Imperial College London

Professor David Nutt DM, FRCP, FRCPsych, FSB, FMedSci

Faculty of MedicineDepartment of Medicine

The Edmond J Safra Chair in Neuropsychopharmacology
 
 
 
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d.nutt

 
 
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Burlington Danes BuildingBurlington DanesHammersmith Campus

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Summary

 

Publications

Publication Type
Year
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1269 results found

Wall MB, Pope R, Freeman TP, Kowalczyk OS, Demetriou L, Mokrysz C, Hindocha C, Lawn W, Bloomfield MA, Freeman AM, Feilding A, Nutt D, Curran HVet al., 2019, Dissociable effects of cannabis with and without cannabidiol on the human brain's resting-state functional connectivity., J Psychopharmacol, Vol: 33, Pages: 822-830

BACKGROUND: Two major constituents of cannabis are Δ9-tetrahydrocannabinol (THC) and cannabidiol (CBD). THC is the main psychoactive component; CBD may buffer the user against the harmful effects of THC. AIMS: We examined the effects of two strains of cannabis and placebo on the human brain's resting-state networks using fMRI. METHODS: Seventeen healthy volunteers (experienced with cannabis, but not regular users) underwent three drug treatments and scanning sessions. Treatments were cannabis containing THC (Cann-CBD; 8 mg THC), cannabis containing THC with CBD (Cann+CBD; 8 mg THC + 10 mg CBD), and matched placebo cannabis. Seed-based resting-state functional connectivity analyses were performed on three brain networks: the default mode (DMN; defined by positive connectivity with the posterior cingulate cortex: PCC+), executive control (ECN; defined by negative connectivity with the posterior cingulate cortex: PCC-) and salience (SAL; defined by positive connectivity with the anterior insula: AI+) network. RESULTS: Reductions in functional connectivity (relative to placebo) were seen in the DMN (PCC+) and SAL (AI+) networks for both strains of cannabis, with spatially dissociable effects. Across the entire salience network (AI+), Cann-CBD reduced connectivity relative to Cann+CBD. The PCC in the DMN was specifically disrupted by Cann-CBD, and this effect correlated with subjective drug effects, including feeling 'stoned' and 'high'. CONCLUSIONS: THC disrupts the DMN, and the PCC is a key brain region involved in the subjective experience of THC intoxication. CBD restores disruption of the salience network by THC, which may explain its potential to treat disorders of salience such as psychosis and addiction.

Journal article

Maron E, Baldwin DS, Balõtšev R, Fabbri C, Gaur V, Hidalgo-Mazzei D, Hood S, Juhola M, Kampman O, Kasper S, Kärkkäinen H, Látalová K, Lähteenvuo M, Mastellos N, McTigue J, Metsallik J, Metspalu A, Nutt D, Nykänen P, Olisa N, Pogarell O, Popovic D, Antoni Ramos-Quiroga J, Ross P, Serretti A, Spies M, Thibaut F, Tiainen K, Tiihonen J, Vieta E, Võhma Ü, Van Westrhenen R, Zubanovic B, Eberhard Jet al., 2019, Manifesto for an international digital mental health network, Digital Psychiatry, Vol: 2, Pages: 14-24, ISSN: 2575-517X

Current mental health services across the world remain expert-centric and are based on traditional workflows, mostly using impractical and ineffective electronic record systems or even paper-based documentation. The international network for digital mental health (IDMHN) is comprised of top-level clinicians, regulatory and ICT experts, genetic scientists, and support organizations. The IDMHN has been formed to enable the implementation of digital innovations in clinical practice, hereby facilitating the transformation of current mental health services to be more personalized and more responsive to patients and healthcare needs. This consensus statement summarizes the consortium’s vision and strategy for further development of digital mental health.

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Palmer E, Tyacke R, Sastre M, Lingford-Hughes A, Nutt D, Ward RJet al., 2019, Alcohol hangover: underlying biochemical, inflammatory and neurochemical mechanisms, Alcohol and Alcoholism, ISSN: 0735-0414

AIM: To review current alcohol hangover research in animals and humans and evaluate key evidence for contributing biological factors. METHOD: Narrative review with alcohol hangover defined as the state the day after a single episode of heavy drinking, when the alcohol concentration in the blood approaches zero. RESULTS: Many of the human studies of hangover are not well controlled, with subjects consuming different concentrations of alcohol over variable time periods and evaluation not blinded. Also, studies have measured different symptoms and use varying methods of measurement. Animal studies show variations with respect to the route of administration (intragastric or intraperitoneal), the behavioural tests utilised and discrepancy in the timepoint used for hangover onset. Human studies have the advantage over animal models of being able to assess subjective hangover severity and its correlation with specific behaviours and/or biochemical markers. However, animal models provide valuable insight into the neural mechanisms of hangover. Despite such limitations, several hangover models have identified pathological changes which correlate with the hangover state. We review studies examining the contribution of alcohol's metabolites, neurotransmitter changes with particular reference to glutamate, neuroinflammation and ingested congeners to hangover severity. CONCLUSION: Alcohol metabolites, neurotransmitter alterations, inflammatory factors and mitochondrial dysfunction are the most likely factors in hangover pathology. Future research should aim to investigate the relationship between these factors and their causal role.

Journal article

Sessa B, Higbed L, Nutt D, 2019, A Review of 3,4-methylenedioxymethamphetamine (MDMA)-Assisted Psychotherapy, FRONTIERS IN PSYCHIATRY, Vol: 10, ISSN: 1664-0640

Journal article

Nutt DJ, Gual A, Anderson P, Rehm Jet al., 2019, Why Less Is Always More in the Treatment of Alcohol Use Disorders., JAMA Psychiatry

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Goodwin GM, Nutt D, 2019, Antidepressants; what's the beef?, ACTA NEUROPSYCHIATRICA, Vol: 31, Pages: 59-60, ISSN: 1601-5215

Journal article

Lingford-Hughes A, Durant C, Paterson L, Turton S, Venkataraman A, Wilson S, Myers J, Muthukumaraswamy S, Mick I, Paterson S, Jones T, Nahar L, Cordero R, Nutt Det al., 2018, Using baclofen to explore GABA-B receptor function in alcohol dependence: insights from pharmacokinetic and pharmacodynamic measures, Frontiers in Psychiatry, Vol: 9, ISSN: 1664-0640

Background: The role of GABA-B neurotransmission in addiction has recently received increased attention, with clinical trials indicating that baclofen, a GABA-B receptor agonist, may reduce alcohol consumption, craving and promote abstinence. However, the optimal dose to treat alcohol dependence is unclear with patients requesting and tolerating much higher doses of baclofen, compared with other clinical uses. We assessed the pharmacokinetics and pharmacodynamics (PK/PD) of baclofen to provide insight into GABA-B sensitivity in this patient group, relative to controls.Methods: Male healthy volunteers (controls, n = 12) and abstinent alcohol dependent individuals (AD, n = 8) received single oral doses of baclofen or placebo in a 3-way crossover design. Controls received placebo/10 mg/60 mg baclofen in a randomized, double-blind design, AD received placebo/60 mg/90 mg baclofen in a single-blind design. PK/PD measures were recorded at baseline and multiple time-points up to 6 h post-dosing, including plasma baclofen, plasma growth hormone (GH), Subjective High Assessment Scale (SHAS) and biphasic alcohol effects scale (BAES). Repeated measures ANOVA analysis explored “change from baseline” dose, time, group, and interaction effects, t-tests compared peak effects.Results: Dose-dependent effects of baclofen on PK and PD measures were observed in both control and AD groups. Whilst there were no significant group differences in any baclofen PK parameters (t1/2, tmax, Cmax, AUC), marked differences in PD effects were clearly evident. In controls, 60 mg baclofen significantly increased total SHAS and BAES scores, and significantly increased plasma GH levels compared with placebo, with peak effects at 60–120 min, in line with its PK profile. In AD, 60 mg baclofen had limited effects on these parameters; SHAS scores, BAES scores and plasma GH levels were significantly blunted compared with controls (significant group*time interactions P = 0.0014, 0.0015 and P

Journal article

Nestor LJ, Paterson LM, Murphy A, McGonigle J, Orban C, Reed L, Taylor E, Flechais R, Smith D, Bullmore ET, Ersche KD, Suckling J, Elliott R, Deakin B, Rabiner I, Lingford Hughes A, Sahakian BJ, Robbins TW, Nutt DJet al., 2018, Naltrexone differentially modulates the neural correlates of motor impulse control in abstinent alcohol-dependent and poly-substance dependent individuals, European Journal of Neuroscience, ISSN: 0953-816X

Identifying key neural substrates in addiction disorders for targeted drug development remains a major challenge for clinical neuroscience. One emerging target is the opioid system, where substance‐dependent populations demonstrate prefrontal opioid dysregulation that predicts impulsivity and relapse. This may suggest that disturbances to the prefrontal opioid system could confer a risk for relapse in addiction due to weakened “top‐down” control over impulsive behaviour. Naltrexone is currently licensed for alcohol dependence and is also used clinically for impulse control disorders. Using a go/no‐go (GNG) task we examined the effects of acute naltrexone on the neural correlates of successful motor impulse control in abstinent alcoholics (AUD), abstinent poly substance‐dependent (poly‐SUD) individuals, and controls during a randomized double blind placebo controlled fMRI study. In the absence of any differences on GNG task performance, the AUD group showed a significantly greater BOLD response compared to the control group in lateral and medial prefrontal regions during both placebo and naltrexone treatments; effects that were positively correlated with alcohol abstinence. There was also a dissociation in the positive modulating effects of naltrexone in the orbitofrontal cortex (OFC) and anterior insula cortex (AIC) of the AUD and poly‐SUD groups respectively. Self‐reported trait impulsivity in the poly‐SUD group also predicted the effect of naltrexone in the AIC. These results suggest that acute naltrexone differentially amplifies neural responses within two distinct regions of a salience network during successful motor impulse control in abstinent AUD and poly‐SUD groups, which are predicted by trait impulsivity in the poly‐SUD group.

Journal article

Haijen ECHM, Kaelen M, Roseman L, Timmermann C, Russ S, Nutt D, Daws R, Hampshire A, Lorenz R, Carhart-Harris Ret al., 2018, Predicting responses to psychedelics: a prospective study, Frontiers in Pharmacology, Vol: 9, ISSN: 1663-9812

Responses to psychedelics are notoriously difficult to predict, yet significant work is currently underway to assess their therapeutic potential and the level of interest in psychedelics among the general public appears to be increasing. We aimed to collect prospective data in order to improve our ability to predict acute- and longer-term responses to psychedelics. Individuals who planned to take a psychedelic through their own initiative participated in an online survey (www.psychedelicsurvey.com). Traits and variables relating to set, setting and the acute psychedelic experience were measured at five different time points before and after the experience. Principle component and regression methods were used to analyse the data. Sample sizes for the five time points included N= 654, N= 535, N= 379, N= 315, and N= 212 respectively. Psychological well-being was increased two weeks after a psychedelic experience and remained at this level after four weeks. This increase was larger for individuals who scored higher for a ‘mystical-type experience’, and smaller for those who scored higher for ‘challenging experience’. Having ‘clear intentions’ for the experience was conducive to mystical-type experiences. Having a positive ‘set’, as well as having the experience with intentions related to ‘recreation’, were both found to decrease the likelihood of having a challenging experience. The trait ‘absorption’ and higher drug doses promoted both mystical-type and challenging experiences. When comparing different types of variables, traits variables seemed to explain most variance in the change in well-being after a psychedelic experience. These results confirm the importance of extra-pharmacological factors in determining responses to a psychedelic. We view this study as an early step towards the development of empirical guidelines that can evolve and improve iteratively with the ultimate purpose of guiding

Journal article

Rucker JJH, Iliff J, Nutt DJ, 2018, Psychiatry & the psychedelic drugs. Past, present & future, Neuropharmacology, Vol: 142, Pages: 200-218, ISSN: 0028-3908

The classical psychedelic drugs, including psilocybin, lysergic acid diethylamide and mescaline, were used extensively in psychiatry before they were placed in Schedule I of the UN Convention on Drugs in 1967. Experimentation and clinical trials undertaken prior to legal sanction suggest that they are not helpful for those with established psychotic disorders and should be avoided in those liable to develop them. However, those with so-called 'psychoneurotic' disorders sometimes benefited considerably from their tendency to 'loosen' otherwise fixed, maladaptive patterns of cognition and behaviour, particularly when given in a supportive, therapeutic setting. Pre-prohibition studies in this area were sub-optimal, although a recent systematic review in unipolar mood disorder and a meta-analysis in alcoholism have both suggested efficacy. The incidence of serious adverse events appears to be low. Since 2006, there have been several pilot trials and randomised controlled trials using psychedelics (mostly psilocybin) in various non-psychotic psychiatric disorders. These have provided encouraging results that provide initial evidence of safety and efficacy, however the regulatory and legal hurdles to licensing psychedelics as medicines are formidable. This paper summarises clinical trials using psychedelics pre and post prohibition, discusses the methodological challenges of performing good quality trials in this area and considers a strategic approach to the legal and regulatory barriers to licensing psychedelics as a treatment in mainstream psychiatry.

Journal article

Roseman L, Demetriou L, Wall M, Nutt D, Carhart-Harris RLet al., 2018, Increased amygdala responses to emotional faces after psilocybin for treatment-resistant depression, Neuropharmacology, Vol: 142, Pages: 263-269, ISSN: 0028-3908

Recent evidence indicates that psilocybin with psychological support may be effective for treating depression. Some studies have found that patients with depression show heightened amygdala responses to fearful faces and there is reliable evidence that treatment with SSRIs attenuates amygdala responses (Ma, 2015). We hypothesised that amygdala responses to emotional faces would be altered post-treatment with psilocybin. In this open-label study, 20 individuals diagnosed with moderate to severe, treatment-resistant depression, underwent two separate dosing sessions with psilocybin. Psychological support was provided before, during and after these sessions and 19 completed fMRI scans one week prior to the first session and one day after the second and last. Neutral, fearful and happy faces were presented in the scanner and analyses focused on the amygdala. Group results revealed rapid and enduring improvements in depressive symptoms post psilocybin. Increased responses to fearful and happy faces were observed in the right amygdala post-treatment, and right amygdala increases to fearful versus neutral faces were predictive of clinical improvements at 1-week. Psilocybin with psychological support was associated with increased amygdala responses to emotional stimuli, an opposite effect to previous findings with SSRIs. This suggests fundamental differences in these treatments’ therapeutic actions, with SSRIs mitigating negative emotions and psilocybin allowing patients to confront and work through them. Based on the present results, we propose that psilocybin with psychological support is a treatment approach that potentially revives emotional responsiveness in depression, enabling patients to reconnect with their emotions.

Journal article

Nutt D, Robbins T, Hayes A, 2018, THuNDRous news for human dopamine researchers: A selective dopamine D1 receptor antagonist will soon be available for clinical research, JOURNAL OF PSYCHOPHARMACOLOGY, Vol: 32, Pages: 1153-1154, ISSN: 0269-8811

Journal article

Erritzoe D, Roseman L, Nour MM, MacLean K, Kaelen M, Nutt DJ, Carhart-Harris RLet al., 2018, Effects of psilocybin therapy on personality structure, Acta Psychiatrica Scandinavica, Vol: 138, Pages: 368-378, ISSN: 1600-0447

ObjectiveTo explore whether psilocybin with psychological support modulates personality parameters in patients suffering from treatment‐resistant depression (TRD).MethodTwenty patients with moderate or severe, unipolar, TRD received oral psilocybin (10 and 25 mg, one week apart) in a supportive setting. Personality was assessed at baseline and at 3‐month follow‐up using the Revised NEO Personality Inventory (NEO‐PI‐R), the subjective psilocybin experience with Altered State of Consciousness (ASC) scale, and depressive symptoms with QIDS‐SR16.ResultsNeuroticism scores significantly decreased while Extraversion increased following psilocybin therapy. These changes were in the direction of the normative NEO‐PI‐R data and were both predicted, in an exploratory analysis, by the degree of insightfulness experienced during the psilocybin session. Openness scores also significantly increased following psilocybin, whereas Conscientiousness showed trend‐level increases, and Agreeableness did not change.ConclusionOur observation of changes in personality measures after psilocybin therapy was mostly consistent with reports of personality change in relation to conventional antidepressant treatment, although the pronounced increases in Extraversion and Openness might constitute an effect more specific to psychedelic therapy. This needs further exploration in future controlled studies, as do the brain mechanisms of postpsychedelic personality change.

Journal article

Heal DJ, Henningfield J, Frenguelli BG, Nutt DJ, Smith SLet al., 2018, Psychedelics - Re-opening the doors of perception, NEUROPHARMACOLOGY, Vol: 142, Pages: 1-6, ISSN: 0028-3908

Journal article

Horder J, Andersson M, Mendez MA, Singh N, Tangen A, Lundberg J, Gee A, Halldin C, Veronese M, Bolte S, Farde L, Sementa T, Cash D, Higgins K, Spain D, Turkheimer F, Mick I, Selvaraj S, Nutt DJ, Lingford-Hughes A, Howes OD, Murphy DG, Borg Jet al., 2018, GABA(A) receptor availability is not altered in adults with autism spectrum disorder or in mouse models, Science Translational Medicine, Vol: 10, ISSN: 1946-6234

Preliminary studies have suggested that γ-aminobutyric acid type A (GABAA) receptors, and potentially the GABAA α5 subtype, are deficient in autism spectrum disorder (ASD). However, prior studies have been confounded by the effects of medications, and these studies did not compare findings across different species. We measured both total GABAA and GABAA α5 receptor availability in two positron emission tomography imaging studies. We used the tracer [11C]flumazenil in 15 adults with ASD and in 15 control individuals without ASD and the tracer [11C]Ro15-4513 in 12 adults with ASD and in 16 control individuals without ASD. All participants were free of medications. We also performed autoradiography, using the same tracers, in three mouse models of ASD: the Cntnap2 knockout mouse, the Shank3 knockout mouse, and mice carrying a 16p11.2 deletion. We found no differences in GABAA receptor or GABAA α5 subunit availability in any brain region of adults with ASD compared to those without ASD. There were no differences in GABAA receptor or GABAA α5 subunit availability in any of the three mouse models. However, adults with ASD did display altered performance on a GABA-sensitive perceptual task. Our data suggest that GABAA receptor availability may be normal in adults with ASD, although GABA signaling may be functionally impaired.

Journal article

Tyacke R, Myers J, Venkataraman A, Mick I, Turton S, Passchier J, Husbands S, Rabiner EA, Gunn R, Murphy P, Parker C, Nutt Det al., 2018, Evaluation of 11C-BU99008, a positron emission tomography ligand for the Imidazoline2 binding site in human brain, Journal of Nuclear Medicine, Vol: 59, Pages: 1597-1602, ISSN: 1535-5667

The imidazoline2 binding sites (I2BS), are thought to be expressed in glia, and implicated in the regulation of glial fibrillary acidic protein. A positron emission tomography (PET) ligand for this target would be important for the investigation of neurodegenerative and neuroinflammatory diseases. 11C BU99008 has previously been identified as a putative PET radioligand. Here we present the first in vivo characterisation of this PET radioligand in humans and assess its test-retest reproducibility. Methods: 14 healthy male volunteers underwent dynamic PET imaging with 11C BU99008 and arterial sampling. Six subjects were used to assess test-retest and eight were used in the pharmacological evaluation, undergoing a second, or third heterologous competition scan with the mixed I2BS/α2 adrenoceptor drug, idazoxan (n=8; 20, 40, 60 and 80 mg) and the mixed irreversible monoamine oxidase (MAO) A/B inhibitor, isocarboxazid (n=4; 50 mg), respectively. Regional time-activity data were generated from arterial plasma input functions corrected for metabolites using the most appropriate model to derive the outcome measure VT (regional total distribution volume). All image processing and kinetic analysis was performed in MIAKAT™ (www.miakat.org). Results: Brain uptake of 11C BU99008 was good with reversible kinetics and a heterogeneous distribution consistent with known I2BS expression. Model selection criteria indicated that the 2-tissue-compartment was preferred. VT estimates were high in the striatum (105±21 mL cm 3), medium in cingulate cortex (62±10 mL cm 3) and low in the cerebellum (41±7 mL cm 3). Test-retest reliability was found to be reasonable. The uptake was dose-dependently reduced by pre-treatment with idazoxan throughout the brain, with an average block across all regions of ~60% (VT≅30 mL cm 3) at the highest dose (80 mg). The median effective dose (ED50) for idazoxan was calculated as 28 mg. Uptake was not blocked by pre-treatme

Journal article

Freeman TP, Mehta MA, Neill JC, Nutt DJ, Tunbridge EM, Young AHet al., 2018, Restrictions on drugs with medical value: Moving beyond stalemate, JOURNAL OF PSYCHOPHARMACOLOGY, Vol: 32, Pages: 1053-1055, ISSN: 0269-8811

Journal article

Timmermann C, Timmermann Slater C, Roseman L, Williams L, Erritzoe D, Martial C, Cassol H, Laureys S, Nutt D, Carhart-Harris Ret al., 2018, DMT models the near-death experience, Frontiers in Psychology, Vol: 9, ISSN: 1664-1078

Near-death experiences (NDEs) are complex subjective experiences, which have been previously associated with the psychedelic experience and more specifically with the experience induced by the potent serotonergic, N,N-Dimethyltryptamine (DMT). Potential similarities between both subjective states have been noted previously, including the subjective feeling of transcending one’s body and entering an alternative realm, perceiving and communicating with sentient ‘entities’ and themes related to death and dying. In this within-subjects placebo-controled study we aimed to test the similarities between the DMT state and NDEs, by administering DMT and placebo to 13 healthy participants, who then completed a validated and widely used measure of NDEs. Results revealed significant increases in phenomenological features associated with the NDE, following DMT administration compared to placebo. Also, we found significant relationships between the NDE scores and DMT-induced ego-dissolution and mystical-type experiences, as well as a significant association between NDE scores and baseline trait ‘absorption’ and delusional ideation measured at baseline. Furthermore, we found a significant overlap in nearly all of the NDE phenomenological features when comparing DMT-induced NDEs with a matched group of ‘actual’ NDE experiencers. These results reveal a striking similarity between these states that warrants further investigation.

Journal article

Rogeberg O, Blomkvist AW, Nutt D, 2018, CANNABIS AND OPIOID OVERDOSES: TIME TO MOVE ON AND EXAMINE POTENTIAL MECHANISMS, ADDICTION, Vol: 113, Pages: 1551-1552, ISSN: 0965-2140

Journal article

Venkataraman A, Keat N, Myers J, Turton S, Mick I, Gunn R, Rabiner E, Passchier J, Parker C, Tyacke R, Nutt Det al., 2018, First evaluation of PET-based human biodistribution and radiation dosimetry of 11C-BU99008, a tracer for imaging the imidazoline2 binding site, EJNMMI Research, Vol: 8, ISSN: 2191-219X

BackgroundWe measured whole body distribution of 11C-BU99008, a new PET biomarker for non-invasive identification of the imidazoline2 binding site. The purpose of this phase I study was to evaluate the biodistribution and radiation dosimetry of 11C-BU99008 in healthy human subjects.MethodsA single bolus injection of 11C-BU99008 (296 ± 10.5 MBq) was administered to four healthy subjects who underwent whole-body PET/CT over 120 min from the cranial vertex to the mid-thigh. Volumes of interest were drawn around visually identifiable source organs to generate time-activity curves (TAC). Residence times were determined from time-activity curves. Absorbed doses to individual organs and the whole body effective dose were calculated using OLINDA/EXM 1.1 for each subject.ResultsThe highest measured activity concentration was in the kidney and spleen. The longest residence time was in the muscle at 0.100 ± 0.023 h, followed by the liver at 0.067 ± 0.015 h and lungs at 0.052 ± 0.010 h. The highest mean organ absorbed dose was within the heart wall (0.028 ± 0.002 mGy/MBq), followed by the kidneys (0.026 ± 0.005 mGy/MBq). The critical organ was the heart wall. The total mean effective dose averaged over subjects was estimated to be 0.0056 ± 0.0004 mSv/MBq for an injection of 11C-BU99008.ConclusionsThe biodistribution of 11C-BU99008 has been shown here for the first time in humans. Our dosimetry data showed the total mean effective dose over all subjects was 0.0056 ± 0.0004 mSv/MBq, which would result in a total effective dose of 1.96 mSv for a typical injection of 350 MBq of 11C-BU99008. The effective dose is not appreciably different from those obtained with other 11C tracers.

Journal article

Venkataraman A, Nutt D, A tale of two moralities: Politicians, doctors, use of addictive substances and lobbying, Drug Science, Policy and Law

Journal article

Fan Z, Calsolaro V, Mayers J, Tyacke R, Venkataraman A, Femminella G, Perneczky R, Gunn R, Rabiner E, Matthews P, Nutt D, Edison Pet al., 2018, Relationship between astrocyte activation using [11C]BU99008 PET, glucose metabolism and amyloid in Alzheimer’s disease: a Dementia Platform UK experimental medicine study, Alzheimer's and Dementia, Vol: 14, Pages: P1640-P1640, ISSN: 1552-5260

Journal article

Calsolaro V, Mayers J, Fan Z, Tyacke R, Venkataraman A, Femminella G, Perneczky R, Gunn R, Rabiner E, Matthews P, Nutt D, Edison Pet al., 2018, Evaluation of novel astrocyte marker [11C]BU99008 PET in Alzheimer’s disease: a Dementia Platform U.K. experimental medicine study, Alzheimer's and Dementia, Vol: 14, Pages: P842-P843, ISSN: 1552-5260

Journal article

van den Brink W, Addolorato G, Aubin H-J, Benyamina A, Caputo F, Dematteis M, Gual A, Lesch O-M, Mann K, Maremmani I, Nutt D, Paille F, Perney P, Rehm J, Reynaud M, Simon N, Soederpalm B, Sommer WH, Walter H, Spanagel Ret al., 2018, Efficacy and safety of sodium oxybate in alcohol-dependent patients with a very high drinking risk level, ADDICTION BIOLOGY, Vol: 23, Pages: 969-986, ISSN: 1355-6215

Journal article

Turton S, Myers J, Mick I, Colasanti A, Venkataraman A, Durant C, Waldman A, Brailsford A, Parkin M, Rabiner EA, Gunn R, Lightman S, Nutt D, Lingford-Hughes ARet al., 2018, Blunted endogenous opioid release following an oral dexamphetamine challenge in abstinent alcohol dependent individuals, Molecular Psychiatry, ISSN: 1359-4184

Addiction has been proposed as a ‘reward deficient’ state, which is compensated for with substance use. There is growing evidence of dysregulation in the opioid system, which plays a key role in reward, underpinning addiction. Low levels of endogenous opioids are implicated in vulnerability for developing alcohol dependence (AD) and high mu-opioid receptor (MOR) availability in early abstinence is associated with greater craving. This high MOR availability is proposed to be the target of opioid antagonist medication to prevent relapse. However, changes in endogenous opioid tone in AD are poorly characterised and are important to understand as opioid antagonists do not help everyone with AD. We used [11C]carfentanil, a selective MOR agonist positron emission tomography (PET) radioligand, to investigate endogenous opioid tone in AD for the first time. We recruited 13 abstinent male AD and 15 control participants who underwent two [11C]carfentanil PET scans, one before and one 3 h following a 0.5 mg/kg oral dose of dexamphetamine to measure baseline MOR availability and endogenous opioid release. We found significantly blunted dexamphetamine-induced opioid release in 5 out of 10 regions-of-interest including insula, frontal lobe and putamen in AD compared with controls, but no significantly higher MOR availability AD participants compared with HC in any region. This study is comparable to our previous results of blunted dexamphetamine-induced opioid release in gambling disorder, suggesting that this dysregulation in opioid tone is common to both behavioural and substance addictions.

Journal article

Rogeberg O, Bergsvik D, Phillips LD, van Amsterdam J, Eastwood N, Henderson G, Lynskey M, Measham F, Ponton R, Rolles S, Schlag AK, Taylor P, Nutt Det al., 2018, A new approach to formulating and appraising drug policy: a multi-criterion decision analysis applied to alcohol and cannabis regulation, International Journal of Drug Policy, Vol: 56, Pages: 144-152, ISSN: 0955-3959

BACKGROUND: Drug policy, whether for legal or illegal substances, is a controversial field that encompasses many complex issues. Policies can have effects on a myriad of outcomes and stakeholders differ in the outcomes they consider and value, while relevant knowledge on policy effects is dispersed across multiple research disciplines making integrated judgements difficult. METHODS: Experts on drug harms, addiction, criminology and drug policy were invited to a decision conference to develop a multi-criterion decision analysis (MCDA) model for appraising alternative regulatory regimes. Participants collectively defined regulatory regimes and identified outcome criteria reflecting ethical and normative concerns. For cannabis and alcohol separately, participants evaluated each regulatory regime on each criterion and weighted the criteria to provide summary scores for comparing different regimes. RESULTS: Four generic regulatory regimes were defined: absolute prohibition, decriminalisation, state control and free market. Participants also identified 27 relevant criteria which were organised into seven thematically related clusters. State control was the preferred regime for both alcohol and cannabis. The ranking of the regimes was robust to variations in the criterion-specific weights. CONCLUSION: The MCDA process allowed the participants to deconstruct complex drug policy issues into a set of simpler judgements that led to consensus about the results.

Journal article

Gabay AS, Carhart-Harris RL, Mazibuko N, Kempton MJ, Morrison PD, Nutt DJ, Mehta MAet al., 2018, Psilocybin and MDMA reduce costly punishment in the Ultimatum Game, SCIENTIFIC REPORTS, Vol: 8, ISSN: 2045-2322

Disruptions in social decision-making are becoming evident in many psychiatric conditions. These are studied using paradigms investigating the psychological mechanisms underlying interpersonal interactions, such as the Ultimatum Game (UG). Rejection behaviour in the UG represents altruistic punishment – the costly punishment of norm violators – but the mechanisms underlying it require clarification. To investigate the psychopharmacology of UG behaviour, we carried out two studies with healthy participants, employing serotonergic agonists: psilocybin (open-label, within-participant design, N = 19) and 3,4-methylenedioxymethamphetamine (MDMA; placebo-controlled, double-blind, crossover design, N = 20). We found that both MDMA and psilocybin reduced rejection of unfair offers (odds ratio: 0.57 and 0.42, respectively). The reduction in rejection rate following MDMA was associated with increased prosociality (R2 = 0.26, p = 0.025). In the MDMA study, we investigated third-party decision-making and proposer behaviour. MDMA did not reduce rejection in the third-party condition, but produced an increase in the amount offered to others (Cohen’s d = 0.82). We argue that these compounds altered participants’ conceptualisation of ‘social reward’, placing more emphasis on the direct relationship with interacting partners. With these compounds showing efficacy in drug-assisted psychotherapy, these studies are an important step in the further characterisation of their psychological effects.

Journal article

Carrillo F, Sigman M, Fernandez Slezak D, Ashton P, Fitzgerald L, Stroud J, Nutt DJ, Carhart-Harris RLet al., 2018, Natural speech algorithm applied to baseline interview data can predict which patients will respond to psilocybin for treatment-resistant depression, JOURNAL OF AFFECTIVE DISORDERS, Vol: 230, Pages: 84-86, ISSN: 0165-0327

Journal article

Kaelen M, Giribaldi B, Raine J, Evans L, Timmermann C, Rodriguez N, Roseman L, Feilding A, Nutt D, Carhart-Harris Ret al., 2018, Correction to: The hidden therapist: evidence for a central role of music in psychedelic therapy., Psychopharmacology, Vol: 235, Pages: 1623-1623, ISSN: 0033-3158

The article The hidden therapist: evidence for a central role of music in psychedelic therapy, written by Mendel Kaelen, Bruna Giribaldi, Jordan Raine, Lisa Evans, Christopher Timmerman, Natalie Rodriguez, Leor Roseman, Amanda Feilding, David Nutt, Robin Carhart-Harris, was originally published electronically on the publisher's internet portal.

Journal article

Dukart J, Holiga Š, Chatham C, Hawkins P, Forsyth A, McMillan R, Myers J, Lingford-Hughes AR, Nutt DJ, Merlo-Pich E, Risterucci C, Boak L, Umbricht D, Schobel S, Liu T, Mehta MA, Zelaya FO, Williams SC, Brown G, Paulus M, Honey GD, Muthukumaraswamy S, Hipp J, Bertolino A, Sambataro Fet al., 2018, Cerebral blood flow predicts differential neurotransmitter activity, Scientific Reports, Vol: 8, ISSN: 2045-2322

Application of metabolic magnetic resonance imaging measures such as cerebral blood flow in translational medicine is limited by the unknown link of observed alterations to specific neurophysiological processes. In particular, the sensitivity of cerebral blood flow to activity changes in specific neurotransmitter systems remains unclear. We address this question by probing cerebral blood flow in healthy volunteers using seven established drugs with known dopaminergic, serotonergic, glutamatergic and GABAergic mechanisms of action. We use a novel framework aimed at disentangling the observed effects to contribution from underlying neurotransmitter systems. We find for all evaluated compounds a reliable spatial link of respective cerebral blood flow changes with underlying neurotransmitter receptor densities corresponding to their primary mechanisms of action. The strength of these associations with receptor density is mediated by respective drug affinities. These findings suggest that cerebral blood flow is a sensitive brain-wide in-vivo assay of metabolic demands across a variety of neurotransmitter systems in humans.

Journal article

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