British Journal of Pharmacology
June 22, 2025
Aurelija Ippolito, Sridhar Vasudevan, Shaun Hurley et al.
9 citations
Serotonergic psychedelic drugs are being studied as treatments for psychiatric disorders like major depression. All such drugs activate the 5-HT2A receptor, but some 5-HT2A receptor agonists are not psychedelic. This investigation tested six psychedelic drugs (psilocin, 5-MeO-DMT, LSD, mescaline, 25B-NBOMe, and DOI) and three non-psychedelic drugs (lisuride, TBG, and IHCH-7079) for their effects on Gq-coupled and β-arrestin2 signaling pathways in cells expressing human 5-HT2A receptors. All psychedelic drugs were unbiased partial agonists at both pathways. The non-psychedelic drugs were not distinguished by signaling bias but showed the lowest signaling efficacy among all drugs tested, a finding confirmed in rat C6 cells. Low 5-HT2A receptor signaling efficacy may explain why some agonists lack psychedelic effects.
British Journal of Pharmacology
June 15, 2025
Daniël Hoyer
9 citations
Psychedelics like psilocybin, LSD, and ayahuasca, along with non-hallucinogenic entactogens such as MDMA, are being investigated as rapidly acting treatments for major depressive disorder, treatment-resistant depression, PTSD, and generalized anxiety disorder. Late-stage clinical trials support their use in assisted psychotherapy. These drugs primarily target serotonin and monoamine systems, with classical psychedelics acting as 5-HT2A receptor agonists. Advanced imaging shows that depression involves reduced brain serotonin levels and impaired neural networks, which psychedelics and entactogens can correct. They promote neuroplasticity and synaptogenesis through monoamine or glutamate receptors and pathways like BDNF and mTORC1, supporting a biological basis for these disorders.
British Journal of Pharmacology
October 2, 2024
Ryan H. Gumpper, David E Nichols
9 citations
Classic serotonergic psychedelics come in three main chemical families: phenethylamines, ergolines, and tryptamines. Each family has distinct structural features that determine its psychedelic activity in humans. The 5-HT2A receptor, a G-protein coupled receptor, is the primary target for these compounds. Recent X-ray and cryoEM structures showing various ligands bound to the receptor reveal the atomic-level details of how different psychedelic molecules interact with this receptor. These structural insights help explain known pharmacological observations about how psychedelic drugs work and may guide future drug development.
British Journal of Pharmacology
May 23, 2025
Trevor Sharp, Aurelija Ippolito
8 citations
Psychedelic drugs like LSD and psilocin, once banned and stigmatized, are now being studied for their long-lasting benefits in mental illnesses such as depression, addictions, and anxiety disorders. Their powerful hallucinatory effects are thought to be mediated by agonist action at 5-HT2A receptors, but the link between the psychedelic experience and therapeutic outcomes remains uncertain. Recent research has identified a new class of 5-HT2A receptor agonists that may retain therapeutic potential without inducing hallucinations, with biased signalling, partial agonism, and increased neuroplasticity offering possible explanations for their effects. This article explores the neuropsychopharmacological properties of both hallucinogenic and non-hallucinogenic 5-HT2A receptor agonists as potential novel psychiatric treatments.
British Journal of Pharmacology
September 6, 2013
Cédric M. Hysek, Yasmin Schmid, Anna Rickli et al.
7 citations
A 125 mg dose of MDMA, a common recreational amount, produces only a moderate increase in body temperature in controlled clinical settings where risk factors like high ambient temperature, physical exertion, and dehydration are avoided. Severe hyperthermia, a rare but life-threatening complication of recreational MDMA use, typically requires additional permissive factors such as repeated or high doses, crowded conditions, or hyperthyroidism. The drug carvedilol, which blocks both α- and β-adrenoceptors, reduced MDMA-induced thermogenesis in humans and reversed established hyperthermia in rats, but its utility for treating severe MDMA toxicity in emergency settings remains unknown and requires further evaluation in case reports or series.
British Journal of Pharmacology
April 1, 2000
M K Mundey, N A Blaylock, R Mason et al.
6 citations
Ibogaine and 18-methoxycoronaridine, alkaloids with reported anti-addictive properties, modulated electrically-evoked contractions in smooth muscle preparations but did not selectively interact with mu-opioid receptors. In guinea-pig ileum, both drugs concentration-dependently inhibited cholinergic contractions (ibogaine pIC50 5.28, 18-methoxycoronaridine pIC50 5.05), an effect not blocked by naloxone. In rat vas deferens, they enhanced purinergic contractions and caused a 3- to 5-fold rightward shift of DAMGO-induced inhibition. In guinea-pig bladder, both drugs doubled the purinergic component of neurogenic contractions without affecting cholinergic contractions. Ibogaine, but not 18-methoxycoronaridine, enhanced spontaneous contractions of rat portal vein. The pronounced enhancement of purinergic contractions is a novel finding warranting further investigation.
British Journal of Pharmacology
November 14, 2025
Valéria Tékus, Éva Borbély, Andreas Goebel et al.
5 citations
A systematic review of Phase 1-3 clinical trials from 2014 to 2024 found no breakthrough in pharmacotherapy for chronic primary pain conditions including fibromyalgia, complex regional pain syndrome, and chronic low back pain. The lack of progress may stem from unsuccessful approaches to reveal pathophysiological mechanisms, lack of translational preclinical animal models, and patient population heterogeneity with comorbidities. Most trials focused on repurposing antidepressants, antiepileptics, psychedelics, and immune modulators. Promising candidates targeted cannabinoid, glutamate, GABAergic, neuroinflammatory, and immune mechanisms. Only cannabidiol (CBD) and (es)ketamine were tested for all three conditions despite similar etiological factors.
British Journal of Pharmacology
July 28, 2025
Omar Qureshi, Jamie Cowley, Ashley Pegg et al.
5 citations
Psychedelic drugs that activate 5-HT2A receptors are known for treating psychiatric disorders, but growing evidence shows they also modulate immune responses by inhibiting pro-inflammatory cytokine release. In vivo studies demonstrate that psychedelics like (R)-DOI reduce inflammation in animal models of asthma and other inflammatory diseases. Clinical studies with psilocybin show effects on circulating cytokine levels, supporting translation from animal models to humans. These findings highlight the promise of targeting inflammation therapeutically. Recent research has identified compounds that maintain therapeutic potential without causing psychedelic effects, termed PIPI drugs (Psychedelic drug Informed but Psychedelic experience Inactive), offering new avenues for treating mental health and inflammation.
British Journal of Pharmacology
May 1, 1976
Paul Bevan, C. M. Bradshaw, E. Szabadi
4 citations
Desipramine both potentiates and antagonizes the responses of single cortical neurones to mescaline. The antagonism may stem from desipramine's α-adrenolytic action, while the potentiation is unlikely due to uptake blocking because desipramine does not block mescaline uptake in the cerebral cortex. The potentiation may instead result from a post-synaptic action of desipramine.
British Journal of Pharmacology
October 21, 2025
Austen B Casey, Boris D. Heifets
3 citations
MDMA, known as the illicit drug ecstasy, shows promise when used alongside psychotherapy for posttraumatic stress disorder (PTSD), though how it works remains unclear. This review traces MDMA's path from military interrogation aid to prohibited substance and now to clinical use. The authors identify three core subjective effects—prosocial behavior, reduced threat perception, and euphoria—and examine how each may contribute to both therapeutic benefits and abuse potential. They emphasize serotonin's central role in MDMA's effects while noting gaps in understanding its mechanism. The review also critiques preclinical models, highlights limitations like sex biases and assumptions about therapeutic alliance, and calls for clarifying mechanisms to develop safer, more effective MDMA-like treatments.
British Journal of Pharmacology
September 2, 2025
Lucas M Wittenkeller, Gary A. Gudelsky, Theresa Winhusen et al.
3 citations
Psychedelics are being studied as treatments for substance use disorders (SUDs), not just depression. A scoping review identified 34 clinical trials targeting alcohol, cannabis, cocaine, methamphetamine, nicotine, and opioid use disorders, mostly open-label without placebo controls. Alcohol use disorder was the most common target. From animal studies, four publications measured dopamine in the nucleus accumbens after psilocybin or MDMA. High-dose psilocybin caused a sustained mild increase in dopamine, suggesting it may help restore tonic dopamine levels, which could be relevant for treating addiction.
British Journal of Pharmacology
June 1, 2026
Szabolcs Koncz, Dóra Pothorszki, Noémi Papp et al.
2 citations
In rats, the (S)-enantiomer of ketamine (esketamine) produces a fourfold stronger wake-promoting effect and a twofold stronger increase in gamma brainwave power during wakefulness compared to the (R)-enantiomer (arketamine). Only esketamine enhances delta power during NREM sleep after gamma activity normalizes, a pattern called the gamma-delta shift. This shift, previously proposed as a marker of antidepressant activity for racemic ketamine, appears specific to esketamine. The findings help clarify which enantiomer drives the EEG changes and suggest that the gamma-delta shift may serve as a biomarker for antidepressant effects, relevant to treatment-resistant depression.
British Journal of Pharmacology
May 13, 2025
Brian Lord, Sirak Simavorian, Ian Fraser et al.
2 citations
A selective GluN2A antagonist, JNJ-78911118, blocks GluN1/2A receptors with an IC50 of 44 nM and shows selectivity over other NMDA receptor subtypes. It increases prefrontal cortex monoamine levels in wild-type but not GluN2A knockout mice, blocks hippocampal long-term potentiation, and boosts dendritic complexity, synapse number, and mEPSC frequency in rat cortical neurons. In rats, no Olney's lesions occurred, but acute increases in heart rate and blood pressure were detected. The molecule reproduces effects of known rapidly acting antidepressants on neurotransmitter levels and synaptic plasticity, offering a tool to study GluN2A biology.
British Journal of Pharmacology
July 1, 2026
Yuanyuan Wang, Yishan Yao, Ruibin Su et al.
1 citation
The psychedelic compound 4-acetoxy-N,N-dimethyltryptamine (4-AcO-DMT) suppresses innate fear responses in rats by activating 5-HT₂A receptors, which recruit vasoactive intestinal polypeptide (VIP) interneurons in the prelimbic cortex. In behavioral experiments, 4-AcO-DMT reduced predator odor-evoked 22-kHz ultrasonic vocalizations, a fear-related response, through this specific cortical microcircuit mechanism. Chemogenetic activation of VIP interneurons abolished the fear-suppressing effect, confirming their role. The findings advance understanding of how serotonergic psychedelics modulate fear circuits at a neurobiological level, with potential implications for treating fear-related psychiatric disorders like phobias and anxiety.
British Journal of Pharmacology
November 23, 2025
Tianhua Wang, Rainer K W Schwarting, Markus Wöhr
1 citation
MDMA (ecstasy) stimulates arousal and euphoria by releasing dopamine, noradrenaline, and serotonin in the brain, but which chemical drives these effects has been unclear. In rats genetically modified to lack central serotonin, MDMA failed to increase psychomotor activity (a marker of arousal) and 50-kHz ultrasonic vocalizations (a marker of euphoria). Rats with reduced serotonin showed no euphoric response and only partial arousal. The findings indicate that central serotonin is necessary for MDMA's arousal- and euphoria-inducing effects, suggesting dopamine and noradrenaline are not sufficient to produce these responses.
British Journal of Pharmacology
November 1, 2025
Yasaman Razavi, Stephen J Kohut, Jack Bergman et al.
1 citation
Adolescent monkeys exposed daily to the cannabis compound Δ9-THC for six months, then tested about a year later as adults on a touchscreen attention task, required higher acute doses of Δ9-THC to impair their performance compared with animals that had not been exposed during adolescence. The impairment itself was dose-related and occurred whether the drug was given by injection or orally, though potency and timing differed. These results suggest that heavy cannabis use during adolescence can produce a lasting tolerance that persists into adulthood, even after a long period of abstinence.
British Journal of Pharmacology
May 5, 2026
Giorgia Corli, Deborah Rudin, Dino Luethi et al.
Some new synthetic cannabinoid receptor agonists (SCRAs) also directly activate the serotonin 5-HT₂A receptor, which may contribute to unexpected psychiatric side effects. Many SCRAs with a valinamide or tert-leucinamide head moiety showed in vitro activity at the 5-HT₂A receptor at high concentrations. In mice, the compound AB-5′F-BUTINACA caused neurological changes, sensorimotor alteration, antinociception, hypothermia, reduced breath rate, and hypolocomotion. These effects were mediated by both CB₁ and 5-HT₂A receptors, as they were prevented by selective antagonists. The findings indicate potential risks of SCRA consumption that could exacerbate unexpected psychiatric conditions.
British Journal of Pharmacology
May 26, 2011
Ján Kehr, Fumio Ichinose, Shimako Yoshitake et al.
The designer drug mephedrone, compared with MDMA (ecstasy) and amphetamine in rats, rapidly increased dopamine levels in the nucleus accumbens by 496% and serotonin levels by 941%, closely matching MDMA's serotonin release but also producing an amphetamine-like fast dopamine surge and elimination. Amphetamine raised dopamine by 412% and serotonin by only 165%. Mephedrone's dopamine levels cleared within 25 minutes, versus 303 minutes for MDMA, suggesting its brief but potent effect on the brain's reward system may underlie strong addictive potential. Locomotor activity increased most with amphetamine; mephedrone and MDMA had weaker, shorter effects.
British Journal of Pharmacology
July 14, 2026
Darta Stalberga, Robert Kronstrand, Bianca Schranz et al.
Synthetic cathinones, a large class of new psychoactive substances, primarily inhibit dopamine, norepinephrine, and serotonin transporters, with high dopamine transporter selectivity linked to abuse potential. In vitro testing of 58 substances showed that N-pyrrolidine cathinones combined with methylenedioxy groups—MDPiHP, MDPEP, and MDPV—had the highest potency at the dopamine transporter. Other N-pyrrolidine cathinones, such as 3F-α-PHP, 3F-α-PiHP, and 4F-α-PiHP, showed the greatest dopamine transporter selectivity relative to the serotonin transporter. Chloromethcathinone and methylmethcathinone compounds, like 3-CMC, displayed an amphetamine-like profile with comparable potency at dopamine and norepinephrine transporters. Some cathinones at high concentrations and phenethylamines at micromolar concentrations also activated the 5-HT2A receptor, while 2C-like arylcyclohexylamines targeted the receptor without transporter inhibition. The majority of compounds, especially N-pyrrolidine cathinones, suggest high abuse potential based on their dopamine transporter selectivity.
British Journal of Pharmacology
July 1, 2026
Susan Wonnacott, Gary J. Stephens, Trevor Sharp
This editorial introduces a themed journal issue on psychedelic and related drugs as potential therapies for a wide range of difficult-to-treat conditions beyond neuropsychiatric disorders. The collection includes reviews and original articles covering the mechanistic basis of how these drugs act, the current status of preclinical research, progress in clinical trials, and insight into regulatory processes for clinical approval. The editorial provides an overview of current controversies and challenges in the field while highlighting the exciting potential these drugs offer.
British Journal of Pharmacology
August 1, 2022
Michael Tagen, Linda E. Klumpers
Delta-8-THC, an intoxicating cannabinoid, has rapidly grown in use. This review summarizes decades of pharmacological studies on delta-8-THC, including receptor binding, cell signaling, animal and human activity, and pharmacokinetics, with special focus on comparisons to delta-9-THC. The pharmacokinetics and pharmacodynamics of the two isomers are very similar. Delta-8-THC is a partial agonist of the CB1 receptor and has cannabimimetic activity in both animals and humans. Its reduced potency in clinical studies compared to delta-9-THC can be explained by weaker CB1 receptor affinity, though other mechanisms may contribute. Gaps in knowledge, particularly in human studies, are highlighted.
British Journal of Pharmacology
October 1, 2021
Kwang-Hyun Hur, Seong-Eon Kim, Shi-Xun Ma et al.
Methoxphenidine, a dissociative designer drug, produces addictive behaviors in rats and mice through reinforcing and rewarding effects, activating dopamine pathways in the nucleus accumbens. It also induces schizophrenia-related symptoms—positive (hyperactivity, impulsivity), negative (anxiety, social withdrawal, depression), and cognitive impairment—by disrupting the hippocampal-prefrontal cortex pathway, a circuit implicated in schizophrenia. These findings support legal restrictions on recreational use and suggest methoxphenidine may serve as a tool for developing animal models of addiction and schizophrenia.
British Journal of Pharmacology
January 1, 2020
Jacques D Nguyen, Kevin M Creehan, Tony M Kerr et al.
Adolescent rats repeatedly inhaling THC vapor developed tolerance to THC-induced hypothermia, with females showing tolerance earlier than males despite similar THC levels in the blood. In adulthood, both sexes retained tolerance, but THC potency was enhanced in females. Male rats exposed to adolescent THC ate more food than controls without gaining more weight. Adolescent THC exposure did not change oxycodone self-administration in either sex but increased fentanyl self-administration in females. The authors conclude that repeated THC vapor inhalation during adolescence has lasting consequences observable in adulthood.
British Journal of Pharmacology
July 1, 2019
Panos Zanos, Jaclyn N. Highland, Xin Liu et al.
In mice, (R)-ketamine's metabolism to (2R,6R)-hydroxynorketamine (HNK) enhances its antidepressant-relevant actions. A deuterated form of (R)-ketamine that blocks this metabolism had less potency in antidepressant-sensitive behavioral tests, while (2R,6R)-HNK itself produced dose-dependent sustained antidepressant effects. However, (R)-ketamine also caused NMDA receptor-mediated adverse effects—including locomotor stimulation, conditioned-place preference, prepulse inhibition deficits, and motor incoordination—at sub-anaesthetic doses, with about half the potency of racemic ketamine. These findings indicate that while antidepressant-relevant effects occur at lower doses, there is a potential risk for sensory dissociation and abuse liability at higher doses.
British Journal of Pharmacology
October 1, 2017
M T Zanda, P Fadda, S Antinori et al.
Methoxetamine (MXE), a novel dissociative psychoactive substance sold online, produces dose-dependent effects on rat behavior and brain chemistry. Low doses (0.5 and 1 mg/kg) increased motor activity and induced anxiety-like or obsessive-compulsive traits, while high doses (5 mg/kg) caused sedation, transient pain relief, reduced social interaction, and antidepressant-like effects in the forced swim test. MXE did not alter self-grooming. Behaviorally active doses increased phosphorylation of ribosomal protein S6 in the medial prefrontal cortex and hippocampus, a molecular change also seen with ketamine, indicating rapid neuroadaptive responses.