafael de la Torre, Magı́ Farré et al.
23 citations
MDMA acutely impairs memory, but this effect is not caused by the rise in cortisol that MDMA also triggers. In a placebo-controlled, within-subject experiment with 17 polydrug MDMA users, blocking the cortisol increase with metyrapone (a cortisol synthesis inhibitor) did not prevent the memory deficit produced by a 75 mg dose of MDMA. Memory was tested at peak drug concentrations. The finding suggests that the neuropharmacological mechanism behind MDMA-induced memory impairment is independent of cortisol.
British Journal of Pharmacology
November 1, 1980
V. P. Poshivalov
23 citations
Mice living in small groups form a rigid, despotic social hierarchy that resists change even when psychotropic drugs are administered, making rapid pharmacological shifts in social rank impossible. Maintaining territory and social interaction are key to this inertia. Drugs such as diazepam, droperidol, and mescaline alter these factors to different degrees and vary in their ability to preserve hierarchy stability. Lowering aggression in a subordinate mouse does not change its social position. However, chronic administration of these drugs can eventually invert the hierarchy when a competitive rival is present, with the speed of inversion depending on the existing hierarchy type. The drugs' capacity to maintain hierarchy inertia may serve as an index of their effect on species-specific behaviors, particularly aggression.
British Journal of Pharmacology
December 19, 2024
David Nutt, Peter Hunt, Anne Katrin Schlag et al.
21 citations
In 2023, the Australian Therapeutic Goods Administration (TGA) approved psilocybin for treatment-resistant depression and MDMA for PTSD, effective from 1 July 2023. The approval followed a campaign led by Mind Medicine Australia, Professor David Nutt, Drug Science, and Monash University professors, supported by clinical, academic, and patient groups. Prescribing rights are limited to psychiatrists authorized under the TGA's Authorised Prescriber Scheme. This paper reviews the background of the decision, its implications for approvals in other jurisdictions, and development pathways for other psychedelic drugs.
British Journal of Pharmacology
June 1, 2024
Isabel Werle, Laura M M Nascimento, Aymee L A Dos Santos et al.
21 citations
A single oral dose of ayahuasca containing 0.3 mg/kg of DMT increased within-session extinction of contextual freezing behavior in rats without affecting recall; two consecutive daily doses enhanced extinction recall. These effects occurred for both 1- and 21-day-old memories in males and females, independent of changes in anxiety or general exploratory activity. Blocking 5-HT2A receptors in the infralimbic cortex prevented within-session extinction, while blocking 5-HT1A receptors prevented between-session extinction. The findings highlight complementary mechanisms by which ayahuasca facilitates behavioral suppression of aversive memories, suggesting potential benefits for stress-related disorders.
British Journal of Pharmacology
October 1, 1986
T Archer, W Danysz, G Jonsson et al.
16 citations
In rats, drugs that block alpha-2 adrenoceptors (yohimbine and phentolamine) injected into the spinal cord prevented or reduced the pain-relieving effects of a serotonin-like drug (5-MeODMT) in three different pain tests (hot-plate, tail-flick, and shock titration). A different blocker (prazosin) reduced the pain relief in two of the tests but not the third. Yohimbine alone lowered pain thresholds in a dose-dependent way. The results indicate that alpha-2 adrenoceptors interact with serotonin-induced pain relief at the spinal level.
British Journal of Pharmacology
December 1, 1971
C. M. Bradshaw, M.h.t. Roberts, E. Szabadi
16 citations
Mescaline applied directly to single neurons in the cerebral cortex produces excitatory or depressant effects similar to those of noradrenaline and serotonin. The direction of the response to mescaline usually matches that of noradrenaline, but the correlation with serotonin is less consistent. The beta-adrenoceptor blocker MJ-1999 and the serotonin antagonist methysergide both block mescaline's effects, suggesting mescaline acts through multiple receptor mechanisms.
British Journal of Pharmacology
December 1, 2024
Yong-Yu Yin, Jiao-Zhao Yan, Qian-Qian Wei et al.
13 citations
Ketamine produces rapid antidepressant-like effects in mice within 60 minutes and increases brain serotonin levels. The sustained effects at 24 hours require an intact serotonin system: depleting serotonin or knocking out the serotonin synthesis enzyme Tph2 eliminated the 24-hour but not the 60-minute effects. Blocking AMPA receptors with NBQX also prevented the rise in serotonin and abolished the sustained antidepressant-like effects. Serotonergic neurotransmission is necessary for ketamine's lasting antidepressant action, and this mechanism involves AMPA receptors.
British Journal of Pharmacology
November 29, 2024
Tate Askey, Reena Lasrado, Maria Maiarù et al.
13 citations
Psychedelic drugs are being considered for clinical use, particularly as anti-nociceptive treatments for chronic pain and co-morbid depression. This review examines preclinical animal models used to study psilocybin's potential as an anti-nociceptive agent. Initial studies in animal models of neuropathic and inflammatory pain are summarized, highlighting areas needing further research. Potential mechanisms include activation of 5-HT2A receptors in serotonergic pathways at spinal and central levels, and neuroplastic actions that improve functional connectivity in brain regions involved in chronic pain. Current clinical aspects and the translational potential of psilocybin from animal models to chronic pain patients are reviewed. Psilocybin is discussed as an ideal anti-nociceptive agent with broad effects against chronic pain and its inflammatory or emotional components.
British Journal of Pharmacology
January 1, 2022
Kristýna Štefková-mazochová, Hynek Danda, Wim Dehaen et al.
13 citations
Deschloroketamine (DCK), a structural analogue of ketamine sold as a recreational drug, was tested in Wistar rats to examine its pharmacokinetics, acute effects, and addictive potential. DCK rapidly entered the brain, with peak levels at 30 minutes and sustained high levels for 2 hours. It blocks NMDA receptors similarly to ketamine, with the S-enantiomer more potent. DCK stimulated locomotion, induced place preference (a sign of reward), and strongly disrupted prepulse inhibition (PPI). Locomotor stimulation faded faster than PPI disruption. S-DCK had stronger stimulatory effects than R-DCK, but both equally disrupted PPI. DCK's behavioral and addictive profiles resemble ketamine's, with a slightly slower clearance, matching its reported longer duration. These findings clarify risks of illicit DCK use.
British Journal of Pharmacology
September 1, 1975
Ian E. Lush
13 citations
In male mice from seven genetically diverse laboratory strains, mescaline (35 mg/kg) inhibited emotional defecation and stimulated open field activity in five strains (A2G, C3H/He, C57BR/cd, CBA/Cam, F/St) but not in two others (ICFW, Schneider). The degree of emotional defecation under saline control correlated positively with mescaline's inhibitory effect. Pre-treatment with tranylcypromine did not alter emotional defecation or mescaline's inhibition of it.
British Journal of Pharmacology
October 28, 2024
Laith Alexander, Dasha Anderson, Luke Baxter et al.
11 citations
Psychedelic drugs are being investigated as a new class of rapid-acting antidepressants, but their mechanisms remain unclear—specifically whether antidepressant and psychedelic effects arise from related or independent processes. This review examines behavioral methods used in animal studies to measure both the psychedelic and antidepressant effects of these drugs. It highlights conceptual and methodological challenges, stresses the importance of using doses comparable to those in human clinical use, and calls for attention to potential sex differences in preclinical research. Understanding these mechanisms could help identify new drug targets and improve treatments.
British Journal of Pharmacology
September 8, 2023
Maleesha Ubhayarathna, Christopher J. Langmead, Natalie Diepenhorst et al.
10 citations
Substance use disorder (SUD) is a chronic condition marked by maintained substance abuse leading to physiological and psychological changes, often altering cognitive and social behaviors. Current therapies combining psychotherapy and medication have high relapse rates, revealing their limitations. The serotonin 2C receptor (5-HT2C receptor) is a candidate for SUD treatment due to its signaling, expression profile, and neurological function. Recent interest in psychedelics, which broadly act at 5-HT2 receptors, has rekindled studies on the 5-HT2C receptor, especially structural analyses. This review examines the structural, molecular, and cellular mechanisms governing 5-HT2C receptor function in SUD, summarizing preclinical and clinical evidence and highlighting future research potential.
British Journal of Pharmacology
August 1, 1986
L Rényi
10 citations
Repeated but not single treatment with the 5-HT agonist 5-MeODMT strongly but reversibly reduced the ejaculatory response and other behavioral responses in rats. Repeated treatment with nonselective, irreversible MAO inhibitors nialamide and pargyline markedly reduced the ejaculatory response but only slightly affected behavioral responses. Repeated treatment with MAO-B inhibitor (-)-deprenyl, MAO-A inhibitor clorgyline, reversible MAO-A inhibitor moclobemide, and low doses of PCA did not affect either response. Combined repeated treatment with clorgyline plus PCA caused an almost complete blockade of all responses. Selective, reversible MAO-A inhibitors amiflamine, alpha-ethyltryptamine, and alpha-methyltryptamine reduced the ejaculatory response after both single and repeated treatments, with behavioral responses blocked only after repeated treatment. The authors conclude that single and repeated treatments with different MAO inhibitors do not produce a common alteration in 5-HT2 receptor functions.