British Journal of Clinical Pharmacology
February 21, 2013
Marieke Niesters, Christian H. Martini, Albert Dahan
498 citations
The anesthetic ketamine is used to treat chronic pain syndromes, especially those with a neuropathic component. Low-dose ketamine produces strong analgesia, likely by blocking the N-methyl-D-aspartate receptor, though other mechanisms such as enhanced descending inhibition and anti-inflammatory effects may contribute. Short-term infusions provide pain relief only during administration, while prolonged infusions of 4–14 days can yield analgesic effects lasting up to three months. Side effects include psychedelic symptoms, nausea, vomiting, somnolence, cardiovascular stimulation, and occasional hepatotoxicity.
British Journal of Clinical Pharmacology
February 1, 2012
Xiaochen Zhao, Swarajya Lakshmi Vattem Venkata, Ruin Moaddel et al.
136 citations
Ketamine is metabolized into several compounds, and this study shows that norketamine is not the main metabolite circulating in the blood after a single 40-minute infusion of 0.5 mg/kg ketamine in patients with treatment-resistant bipolar depression. Instead, dehydronorketamine was the major metabolite in four out of nine patients, norketamine in three, and hydroxynorketamine in two. Large inter-patient variation in metabolite levels was observed. The findings suggest that future research on ketamine's effects should measure these downstream metabolites.
British Journal of Clinical Pharmacology
June 1, 2002
Jordi Riba, P. Anderer, Adelaida Morte et al.
126 citations
Ayahuasca, a psychoactive tea from South America, produces measurable changes in brain electrical activity that parallel its subjective psychedelic and stimulant effects. In a double-blind crossover trial, 18 volunteers received low and high doses of freeze-dried ayahuasca. Electroencephalography recordings from baseline to eight hours showed dose-dependent decreases in absolute power across all frequency bands, especially theta, and decreases in relative delta and theta power with increases in beta power. Effects began within 15–30 minutes, peaked between 45 and 120 minutes, and returned to baseline by four to six hours. The pattern resembles that of other serotonergic psychedelics and supports the role of 5-HT2 and dopamine D2 receptor activation.
British Journal of Clinical Pharmacology
March 19, 2019
Friederike Holze, Urs Duthaler, Patrick Vizeli et al.
72 citations
After a 100 μg oral dose of LSD, plasma levels peak at about 1.7 hours and decline with a half-life of 3.6 hours. The main metabolite O-H-LSD peaks later, around 5 hours, and has a longer half-life of 5.2 hours. No sex differences in pharmacokinetics were observed. Subjective effects last an average of 8.5 hours, peaking at 2.5 hours. The concentration needed to produce half-maximal effects is 1.0 ng/mL for good effects and 1.9 ng/mL for bad effects, showing that subjective experiences closely track plasma concentrations over time.
British Journal of Clinical Pharmacology
December 11, 2015
Matthias E. Liechti, Boris B. Quednow, Evangelia Liakoni et al.
57 citations
Gamma-hydroxybutyrate (GHB) produced mixed stimulant-sedative effects in healthy men, with higher doses causing more sedation and dizziness but no changes in heart rate or blood pressure. Plasma exposure to GHB rose disproportionately with dose—a 40% greater increase than expected from dose alone—indicating nonlinear pharmacokinetics. The psychotropic effects were closely tied to plasma concentrations, and no acute tolerance developed over time.
British Journal of Clinical Pharmacology
April 1, 1985
Michael Schächter, D.p. Geaney, Dg Grahame‐smith et al.
20 citations
Schizophrenic patients treated with depot thioxanthenes and phenothiazines showed an approximately 30% increase in platelet 5-HT receptor number and a roughly 30% decrease in receptor affinity compared to controls. The decrease in affinity likely resulted from residual neuroleptic in the platelet membrane preparation. A weak positive correlation existed between receptor number and total neuroleptic dosage. The increased receptor number aligns with earlier reports of enhanced 5-HT-induced platelet aggregation in patients on long-term phenothiazines and thioxanthenes, suggesting 5-HT up-regulation in human platelets from depot neuroleptic therapy. Whether parallel changes occur in brain 5-HT receptors remains unknown.
British Journal of Clinical Pharmacology
July 17, 2023
Balázs Szigeti, Lawrence D. Phillips, David Nutt
13 citations
Randomized controlled trials (RCTs) are often considered the gold standard in medical research, but they have limitations including reliance on null hypothesis significance testing and poor generalizability. Bayesian analysis of real-world evidence (RWE) offers a complementary approach. In a case series of 20 children with epilepsy treated with medical cannabis, all experienced reduced seizures; Bayesian analysis with a flat prior gives a 95% probability that the next patient will improve (95% credible interval 87%–100%). For treatment-resistant depression treated with psilocybin, the probability of a favorable response ranges from 62% (QIDS-16) to 82% (MADRS). These analyses require fewer patients than traditional RCTs and provide directly actionable probabilities for clinicians and patients.
British Journal of Clinical Pharmacology
January 1, 2024
Friederike Holze, Livio Erne, Urs Duthaler et al.
12 citations
After oral doses of 85 and 170 μg, LSD reaches peak blood concentrations of 1.8 and 3.4 ng/mL at about 1.7 hours, with elimination half-lives of 3.7 and 4.0 hours. Only 1% of the dose is excreted unchanged in urine within 24 hours, while 16% is eliminated as the metabolite 2-oxo-3-hydroxy-LSD. Subjective drug effects last 9.3 to 11 hours, with maximal intensity reaching 77% to 87%. LSD shows dose-proportional pharmacokinetics and first-order elimination, and its effects are dose-dependent. The findings confirm earlier work on LSD's metabolism and time course.
British Journal of Clinical Pharmacology
April 22, 2022
Ahmad Shamabadi, Ali Ahmadzade, Alireza Hasanzadeh
11 citations
A systematic review of systematic reviews found preliminary evidence that ketamine may reduce suicidal thoughts in the short term, but long-term effects remain unknown. Most of the 27 reviewed studies reported positive effects, though only four showed mixed or negative results. Among nine reviews of esketamine, only five found significant benefit. Common side effects included a temporary rise in pulse and blood pressure, dissociation, confusion, blurred vision, nausea, and vertigo, mostly mild. Over two-thirds of the included reviews were rated low or critically low quality, highlighting the need for further research.
British Journal of Clinical Pharmacology
December 1, 2024
Jeremy Weleff, Julio C Nunes, Gabriel P. A. Costa et al.
8 citations
Chronic pain and opioid use disorder (OUD) are two interconnected public health crises that lack effective treatments. This review examines whether psychedelics could serve as novel therapeutics by acting on shared brain mechanisms underlying both conditions. Preclinical and human evidence suggests psychedelics may reverse pain- and opioid-induced neuroadaptations like central sensitization. The authors map how psychedelics could modulate overlapping dimensions of pain (sensory, affective, cognitive) and opioid-related phenomena (craving, withdrawal). They note a scarcity of controlled studies but propose mechanistic insights and methodological guidelines for future clinical trials. The goal is to accelerate development of alternatives to opioids amid the escalating crisis.
British Journal of Clinical Pharmacology
November 25, 2024
Aaron Klaiber, Mélusine Humbert‐droz, Laura Ley et al.
6 citations
Mescaline doses up to 800 mg appear safe in controlled clinical settings for healthy individuals. In two double-blind, placebo-controlled studies with 48 participants and 96 administrations, positive subjective effects increased with dose and consistently outweighed negative effects. Autonomic effects rose moderately: systolic blood pressure exceeded 180 mmHg in 6% of administrations, heart rate above 100 beats/min occurred in 3%, and body temperature above 38 °C in 5%. Nausea limited higher doses. Kidney and liver function and blood cell counts remained normal. Flashbacks followed 2% of administrations. Adverse effects totaled 51 at 100 mg and 180 at 800 mg.
British Journal of Clinical Pharmacology
August 1, 2024
Kaizheng Chen, Yaming Xie, Songyuan Chi et al.
6 citations
Low-dose esketamine given during surgery for vestibular schwannoma did not reduce pain at rest or with movement in the first 24 hours after the operation. The trial randomly assigned 90 adults to receive either 0.2 mg/kg of esketamine or a placebo after dural closure. Esketamine moderately increased brain activity as measured by the bispectral index for at least 30 minutes after administration, prolonged the time to removal of the breathing tube, and lowered the required dose of remifentanil at that point, but did not affect heart rate, blood pressure, or the time to regain spatial orientation. Rates of nausea and vomiting were similar between groups, and no hallucinations or excessive sedation occurred.
British Journal of Clinical Pharmacology
December 1, 2024
Gisela Lima, Carla Soares, Marta Teixeira et al.
4 citations
Psychedelics are being explored for physical and mental health applications beyond psychiatry, including chronic pain, palliative care, and neuroprotection in ischemia. This article reviews dimethyltryptamine (DMT) and ayahuasca pharmacology, effects, safety, and toxicity, and details the anaesthetist's role in clinical and experimental research—covering participant screening, dosing sessions, adverse effect management, and toxicity treatment. It draws on a current neuroimaging study protocol. The authors argue that anaesthetists are uniquely positioned to manage psychedelic therapy in medically complex, polymedicated patients, but note that non-mental medical applications remain underexplored.
British Journal of Clinical Pharmacology
June 16, 2025
Wellenberg K Simon, Tanja M Gampfer, Wagmann Lea et al.
1 citation
A workflow using zebrafish embryos (ZEs) followed by human microdosing (HMD) can identify human urine biomarkers for drugs of abuse and new psychoactive substances. Metabolites of amphetamine, cocaine, LSD, MDMA, methamphetamine, THC, MDMB-CHMICA, and MDPPP were first identified in ZEs exposed via immersion or injection, then compared with known human metabolites and confirmed by HMD. Both methods identified main human urine metabolites, except for LSD (due to low dose) and cannabinoids (due to low oral bioavailability). ZEs produced more metabolites, including conjugates, than HMD. The approach provides quick, reliable data for urinary drug screening, though challenges remain with HMD, including different administration routes and low-dose detectability.
British Journal of Clinical Pharmacology
July 1, 2026
Marije E. Otto, Gabriël E. Jacobs, Joost C Van Mechelen et al.
Oral (S)-ketamine for treatment-resistant depression undergoes extensive first-pass metabolism, yielding low parent drug but high levels of active metabolites like (S)-norketamine. Using data from 17 healthy participants in a crossover trial, researchers developed a population PK model linking (S)-ketamine and (S)-norketamine concentrations to subjective 'Feeling High' scores. A significant relationship was found for (S)-norketamine alongside (S)-ketamine, though model variance was high. The analysis suggests that (S)-norketamine, not (S)-ketamine itself, primarily drives subjective effects after oral administration and may contribute to antidepressant effects in patients.
British Journal of Clinical Pharmacology
June 24, 2026
Catherine M K E De Cuba, Annika A De Goede, Joost C Van Mechelen et al.
A single intravenous dose of S-ketamine produced acute and delayed effects on brain activity and motor cortex excitability that lasted up to seven days in 16 healthy adults. Intravenous S-ketamine reduced motor-evoked potential amplitude acutely and caused a sustained weakening of long-interval intracortical inhibition, which followed a linear relationship with drug concentration. Transcranial magnetic stimulation combined with electroencephalography showed acute changes in brain electrical activity across all treatments, but delayed changes only after intravenous and high-dose oral S-ketamine. Electroencephalography revealed acute decreases in alpha, beta, and delta power with eyes closed, and sustained increases in delta power with eyes open, the latter also showing a linear concentration-effect relationship. These delayed pharmacodynamic effects are distinct from acute effects and may help explain S-ketamine's antidepressant action.
British Journal of Clinical Pharmacology
May 8, 2026
Ioanna Artemis Vamvakopoulou, Dasha Nicholls, David Nutt et al.
Rates of mental illness among young people are rising, but few new treatments have emerged. Psychedelic-assisted therapy with psilocybin and MDMA has shown promise for adults with depression, anxiety, and PTSD, and interest is growing in its use for adolescents. A comprehensive review of all research on children and young people—from 1950s experiments to recent observational and retrospective studies of traditional and non-medical use—finds that psychedelics appear safe overall and may improve mental wellbeing in this age group. However, young people may face greater risks of anxiety, challenging experiences, and ego dissolution, warranting more thorough clinical research. The authors recommend a rigorous ethical framework with family involvement and consideration of lower doses to reduce potential harms.
British Journal of Clinical Pharmacology
February 1, 2000
Rafael de la Torre, Magı́ Farré, Jordi Ortuño et al.
MDMA (ecstasy) shows nonlinear pharmacokinetics in humans: as the dose increases, plasma concentrations rise disproportionately, meaning small dose increases lead to much higher drug levels. In a controlled trial with 14 healthy volunteers given 50–150 mg, urinary recovery of the metabolite HMMA stayed constant while MDMA recovery rose, suggesting saturation or inhibition of the demethylenation metabolic step. Nonrenal clearance was dose-dependent while urinary clearance remained constant. This nonlinearity occurs regardless of CYP2D6 genotype, implying that even moderate dose increases in recreational use can produce unexpectedly high plasma concentrations, raising the risk of acute toxicity for all users, not just the 10% genetically deficient in CYP2D6.
British Journal of Clinical Pharmacology
July 20, 2026
Laxna Bhujel, Angela L Chiew, Bhashita Jagarlamudi et al.
Higher cumulative recreational nitrous oxide (N2O) exposure is the strongest predictor of severe neurological outcomes, showing a dose-dependent relationship with neurotoxicity. In a retrospective cohort study of 81 individuals hospitalized across six Sydney hospitals from 2020 to 2025, greater cumulative N2O exposure was associated with worse neurological impairment, including subacute combined degeneration of the spinal cord and peripheral neuropathy, and correlated with greater neuropathy severity. Median homocysteine was 50 μmol/L and median methylmalonic acid (MMA) was 0.68 μmol/L. Homocysteine and MMA were sensitive markers associated with neurological toxicity, making them useful screening biomarkers, but their limited specificity reduces utility as confirmatory tests. B12 and holotranscobalamin showed high specificity but low sensitivity for detecting cases with spinal cord degeneration.
British Journal of Clinical Pharmacology
July 24, 2024
Eric L. Garland
The opioid crisis partly stems from overprescribing opioid analgesics for chronic pain, though not all patients can taper off opioids. Mindfulness-Oriented Recovery Enhancement (MORE) integrates mindfulness training, cognitive behavioral therapy, and positive psychology to target reward and stress systems underlying addiction, emotion dysregulation, and chronic pain. Across 13 completed randomized clinical trials involving over 1300 patients, MORE demonstrated efficacy against active control conditions for reducing opioid dosing, opioid misuse, illicit drug use, depression, post-traumatic stress symptoms, and chronic pain. Implementation opportunities include facilitating opioid tapering in primary care and specialty pain clinics and enhancing medication-assisted treatment for opioid use disorder.
British Journal of Clinical Pharmacology
November 1, 2022
Bruno Revol, Maryse Lapeyre-Mestre, Nathalie Fouilhé Sam-Lai et al.
All four N-methyl-D-aspartate receptor (NMDAR) antagonists examined—dextromethorphan, ketamine, amantadine, and memantine—showed a statistically significant association with reports of drug abuse and dependence in the World Health Organization pharmacovigilance database (VigiBase®), which contains over 21 million case reports from more than 130 countries. The strongest signal was for dextromethorphan, followed by ketamine, with weaker but still significant signals for amantadine and memantine. This suggests a possible class effect for abuse potential among NMDAR antagonists. The authors call for further investigation and alert health professionals to this risk, especially given growing interest in these drugs as non-opioid pain treatments during the opioid epidemic.