Publications
1392 results found
Thurgur H, Lynskey M, Schlag AK, et al., 2024, Feasibility of a cannabidiol-dominant cannabis-based medicinal product for the treatment of long COVID symptoms: A single-arm open-label feasibility trial., Br J Clin Pharmacol, Vol: 90, Pages: 1081-1093
AIMS: To conduct a single-arm open-label feasibility trial of the safety and tolerability of a full-spectrum cannabidiol (CBD)-dominant cannabis-based medicinal product for treating the symptoms of long COVID. METHODS: The treatment phase ran for a total of 21 weeks, followed by ~3 weeks without the study drug. Participants received up to 3 mL of MediCabilis 5% CBD Oil (50 mg CBD/mL, <2 mg δ-9-tetrahydrocannabinol/mL) per day orally. Monthly patient-reported outcome measures of common symptoms and daily self-report of symptoms were collected via a smartphone app. Key measures of heart rate, activity, sleep and oxygen saturation were assessed using wearable technology. RESULTS: Twelve (1 male, 11 female) individuals diagnosed with long COVID were recruited into the trial. All participants adhered to the treatment protocol for the duration of the study and there were no serious adverse events. Response rates for the research assessments were high with over 90% completion of patient-reported outcome measures and daily self-report. CONCLUSION: The study drug was safe and well-tolerated, demonstrating feasibility of CBD-dominant cannabis-based medicinal products in individuals diagnosed with long COVID. However, there were limitations in research design related to recruitment strategy demonstrating a lack of feasibility in the approach implemented in this study. Future work with larger samples and incorporating a control group are required to test the efficacy of this treatment.
Lynskey MT, Athanasiou-Fragkouli A, Thurgur H, et al., 2024, Medicinal cannabis for treating post-traumatic stress disorder and comorbid depression: real-world evidence., BJPsych Open, Vol: 10, ISSN: 2056-4724
BACKGROUND: Cannabis-based medicinal products (CBMPs) are increasingly being used to treat post-traumatic stress disorder (PTSD), despite limited evidence of their efficacy. PTSD is often comorbid with major depression, and little is known about whether comorbid depression alters the effectiveness of CBMPs. AIMS: To document the prevalence of depression among individuals seeking CBMPs to treat PTSD and to examine whether the effectiveness of CBMPs varies by depression status. METHOD: Data were available for 238 people with PTSD seeking CBMP treatment (5.9% of the treatment-seeking sample) and 3-month follow-up data were available for 116 of these. Self-reported PTSD symptoms were assessed at treatment entry and at 3-month follow-up using the PTSD Checklist - Civilian Version (PCL-C). The probable presence of comorbid depression at treatment entry was assessed using the nine-item Patient Health Questionnaire (PHQ-9). Additional data included sociodemographic characteristics and self-reported quality of life. RESULTS: In total, 77% met screening criteria for depression, which was associated with higher levels of PTSD symptomatology (mean 67.8 v. 48.4, F(1,236) = 118.5, P < 0.001) and poorer general health, quality of life and sleep. PTSD symptomatology reduced substantially 3 months after commencing treatment (mean 58.0 v. 47.0, F(1,112) = 14.5, P < 0.001), with a significant interaction (F(1,112) = 6.2, P < 0.05) indicating greater improvement in those with depression (mean difference 15.3) than in those without (mean difference 7). CONCLUSIONS: Depression is common among individuals seeking CBMPs to treat PTSD and is associated with greater symptom severity and poorer quality of life. Effectiveness of CBMPs for treating PTSD does not appear to be impaired in people with comorbid depression.
Nutt DJ, Peill JM, Weiss B, et al., 2023, Psilocybin and Other Classic Psychedelics in Depression., Curr Top Behav Neurosci, ISSN: 1866-3370
Psychedelic drugs such as psilocybin and ketamine are returning to clinical research and intervention across several disorders including the treatment of depression. This chapter focusses on psychedelics that specifically target the 5-HT2A receptor such as psilocybin and DMT. These produce plasma-concentration related psychological effects such as hallucinations and out of body experiences, insightful and emotional breakthroughs as well as mystical-type experiences. When coupled with psychological support, effects can produce a rapid improvement in mood among people with depression that can last for months. In this chapter, we summarise the scientific studies to date that explore the use of psychedelics in depressed individuals, highlighting key clinical, psychological and neuroimaging features of psychedelics that may account for their therapeutic effects. These include alterations in brain entropy that disrupt fixed negative ruminations, a period of post-treatment increased cognitive flexibility, and changes in self-referential psychological processes. Finally, we propose that the brain mechanisms underlying the therapeutic effect of serotonergic psychedelics might be distinct from those underlying classical serotonin reuptake-blocking antidepressants.
Nutt DJ, 2023, Pharmacological Dissection of Antipsychotics, BIOLOGICAL PSYCHIATRY, Vol: 94, Pages: 524-525, ISSN: 0006-3223
Wall MB, Harding R, Zafar R, et al., 2023, Neuroimaging in psychedelic drug development: past, present, and future, MOLECULAR PSYCHIATRY, ISSN: 1359-4184
Simonsson O, Carlbring P, Carhart-Harris R, et al., 2023, Assessing the risk of symptom worsening in psilocybin-assisted therapy for depression: A systematic review and individual participant data meta-analysis, PSYCHIATRY RESEARCH, Vol: 327, ISSN: 0165-1781
Thurgur H, Schlag AK, Iveson E, et al., 2023, Cannabis-based medicinal products (CBMPs) for the treatment of Long COVID symptoms: current and potential applications, Exploration of Medicine, Pages: 487-503
<jats:p>Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection can result in a range of persistent symptoms impacting everyday functioning for a considerable proportion of patients, a condition termed Long coronavirus disease (COVID) or post COVID-19 syndrome. The severity and set of symptoms vary between patients, and include fatigue, cognitive dysfunction, sleep disturbances, palpitations, tachycardia, pain, depression, and anxiety. The high prevalence of Long COVID combined with the lack of treatment approaches has resulted in considerable unmet clinical needs. There is a growing body of evidence that cannabis-based medicinal products (CBMPs) can be used to treat symptoms including pain, anxiety, depression, fatigue, sleep, headaches, and cognitive dysfunction, which are commonly reported in Long COVID. This article provides an overview of the pathophysiology of Long COVID and discusses preliminary pre-clinical, clinical trials, and real-world evidence (RWE) for CBMPs in the context of Long COVID. This review summarises current clinical trials and studies exploring CBMPs in Long COVID. The current evidence provides a rationale to further explore CBMPs as a treatment for Long COVID symptoms. In addition to further randomised controlled trials (RCTs), the increasing availability of CBMPs globally, coupled with the continued prevalence of Long COVID in the population, also highlights the value of real-world data in the research of CBMPs in Long COVID. Critically, there is an evident need for multidisciplinary approaches of CBMPs and Long COVID in real-world clinical practice settings.</jats:p>
Szigeti B, Nutt D, Carhart-Harris R, et al., 2023, The difference between 'placebo group' and 'placebo control': a case study in psychedelic microdosing, Scientific Reports, Vol: 13, Pages: 1-10, ISSN: 2045-2322
In medical trials, ‘blinding’ ensures the equal distribution of expectancy effects between treatment arms in theory; however, blinding often fails in practice. We use computational modelling to show how weak blinding, combined with positive treatment expectancy, can lead to an uneven distribution of expectancy effects. We call this ‘activated expectancy bias’ (AEB) and show that AEB can inflate estimates of treatment effects and create false positive findings. To counteract AEB, we introduce the Correct Guess Rate Curve (CGRC), a statistical tool that can estimate the outcome of a perfectly blinded trial based on data from an imperfectly blinded trial. To demonstrate the impact of AEB and the utility of the CGRC on empirical data, we re-analyzed the ‘self-blinding psychedelic microdose trial’ dataset. Results suggest that observed placebo-microdose differences are susceptible to AEB and are at risk of being false positive findings, hence, we argue that microdosing can be understood as active placebo. These results highlight the important difference between ‘trials with a placebo-control group’, i.e., when a placebo control group is formally present, and ‘placebo-controlled trials’, where patients are genuinely blind. We also present a new blinding integrity assessment tool that is compatible with CGRC and recommend its adoption.
Szigeti B, Phillips LDD, Nutt D, 2023, Bayesian analysis of real-world data as evidence for drug approval: Remembering Sir Michael Rawlins, BRITISH JOURNAL OF CLINICAL PHARMACOLOGY, ISSN: 0306-5251
Jauhar S, Arnone D, Baldwin DS, et al., 2023, A leaky umbrella has little value: evidence clearly indicates the serotonin system is implicated in depression, MOLECULAR PSYCHIATRY, ISSN: 1359-4184
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- Citations: 1
Parker CAA, Nutt DJJ, Tyacke RJJ, 2023, Imidazoline-I2 PET Tracers in Neuroimaging, INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES, Vol: 24, ISSN: 1661-6596
Gattuso JJ, Perkins D, Ruffell S, et al., 2023, Default Mode Network Modulation by Psychedelics: A Systematic Review, INTERNATIONAL JOURNAL OF NEUROPSYCHOPHARMACOLOGY, Vol: 26, Pages: 155-188, ISSN: 1461-1457
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- Citations: 7
Timmermann Slater CB, Roseman L, Haridas S, et al., 2023, Human brain effects of DMT assessed via EEG-fMRI, Proceedings of the National Academy of Sciences of USA, Vol: 120, Pages: 1-12, ISSN: 0027-8424
Psychedelics have attracted medical interest, but their effects on human brain function are incompletely understood. In a comprehensive, within-subjects, placebo-controlled design, we acquired multimodal neuroimaging [i.e., EEG-fMRI (electroencephalography-functional MRI)] data to assess the effects of intravenous (IV) N,N-Dimethyltryptamine (DMT) on brain function in 20 healthy volunteers. Simultaneous EEG-fMRI was acquired prior to, during, and after a bolus IV administration of 20 mg DMT, and, separately, placebo. At dosages consistent with the present study, DMT, a serotonin 2A receptor (5-HT2AR) agonist, induces a deeply immersive and radically altered state of consciousness. DMT is thus a useful research tool for probing the neural correlates of conscious experience. Here, fMRI results revealed robust increases in global functional connectivity (GFC), network disintegration and desegregation, and a compression of the principal cortical gradient under DMT. GFC × subjective intensity maps correlated with independent positron emission tomography (PET)-derived 5-HT2AR maps, and both overlapped with meta-analytical data implying human-specific psychological functions. Changes in major EEG-measured neurophysiological properties correlated with specific changes in various fMRI metrics, enriching our understanding of the neural basis of DMT’s effects. The present findings advance on previous work by confirming a predominant action of DMT—and likely other 5-HT2AR agonist psychedelics—on the brain’s transmodal association pole, i.e., the neurodevelopmentally and evolutionarily recent cortex that is associated with species-specific psychological advancements, and high expression of 5-HT2A receptors.
Vamvakopoulou IA, Narine KAD, Campbell I, et al., 2023, Mescaline: The forgotten psychedelic*, NEUROPHARMACOLOGY, Vol: 222, ISSN: 0028-3908
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- Citations: 6
Shukuroglou M, Roseman L, Wall M, et al., 2023, Changes in music-evoked emotion and ventral striatal functional connectivity after psilocybin therapy for depression, JOURNAL OF PSYCHOPHARMACOLOGY, Vol: 37, Pages: 70-79, ISSN: 0269-8811
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- Citations: 2
Bourke SL, Schlag AK, O'Sullivan SE, et al., 2022, Cannabinoids and the endocannabinoid system in fibromyalgia: A review of preclinical and clinical research, PHARMACOLOGY & THERAPEUTICS, Vol: 240, ISSN: 0163-7258
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- Citations: 4
Watts R, Kettner H, Geerts D, et al., 2022, The Watts Connectedness Scale: a new scale for measuring a sense of connectedness to self, others, and world, PSYCHOPHARMACOLOGY, Vol: 239, Pages: 3461-3483, ISSN: 0033-3158
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- Citations: 14
Vamvakopoulou IA, Fonville L, Hayes A, et al., 2022, Selective D3 receptor antagonism modulates neural response during negative emotional processing in substance dependence, Frontiers in Psychiatry, Vol: 13, Pages: 1-20, ISSN: 1664-0640
Introduction: Negative affective states contribute to the chronic-relapsingnature of addiction. Mesolimbic dopamine D3 receptors are well placed to modulate emotion and are dysregulated in substance dependence. Selective antagonists might restore dopaminergic hypofunction, thus representing a potential treatment target. We investigated the effects of selective D3 antagonist, GSK598809, on the neural response to negativeemotional processing in substance dependent individuals and healthy controls.Methodology: Functional MRI BOLD response was assessed during an evocative image task, 2h following acute administration of GSK598809 (60mg) or placebo in a multi-site, double-blind, pseudo-randomised, cross-over design. Abstinent drug dependent individuals (DD, n=36) comprising alcohol-only (AO, n=19) and cocaine-alcohol polydrug (PD, n=17) groups, and matched controls (n=32) were presented with aversive and neutral images in a block design (contrast of interest: aversive>neutral). Whole-brain mixed-effects and a priori ROI analyses tested for group and drug effects, with identical models exploring subgroup effects.Results: No group differences in task-related BOLD signal were identified between DD and controls. However, subgroup analysis revealed greater amygdala/insular BOLD signal in PD compared with AO groups. Following drug administration, GSK598809 increased BOLD response across HC and DD groups in thalamus, caudate, putamen, and pallidum, andreduced BOLD response in insular and opercular cortices relative to placebo. Multivariate analyses in a priori ROIs revealed differential effects of D3 antagonism according to subgroup in substantia nigra; GSK598809 increased BOLD response in AO and decreased response in PD groups.Conclusion: Acute GSK598809 modulates the BOLD response to aversive image processing, providing evidence that D3 antagonism may impact emotional regulation. Enhanced BOLD response within D3-rich mesolimbic regions is consistent with its pharmacology a
Singleton SP, Luppi AI, Carhart-Harris RL, et al., 2022, Receptor-informed network control theory links LSD and psilocybin to a flattening of the brain's control energy landscape, NATURE COMMUNICATIONS, Vol: 13
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- Citations: 12
Vohryzek J, Cabral J, Lord L-D, et al., 2022, Brain dynamics predictive of response to psilocybin for treatment-resistant depression
<jats:title>Abstract</jats:title> <jats:p>Psilocybin therapy for depression has started to show promise, yet the underlying causal mechanisms are not currently known. Here we leveraged the differential outcome in responders and non-responders to psilocybin (10mg and 25mg, 7 days apart) therapy for depression - to gain new insights into regions and networks implicated in the restoration of healthy brain dynamics. We used whole-brain modelling to fit the spatiotemporal brain dynamics at rest in both responders and non-responders before treatment. Dynamic sensitivity analysis of systematic perturbation of these models enabled us to identify specific brain regions implicated in a transition from a depressive brain state to a heathy one. Binarizing the sample into treatment responders (> 50% reduction in depressive symptoms) versus non-responders enabled us to identify a subset of regions implicated in this change. Interestingly, these regions correlate with in vivo density maps of serotonin receptors 5-HT<jats:sub>2A</jats:sub> and 5-HT<jats:sub>1A</jats:sub>, which psilocin, the active metabolite of psilocybin, has an appreciable affinity for, and where it acts as a full-to-partial agonist. Serotonergic transmission has long been associated with depression and our findings provide causal mechanistic evidence for the role of brain regions in the recovery from depression via psilocybin.</jats:p>
Nutt DJ, Tyacke RJ, Spriggs M, et al., 2022, Functional Alternatives to Alcohol, NUTRIENTS, Vol: 14
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- Citations: 2
Zhou C, Nutt DJ, Davies SJC, 2022, Visualizing classification of drugs used in psychotic disorders: A 'subway map' representing mechanisms, established classes and informal categories, JOURNAL OF PSYCHOPHARMACOLOGY, Vol: 36, Pages: 1007-1015, ISSN: 0269-8811
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- Citations: 6
Agunbiade K, Fonville L, McGonigle J, et al., 2022, Alterations in white matter microstructure in alcohol and alcohol-polydrug dependence: Associations with lifetime alcohol and nicotine exposure, ADDICTION BIOLOGY, Vol: 27, ISSN: 1355-6215
Mohamed MA, Zeng Z, Gennaro M, et al., 2022, Astrogliosis in aging and Parkinson’s disease dementia: a new clinical study with 11C-BU99008 PET, Brain Communications, Vol: 4, ISSN: 2632-1297
The role of astrogliosis in the pathology of brain aging and neurodegenerative diseases has recently drawn great attention. Imidazoline-2 binding sites (I2BS) represent a possible target to map the distribution of reactive astrocytes. In this study, we use 11C-BU99008, an I2BS-specific PET radioligand, to image reactive astrocytes in vivo in healthy controls (HCs) andpatients with established Parkinson’s disease dementia (PDD).Eighteen HCs (age: 45−78 years) and six patients with PDD (age: 64−77 years) had one 11C-BU99008 PET-CT scan with arterial input function. All subjects underwent one 3T MRI brain scan to facilitate the analysis of the PET-CT data and to capture individual cerebral atrophy. Regional 11C-BU99008 volumes of distribution (VT) were calculated for each subject by two-tissue compartmental modelling.Positive correlations between 11C-BU99008 VT values and age were found for all tested regions across the brain within HCs (p<0.05); furthermore, multiple regression indicated that aging affects 11C-BU99008 VT values in a region-specific manner. Independent samples t-test indicated that there was no significant group difference in 11C-BU99008 VT values betweenPDD (n=6; mean age = 71.97±4.66 years) and older HCs (n=9; mean age = 71.90±5.51 years).Our dataset shows that astrogliosis is common with aging in a region-specific manner. However, in this set-up, 11C-BU99008 PET cannot differentiate patients with PDD from healthy controls of similar age.
Nutt DJ, Phillips LD, Barnes MP, et al., 2022, A Multicriteria Decision Analysis Comparing Pharmacotherapy for Chronic Neuropathic Pain, Including Cannabinoids and Cannabis-Based Medical Products, CANNABIS AND CANNABINOID RESEARCH, Vol: 7, Pages: 482-500, ISSN: 2578-5125
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- Citations: 15
Van den Eynde V, Abdelmoemin WR, Abraham MM, et al., 2022, The prescriber's guide to classic MAO inhibitors (phenelzine, tranylcypromine, isocarboxazid) for treatment-resistant depression, CNS SPECTRUMS, ISSN: 1092-8529
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- Citations: 10
Wall MB, Freeman TP, Hindocha C, et al., 2022, Individual and combined effects of cannabidiol and Δ<SUP>9</SUP>-tetrahydrocannabinol on striato-cortical connectivity in the human brain, JOURNAL OF PSYCHOPHARMACOLOGY, Vol: 36, Pages: 732-744, ISSN: 0269-8811
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- Citations: 7
Hayes A, McGonigle J, Elliott R, et al., 2022, The Relationship Between Reward and Impulsivity in Substance Dependence: An fMRI Study, Publisher: ELSEVIER SCIENCE INC, Pages: S103-S103, ISSN: 0006-3223
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- Citations: 1
Sakal C, Lynskey M, Schlag AK, et al., 2022, Developing a real-world evidence base for prescribed cannabis in the United Kingdom: preliminary findings from Project Twenty21, PSYCHOPHARMACOLOGY, Vol: 239, Pages: 1147-1155, ISSN: 0033-3158
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- Citations: 14
Daws R, Timmermann C, Giribaldi B, et al., 2022, Increased global integration in the brain after psilocybin therapy for depression, Nature Medicine, Vol: 28, ISSN: 1078-8956
Psilocybin therapy shows antidepressant potential, but its therapeutic actions are not well understood. We assessed the sub-acute impact of psilocybin on brain function in two clinical trials of depression. The first was an open-label trial of orally administered psilocybin (10mg and 25mg, 7 days apart) in treatment-resistant depression (TRD). fMRI was recorded at baseline and one day after the 25mg dose. Beck’s depression inventory (BDI) was the primary outcome measure (MR/J00460X/1). The second trial was a double-blind phase 2 randomised control trial (DB-RCT) comparing psilocybin therapy with escitalopram. Major depressive disorder (MDD) patients received either: 2 x 25mg oral psilocybin, 3 weeks apart, plus 6 weeks of daily placebo (‘psilocybin-arm’); or 2 x 1mg oral psilocybin, 3 weeks apart, plus 6 weeks of daily escitalopram [10-20mg] (‘escitalopram-arm’). fMRI wasrecorded at baseline and 3 weeks after the 2nd psilocybin dose (NCT03429075). In both trials, the antidepressant response to psilocybin was rapid, sustained and correlated with decreases in functional MRI (fMRI) brain network modularity, implying that psilocybin’s antidepressant action may depend on a global increase in brainnetwork integration. Network cartography analyses indicated that 5-HT2A receptor rich higher-order functional networks became more functionally inter-connected and flexible post psilocybin. The antidepressant response to escitalopram was milder and no changes in brain network organisation were observed. Consistent efficacy related brain changes, correlating with robust antidepressant effects across two studies, suggest an antidepressant mechanism for psilocybin therapy: Global increases in brain network integration.
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