Clinical pharmacology in drug development
November 1, 2016
Paul Glue, Gavin Cape, Donna Tunnicliff et al.
66 citations
Noribogaine, the active metabolite of ibogaine, was tested for the first time in patients on methadone opioid substitution therapy. In a randomized, double-blind, placebo-controlled trial with 27 patients, doses of 60, 120, or 180 mg were well tolerated, with common side effects including temporary changes in light perception, headache, and nausea. The drug showed dose-linear increases in blood concentration and a slow elimination half-life of 24–30 hours. Noribogaine caused a concentration-dependent increase in heart rate–corrected QT interval (QTcI), with average increases of about 16, 28, and 42 milliseconds at the three doses. There was a nonstatistically significant trend toward reduced opioid withdrawal symptoms, most notably at 120 mg, but study design issues may have affected results.
Journal of clinical pharmacology
February 1, 2015
Paul Glue, Michelle Lockhart, Fred Lam et al.
61 citations
Noribogaine, the active metabolite of ibogaine, may help suppress withdrawal symptoms in opioid-dependent people. In a Phase I ascending single-dose, placebo-controlled, randomized, double-blind, parallel-group study in 36 healthy drug-free male volunteers, oral doses of 3, 10, 30, or 60 mg were given. Noribogaine was rapidly absorbed, reaching peak concentrations 2-3 hours after dosing, and showed dose-linear increases in exposure between 3 and 60 mg. The drug was slowly eliminated, with mean half-lives of 28-49 hours and a high volume of distribution (mean 1417-3086 L). No safety or tolerability issues were identified, and no mu-opioid agonist effects were observed in pupillometry or cold-pressor testing. Single oral doses of 3-60 mg were safe and well tolerated.
Journal of clinical pharmacology
June 1, 2015
Paul Glue, Helen Winter, Kira Garbe et al.
39 citations
Conversion of ibogaine to its active metabolite noribogaine is primarily mediated by the CYP2D6 enzyme. In a study of 21 healthy subjects given a single 20 mg oral dose of ibogaine after 6 days of pretreatment with either placebo or the CYP2D6 inhibitor paroxetine, those pretreated with paroxetine showed rapid absorption of ibogaine, with detectable levels lasting up to 72 hours and an elimination half-life of 10.2 hours. Noribogaine exposure was similar between groups, but the active moiety (ibogaine plus noribogaine) exposure was about 2-fold higher in paroxetine-pretreated subjects. CYP2D6 phenotype correlated strongly with ibogaine AUC and Cmax. The findings suggest genotyping patients before ibogaine treatment and halving the dose in CYP2D6 poor metabolizers to ensure safety.
Journal of ethnopharmacology
August 2, 2016
Bridget Forsyth, Liana Machado, Tim Jowett et al.
35 citations
A single 20mg dose of ibogaine had minimal influence on psychological tests and mood ratings in healthy male volunteers. The ability to selectively ignore distracting spatial information showed some evidence of modulation, but only in the less challenging condition, raising questions about reliability. No stimulant effects were identified. The study assessed relationships between changes in test scores and concentrations of active moiety (the sum of molar noribogaine and ibogaine concentrations), but future research is needed to confirm whether these concentrations impact selective attention abilities while leaving other cognitive functions and mood state unaffected.
Journal of Psychopharmacology
October 1, 2017
Cameron Castle, Andrew Gray, Shona Neehoff et al.
20 citations
Ketamine produces dose-dependent dissociative symptoms in patients with treatment-resistant anxiety, while midazolam does not. The Clinician-Administered Dissociative States Scale (CADSS) shows high internal consistency (Cronbach alpha = 0.937) for measuring these symptoms, though it does not capture thought disorder. Individual items varied in their sensitivity to ketamine dose and magnitude of change. Removing items did not meaningfully improve the scale's reliability, and acceptable consistency remained even after excluding items unresponsive at lower doses. The CADSS is an internally consistent tool for assessing ketamine-induced dissociation in clinical trials for anxiety.
Journal of psychopharmacology (Oxford, England)
June 5, 2025
Ben Beaglehole, Paul Glue, Shona Neehoff et al.
19 citations
In an open-label extension of a prior crossover trial, oral ketamine was given for six weeks to people with treatment-resistant depression, post-traumatic stress disorder, or obsessive-compulsive disorder. Doses started at 1-1.5 mg/kg and increased to 1.5-2.5 mg/kg, taken one to three times per week. Symptom scores remained low throughout the six weeks, and the oral formulation was well tolerated with few side effects. The findings suggest that oral ketamine can sustain improvements in these treatment-resistant conditions and offers a practical alternative for maintenance therapy.
Journal of psychopharmacology (Oxford, England)
February 1, 2021
Dylan Truppman Lattie, Hayley Nehoff, Shona Neehoff et al.
13 citations
Ketamine produced rapid, dose-related reductions in fear and anxiety among patients with treatment-resistant anxiety disorders. In a study of 24 patients receiving short-term ascending subcutaneous doses followed by a 3-month maintenance phase, scores on all three Fear Questionnaire subscales (agoraphobia, social phobia, blood-injury phobia) and the Spielberger State Anxiety Inventory decreased quickly after acute dosing and continued to decline progressively during maintenance therapy. Ketamine appears to have broad, dose-related anti-phobic effects, suggesting potential for treating other phobic conditions.
Journal of psychopharmacology (Oxford, England)
January 1, 2025
Ben Beaglehole, Paul Glue, Shona Neehoff et al.
12 citations
Ketamine reduces obsessive-compulsive symptoms more than a psychoactive control (fentanyl) in people with severe, treatment-resistant OCD. In a small double-blind trial, participants received a single intramuscular dose of either 0.5 mg/kg ketamine, 1.0 mg/kg ketamine, or 50 µg fentanyl. Both ketamine doses produced greater and dose-related reductions on the Yale-Brown Obsessive-Compulsive Scale, with effects separating from fentanyl within 1–2 hours and persisting for up to 168 hours. Ketamine caused short-term dissociative and cardiovascular effects; two of twelve participants dropped out due to not tolerating dissociation. The findings provide preliminary evidence for ketamine's efficacy and tolerability in an outpatient cohort.
Trials
May 21, 2024
Chiranth Bhagavan, Paul Glue, Will Evans et al.
7 citations
A clinical trial will test whether MDMA-assisted therapy can reduce anxiety and depression in people with advanced-stage cancer. Up to 32 participants will be randomly assigned to receive either 120 mg of MDMA (with an optional 60 mg supplement) or a low dose of methylphenidate as a psychoactive control, each combined with therapeutic support sessions. The study will track mood, anxiety, quality of life, and other measures for up to 12 months. This research aims to establish the safety and effectiveness of a novel treatment for mental suffering in patients with life-threatening illness.
BJPsych Open
October 1, 2025
Ben Beaglehole, Paul Glue, Shona Neehoff et al.
5 citations
Intramuscular ketamine shows preliminary effectiveness and is well tolerated by people with posttraumatic stress disorder in a community setting. The findings are encouraging given the known limitations of existing treatments, but more research is needed to determine the best dosing schedule and long-term role of ketamine for PTSD.
BMJ open
May 1, 2024
Ben Beaglehole, Richard Porter, Katie Douglas et al.
5 citations
A randomized controlled trial will test the feasibility of adding behavioral activation therapy (BAT) to oral ketamine for treatment-resistant major depressive disorder. The study aims to recruit 60 adults aged 18–65 years, randomizing them to eight weeks of oral ketamine with BAT or oral ketamine alone. Feasibility will be measured by attendance, acceptability, and retention. The primary efficacy outcome is the Montgomery-Asberg Depression Rating Scale, assessed weekly during treatment and fortnightly during 12 weeks of follow-up. For a definitive trial to be recommended, the study must meet recruitment targets and show a greater than 20% reduction in relapse rates favoring the combined treatment arm.
The British journal of psychiatry : the journal of mental science
January 7, 2025
Natalie T Mills, Stevan Nikolin, Nick Glozier et al.
3 citations
Anxiety disorders and treatment-resistant major depressive disorder (TRD) often occur together. In a randomized controlled trial comparing subcutaneous ketamine to midazolam in 174 people with TRD, ketamine reduced anxiety only when given at flexible, response-guided doses (0.5-0.9 mg/kg). At a fixed low dose (0.5 mg/kg), the reduction in anxiety was not statistically significant. The anxiety-reducing effect was linked to overall depression improvement and was not sustained four weeks after treatment ended. The findings suggest that adequate dosing is necessary for ketamine's anxiolytic effect in this population.
Journal of affective disorders
October 15, 2025
Mary Lou Chatterton, Johana Kevin Perez, Thao Thai et al.
2 citations
Subcutaneous ketamine appears cost-effective for treatment-resistant depression from a health sector perspective when the costs of the control treatment (midazolam) are included, but not from a societal perspective. A cost-utility analysis alongside a randomized controlled trial with 174 participants compared ketamine to midazolam given twice weekly for four weeks. At the end of the trial, quality of life scores were significantly higher for ketamine. When control arm costs were included, ketamine was less costly and more effective, with an 89% probability of being cost-effective at a $50,000 per quality-adjusted life year threshold. Excluding those costs made ketamine not cost-effective, highlighting the importance of comparator choice.
The British Journal of Psychiatry
July 6, 2026
Nick Glozier, Richard W. Morris, Elizabeth Stratton et al.
A 4-week course of subcutaneous racemic ketamine produced short-term clinical benefit in a minority of people with treatment-resistant depression, with response rates declining substantially after treatment cessation. Among 130 participants, 30% responded at treatment end (Montgomery-Åsberg Depression Rating Scale reduction ≥50%), but only 17% remained responders 4 weeks later, and over 50% experienced less than a 25% reduction in depression scores. No difference in response was found between fixed and flexible dosing regimens. Prior ketamine treatment during an earlier randomized trial did not affect later outcomes. No suicides or suicidal behavior requiring admission occurred, and only expected side effects were observed.
The International Journal of Neuropsychopharmacology
July 6, 2026
Shabah M. Shadli, Neda Nasrollahi, Calvin K. Young et al.
Ketamine at low doses (0.5-1.0 mg/kg I.M.) quickly reduces symptoms in treatment-resistant major depressive disorder (TR-MDD), post-traumatic stress disorder (TR-PTSD), and obsessive-compulsive disorder (TR-OCD), but its neural effects differ by diagnosis. EEG recordings of resting frontal activity before and after ketamine or fentanyl showed that TR-PTSD patients had dose- and band-frequency-dependent power changes (especially alpha at 0.5 mg/kg), while TR-MDD patients showed no such changes. TR-OCD responses differed qualitatively from both. Correlations between EEG power changes and symptom scale improvements varied by band and electrode across different disorder-specific scales. Ketamine's effects and their therapeutic links vary by brain site and frequency band depending on the DSM diagnosis, suggesting disorder-specific systems require a ketamine-sensitive factor to generate the disorder.
Archives of suicide research : official journal of the International Academy for Suicide Research
May 9, 2026
Gregory Carter, Maree Hackett, Stevan Nikolin et al.
Ketamine's effect on suicidal ideation in adults with treatment-resistant depression remains uncertain. In a phase III double-blind randomized trial comparing subcutaneous racemic ketamine to midazolam over four weeks, one cohort showed no significant difference between groups on either the MADRS item 10 or the C-SSRS measure of suicidal ideation. A second cohort showed a non-significant reduction on the MADRS item 10 but a significant reduction on the C-SSRS. Baseline suicidal ideation scores were low in both cohorts. Adverse events requiring clinical review occurred in 13.8% of all treatment sessions. The authors suggest flexible-dose subcutaneous racemic ketamine may have beneficial effects on suicidal ideation scores, but future studies need to be powered for suicidal ideation as a primary outcome.
Wilderness & environmental medicine
March 18, 2026
Elizabeth E Davidson, Sean L Davidson, Paul Glue
Anomalous perceptual experiences (APEs)—such as visual, auditory, somatic, and sensed presence phenomena—occur in ultra-endurance athletes without psychiatric illness. A systematic review of 14 studies (case reports, case series, field studies, and cross-sectional surveys) found APEs across mountaineering, ultramarathon running, solo sailing, marathon volleyball, and dogsled racing. Sleep deprivation was the most consistent contributing factor, followed by exhaustion and low-light conditions. Symptoms typically emerged after 24 hours of exertion, especially in darkness. Interpretations ranged from distressing to neutral or supportive, and no long-term psychiatric sequelae were reported. APEs appear to be transient, nonpathologic phenomena triggered by extreme stress, with implications for athlete safety and event planning.
Journal of the Royal Society of New Zealand
February 1, 2026
Neil McNaughton, Shabah M Shadli, B Beaglehole et al.
Neurotic disorders such as depression, anxiety, and PTSD are diagnosed by symptoms rather than biological causes, making them costly and difficult to treat. Researchers in New Zealand have developed an EEG biomarker for anxiety disorders that can detect resistance to conventional treatments, with similar work underway for depression. Ketamine has been identified as a novel treatment for treatment-resistant neurotic disorders, supported by a proposed "double hit" hypothesis of its mechanisms. Similar results have been obtained with ketamine, LSD, and psilocybin, and treatment-related EEG changes have been demonstrated. These developments, potentially combined with psychotherapy, may lead to faster, broader, and more effective treatments, especially with the recent development of oral tablet delivery for home dosing.