Publications
1392 results found
Goldstone AP, Ling YY, Nestor LJ, et al., 2021, EFFECT OF ACUTE DESACYL GHRELIN ADMINISTRATION ON EATING AND ADDICTIVE BEHAVIOURS: THE GUT HORMONE IN ADDICTION STUDY, Publisher: WILEY, Pages: 51A-51A, ISSN: 0145-6008
Daws R, Timmerman C, Giribaldi B, et al., 2021, Decreased brain modularity after psilocybin therapy for depression.
<jats:title>Abstract</jats:title> <jats:p><jats:bold>Importance </jats:bold>Psilocybin therapy shows antidepressant potential; our data link its antidepressant effects to decreased brain network modularity post-treatment. <jats:bold>Objective </jats:bold>To assess the sub-acute impact of psilocybin on brain activity in patients with depression. <jats:bold>Design </jats:bold>Pre vs post-treatment resting-state functional MRI (fMRI) was recorded in two trials: 1) Open-label treatment-resistant depression (TRD) trial with baseline vs 1 day post-treatment fMRI (April-2015 to April-2016); 2) Two-arm double-blind RCT in major depressive disorder (MDD), fMRI baseline vs 3 week after psilocybin-therapy or 6 weeks of daily escitalopram (January-2019 to March-2020). <jats:bold>Setting </jats:bold>Study visits occurred at the NIHR Imperial Clinical Research Facility.<jats:bold>Participants </jats:bold>Adult male and female patients with TRD or MDD. <jats:bold>Intervention(s) (for clinical trials) or Exposure(s) (for observational studies)</jats:bold>Study 1: Two oral doses of psilocybin (10mg and 25mg, fixed order, 7 days apart). fMRI was recorded at baseline and one day after the 25mg dose. Study 2: 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 was recorded at baseline and 3 weeks after the 2nd psilocybin dose, which was the final day of the 6-week daily capsule ingestion. <jats:bold>Main Outcome(s) and Measure(s) </jats:bold>Beck Depression Inventory and fMRI network modularity. <jats:bold> </jats:bold><jats:bold>Results </jats:bold>Study 1: In 16 adults (mean age [SD], 42.8 [10.1] years, 4 [25%] female), psilocybin therapy<jats:underline> </ja
Singleton SP, Luppi AI, Carhart-Harris RL, et al., 2021, LSD and psilocybin flatten the brain’s energy landscape: insights from receptor-informed network control theory
<jats:title>Abstract</jats:title><jats:p>Psychedelics like lysergic acid diethylamide (LSD) and psilocybin offer a powerful window into the function of the human brain and mind, by temporarily altering subjective experience through their neurochemical effects. A recent model postulates that serotonin 2a (5-HT2a) receptor agonism allows the brain to explore its dynamic landscape more readily, as reflected by more diverse (entropic) brain activity. We postulate that this increase in entropy may arise in part from a flattening of the brain’s control energy landscape, which can be observed using network control theory to quantify the energy required to transition between recurrent brain states measured using functional magnetic resonance imaging (fMRI) in individuals under LSD, psilocybin, and placebo conditions. We show that LSD and psilocybin reduce the amount of control energy required for brain state transitions, and, furthermore, that, across individuals, LSD’s reduction in control energy correlates with more frequent state transitions and increased entropy of brain state dynamics. Through network control analysis that incorporates the spatial distribution of 5-HT2a receptors from publicly available (non-drug) positron emission tomography (PET) maps, we demonstrate the specific role of this receptor in reducing control energy. Our findings provide evidence that 5-HT2a receptor agonist compounds allow for more facile state transitions and more temporally diverse brain activity. More broadly, by combining receptor-informed network control theory with pharmacological modulation, our work highlights the potential of this approach in studying the impacts of targeted neuropharmacological manipulation on brain activity dynamics.</jats:p><jats:sec><jats:title>Significance Statement</jats:title><jats:p>We present a multi-modal framework for quantifying the effects of two psychedelic drugs (LSD and psilocybin) on br
Rolles S, Schlag AK, Measham F, et al., 2021, A multi criteria decision analysis (MCDA) for evaluating and appraising government policy responses to non medical heroin use, INTERNATIONAL JOURNAL OF DRUG POLICY, Vol: 91, ISSN: 0955-3959
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- Citations: 6
Borissova A, Ferguson B, Wall MB, et al., 2021, Acute effects of MDMA on trust, cooperative behaviour and empathy: A double-blind, placebo-controlled experiment, JOURNAL OF PSYCHOPHARMACOLOGY, Vol: 35, Pages: 547-555, ISSN: 0269-8811
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- Citations: 12
Ashok AH, Myers J, Frost G, et al., 2021, Acute acetate administration increases endogenous opioid levels in the human brain: A [<SUP>11</SUP>C]carfentanil molecular imaging study, JOURNAL OF PSYCHOPHARMACOLOGY, Vol: 35, Pages: 606-610, ISSN: 0269-8811
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- Citations: 3
Carhart-Harris R, Giribaldi B, Watts R, et al., 2021, Trial of Psilocybin versus Escitalopram for Depression, NEW ENGLAND JOURNAL OF MEDICINE, Vol: 384, Pages: 1402-1411, ISSN: 0028-4793
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- Citations: 416
Rolles S, Nutt DJ, Schlag AK, 2021, Some Contributions on How to Formulate Drug Policies and Provide Evidence-Based Regulation, AMERICAN JOURNAL OF BIOETHICS, Vol: 21, Pages: 28-31, ISSN: 1526-5161
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- Citations: 1
Fonville L, Paterson L, Herlinger K, et al., 2021, Functional evaluation of NK1 antagonism on cue reactivity in opiate dependence; an fMRI study, Drug and Alcohol Dependence, Vol: 221, Pages: 1-7, ISSN: 0376-8716
BackgroundOpiate addiction is a major health challenge with substantial societal cost. Though harm minimisation strategies have been effective, there is a growing need for new treatments for detoxification and relapse prevention. Preclinical research has found neurokinin 1 (NK1) receptors have prominent effects on opiate reward and reinforcement, and human studies have found NK1 antagonism led to reductions in craving and withdrawal. However, its effect on brain mechanisms in opiate addiction has not yet been examined.MethodsThis study aims to assess the impact of NK1 antagonist aprepitant on heroin cue-elicited changes in blood-oxygenation level dependent (BOLD) signal in opiate dependent individuals undergoing detoxification. Participants will attend two scanning sessions and receive a single dose of aprepitant (320 mg) and a placebo in a randomised, cross-over design. During functional magnetic resonance imaging participants will undergo two runs of a cue reactivity task, which consists of passive viewing of drug cues or neutral cues in a block design fashion. We hypothesise that NK1 antagonism will attenuate the BOLD response to drug cues in the caudate nucleus and amygdala. Regions of interest were selected based on NK1 receptor density and their role in cue reactivity and craving.
Sessa B, Higbed L, O'Brien S, et al., 2021, First study of safety and tolerability of 3,4-methylenedioxymethamphetamine-assisted psychotherapy in patients with alcohol use disorder, JOURNAL OF PSYCHOPHARMACOLOGY, Vol: 35, Pages: 375-383, ISSN: 0269-8811
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- Citations: 34
Szigeti B, Kartner L, Blemings A, et al., 2021, Self-blinding citizen science to explore psychedelic microdosing, eLife, Vol: 10, Pages: 1-26, ISSN: 2050-084X
Microdosing is the practice of regularly using low doses of psychedelic drugs. Anecdotal reports suggest that microdosing enhances well-being and cognition; however, such accounts are potentially biased by the placebo effect. This study used a ‘self-blinding’ citizen science initiative, where participants were given online instructions on how to incorporate placebo control into their microdosing routine without clinical supervision. The study was completed by 191 participants, making it the largest placebo-controlled trial on psychedelics to-date. All psychological outcomes improved significantly from baseline to after the 4 weeks long dose period for the microdose group; however, the placebo group also improved and no significant between-groups differences were observed. Acute (emotional state, drug intensity, mood, energy, and creativity) and post-acute (anxiety) scales showed small, but significant microdose vs. placebo differences; however, these results can be explained by participants breaking blind. The findings suggest that anecdotal benefits of microdosing can be explained by the placebo effect.
Andersen KAA, Carhart-Harris R, Nutt DJ, et al., 2021, Therapeutic effects of classic serotonergic psychedelics: A systematic review of modern-era clinical studies, ACTA PSYCHIATRICA SCANDINAVICA, Vol: 143, Pages: 101-118, ISSN: 0001-690X
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- Citations: 93
Mirzaei N, Mota B, Birch A, et al., 2021, Imidazoline ligand BU224 reverses cognitive deficits, reduces microgliosis and enhances synaptic connectivity in a mouse model of Alzheimer’s disease, British Journal of Pharmacology, Vol: 178, Pages: 654-671, ISSN: 0007-1188
Background and PurposeActivation of type‐2 Imidazoline receptors has been shown to exhibit neuroprotective properties including anti‐apoptotic and anti‐inflammatory effects, suggesting a potential therapeutic value in Alzheimer's disease (AD). Here, we explored the effects of the Imidazoline‐2 ligand BU224 in a model of amyloidosis.Experimental approach6‐month‐old female transgenic 5XFAD and wild‐type (WT) mice were treated intraperitoneally with 5 mg.kg‐1 BU224 or vehicle twice a day for 10 days. Behavioural tests were performed for cognitive functions and neuropathological changes were investigated by immunohistochemistry, Western blot, ELISA and qPCR. Effects of BU224 on APP processing, spine density and calcium imaging were analysed in brain organotypic cultures and N2a cells.Key ResultsBU224 treatment attenuated spatial and perirhinal cortex‐dependent recognition memory deficits in 5XFAD mice. Fear conditioning testing revealed that BU224 also improved both associative learning and hippocampal‐ and amygdala‐dependent memory in transgenic but not in WT mice. In the brain, BU224 reduced levels of the microglial marker Iba1 and pro‐inflammatory cytokines IL‐1β and TNFα, and increased the expression of astrocytic marker GFAP in 5XFAD mice. These beneficial effects were not associated with changes in amyloid pathology, neuronal apoptosis, mitochondrial density, oxidative stress or autophagy markers. Interestingly, ex vivo and in vitro studies suggested that BU224 treatment increased the size of dendritic spines and induced a 3‐fold reduction in Aβ‐induced functional changes in NMDA receptors.Conclusions and implicationsOur data indicate that sub‐chronic treatment with BU224 improves memory and reduces inflammation in transgenic AD mice, at stages when animals display severe pathology.
Nutt D, Carhart-Harris R, 2021, The Current Status of Psychedelics in Psychiatry, JAMA PSYCHIATRY, Vol: 78, Pages: 121-122, ISSN: 2168-622X
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- Citations: 78
Sanz C, Pallavicini C, Carrillo F, et al., 2021, The entropic tongue: Disorganization of natural language under LSD, CONSCIOUSNESS AND COGNITION, Vol: 87, ISSN: 1053-8100
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- Citations: 17
Herlinger K, Ling YY, Nestor LJ, et al., 2020, Comparison of food cue reactivity, eating behaviours, mood and impulsivity in obesity, ex-smokers and abstinent alcohol dependence, 33rd Congress of the European-College-of-Neuropsychopharmacology (ECNP), Publisher: ELSEVIER, Pages: S15-S15, ISSN: 0924-977X
Alamia A, Timmermann C, VanRullen R, et al., 2020, DMT alters cortical travelling waves, eLife, Vol: 9, Pages: 1-16, ISSN: 2050-084X
Psychedelic drugs are potent modulators of conscious states and therefore powerful tools for investigating their neurobiology. N,N, Dimethyltryptamine (DMT) can rapidly induce an extremely immersive state of consciousness characterized by vivid and elaborate visual imagery. Here, we investigated the electrophysiological correlates of the DMT-induced altered state from a pool of participants receiving DMT and (separately) placebo (saline) while instructed to keep their eyes closed. Consistent with our hypotheses, results revealed a spatio-temporal pattern of cortical activation (i.e. travelling waves) similar to that elicited by visual stimulation. Moreover, the typical top-down alpha-band rhythms of closed-eyes rest were significantly decreased, while the bottom-up forward wave was significantly increased. These results support a recent model proposing that psychedelics reduce the ‘precision-weighting of priors’, thus altering the balance of top-down versus bottom-up information passing. The robust hypothesis-confirming nature of these findings imply the discovery of an important mechanistic principle underpinning psychedelic-induced altered states.
Schlag AK, Baldwin DS, Barnes M, et al., 2020, Medical cannabis in the UK: From principle to practice, JOURNAL OF PSYCHOPHARMACOLOGY, Vol: 34, Pages: 931-937, ISSN: 0269-8811
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- Citations: 21
Turton S, Myers J, Mick I, et al., 2020, Blunted endogenous opioid release following an oral dexamphetamine challenge in abstinent alcohol dependent individuals, Molecular Psychiatry, Vol: 25, Pages: 1749-1758, 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.
Wardle H, Banks J, Bebbington P, et al., 2020, Open letter from UK based academic scientists to the secretaries of state for digital, culture, media and sport and for health and social care regarding the need for independent funding for the prevention and treatment of gambling harms, BMJ-BRITISH MEDICAL JOURNAL, Vol: 370, ISSN: 0959-535X
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- Citations: 5
Nutt D, Nestor L, Suckling J, et al., 2020, Disturbances across whole brain networks during reward anticipation in an abstinent addiction population., NeuroImage: Clinical, Vol: 27, Pages: 1-10, ISSN: 2213-1582
The prevalent spatial distribution of abnormalities reported in cognitive fMRI studies in addiction suggests there are extensive disruptions across whole brain networks. Studies using resting state have reported disruptions in network connectivity in addiction, but these studies have not revealed characteristics of network functioning during critical psychological processes that are disrupted in addiction populations. Analytic methods that can capture key features of whole brain networks during psychological processes may be more sensitive in revealing additional and widespread neural disturbances in addiction, that are the provisions for relapse risk, and targets for medication development. The current study compared a substance addiction (ADD; n = 83) group in extended abstinence with a control (CON; n = 68) group on functional MRI (voxel-wise activation) and global network (connectivity) measures related to reward anticipation on a monetary incentive delay task. In the absence of group differences on MID performance, the ADD group showed reduced activation predominantly across temporal and visual regions, but not across the striatum. The ADD group also showed disruptions in global network connectivity (lower clustering coefficient and higher characteristic path length), and significantly less connectivity across a sub-network comprising frontal, temporal, limbic and striatal nodes. These results show that an addiction group in extended abstinence exhibit localised disruptions in brain activation, but more extensive disturbances in functional connectivity across whole brain networks. We propose that measures of global network functioning may be more sensitive in highlighting latent and more widespread neural disruptions during critical psychological processes in addiction and other psychiatric disorders.
Marques TR, Ashok AH, Angelescu I, et al., 2020, GABA-A receptor differences in schizophrenia: a positron emission tomography study using [C-11]Ro154513, Molecular Psychiatry, Vol: 26, Pages: 2616-2625, ISSN: 1359-4184
A loss of GABA signaling is a prevailing hypothesis for the pathogenesis of schizophrenia. Preclinical studies indicate that blockade of the α5 subtype of the GABA receptor (α5-GABAARs) leads to behavioral phenotypes associated with schizophrenia, and postmortem evidence indicates lower hippocampal α5-GABAARs protein and mRNA levels in schizophrenia. However, it is unclear if α5-GABAARs are altered in vivo or related to symptoms. We investigated α5-GABAARs availability in antipsychotic-free schizophrenia patients and antipsychotic-medicated schizophrenia patients using [11C]Ro15-4513 PET imaging in a cross-sectional, case–control study design. Thirty-one schizophrenia patients (n = 10 antipsychotic free) and twenty-nine matched healthy controls underwent a [11C]Ro15-4513 PET scan and MRI. The α5 subtype GABA-A receptor availability was indexed using [11C]Ro15-4513 PET imaging. Dynamic PET data were analyzed using the two-tissue compartment model with an arterial plasma input function and total volume of distribution (VT) as the outcome measure. Symptom severity was assessed using the PANSS scale. There was significantly lower [11C]Ro15-4513 VT in the hippocampus of antipsychotic-free patients, but not in medicated patients (p = 0.64), relative to healthy controls (p < 0.05; effect size = 1.4). There was also a significant positive correlation between [11C]Ro15-4513 VT and total PANSS score in antipsychotic-free patients (r = 0.72; p = 0.044). The results suggest that antipsychotic-free patients with schizophrenia have lower α5-GABAARs levels in the hippocampus, consistent with the hypothesis that GABA hypofunction underlies the pathophysiology of the disorder.
Nutt D, Erritzoe D, Carhart-Harris R, 2020, Psychedelic Psychiatry's Brave New World, CELL, Vol: 181, Pages: 24-28, ISSN: 0092-8674
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- Citations: 117
Erritzoe D, Ashok AH, Searle GE, et al., 2020, Serotonin release measured in the human brain: A PET study with [11C]CIMBI-36 and d-amphetamine challenge, Neuropsychopharmacology, Vol: 45, Pages: 804-810, ISSN: 0893-133X
Positron emission tomography (PET) enables non-invasive estimation of neurotransmitter fluctuations in the living human brain. While these methods have been applied to dopamine and some other transmitters, estimation of 5-hydroxytryptamine (5-HT; Serotonin) release has proved to be challenging. Here we demonstrate the utility of the novel 5-HT2A receptor agonist radioligand, [11C]CIMBI-36, and a d-amphetamine challenge to evaluate synaptic 5-HT changes in the living human brain. Seventeen healthy male volunteers received [11C]CIMBI-36 PET scans before and 3 hours after an oral dose of d-amphetamine (0.5 mg/kg). Dynamic PET data were acquired over 90 minutes, and the total volume of distribution (VT) in the frontal cortex and the cerebellum derived from a kinetic analysis using MA1. The frontal cortex binding potential (BPNDfrontal) was calculated as (VTfrontal/VTcerebellum)-1. BPNDfrontal = 1- (BPNDfrontalpost-dose/ BPNDfrontalbaseline) was used as an index of 5-HT release. Statistical inference was tested by means of a paired Students t-test evaluating a reduction in post-amphetamine [11C]CIMBI-36 BPNDfrontal .Following d-amphetamine administration, [11C]CIMBI-36 BPNDfrontal was reduced by 14 ± 13 % (p = 0.002). Similar effects were observed in other cortical regions examined in an exploratory analysis.[11C]CIMBI-36 binding is sensitive to synaptic serotonin release in the human brain, and when combined with a d-amphetamine challenge, the evaluation of the human brain serotonin system in neuropsychiatric disorders, such as major depression and Parkinson’s disease is enabled.
Nutt D, 2020, New psychoactive substances: Pharmacology influencing UK practice, policy and the law, BRITISH JOURNAL OF CLINICAL PHARMACOLOGY, Vol: 86, Pages: 445-451, ISSN: 0306-5251
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- Citations: 6
Campeny E, Lopez-Pelayo H, Nutt D, et al., 2020, The blind men and the elephant: Systematic review of systematic reviews of cannabis use related health harms, EUROPEAN NEUROPSYCHOPHARMACOLOGY, Vol: 33, Pages: 1-35, ISSN: 0924-977X
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- Citations: 69
Hayes A, Wing V, McGonigle J, et al., 2020, The relationship between reward processing and impulsivity in addiction: a functional magnetic resonance imaging study, ECNP Workshop on Junior Scientists in Europe, Publisher: ELSEVIER, Pages: S70-S71, ISSN: 0924-977X
Introduction: Evidence suggests that abnormalities in reward processing and increased impulsivity contribute to the pathophysiology of addiction. However, the relationship between the two is currently not well characterised. This study used fMRI to investigate the BOLD response during reward and inhibitory control tasks and how such responses were associated with subjective and behavioural measures of impulsivity in abstinent alcohol, cocaine and polydrug addiction. We hypothesized a negative correlation between non-drug related reward anticipation and impulsivity measures in polydrug and alcohol dependence compared with healthy controls owing to increased impulsivity and thus more inhibitory control effort needed to maintain successful abstinence.Methods: Abstinent alcohol dependent (AD, n=27), polydrug dependent (PD, n=57) and healthy control (HC, n=65) participants were recruited [1] (REC number 11/H0707/9). Participants completed a battery of impulsivity measures; the Barratt Impulsiveness Scale (BIS-11) and the Urgency, Premeditation, (lack of), Perseverance (lack of), Sensation Seeking, Positive Urgency, Impulsive Behaviour Scale (UPPS-P) to measure trait impulsivity, the Kirby Delay Discounting task to measure choice impulsivity and the Stop Signal Task (SST) to measure impulsive action. Participants also underwent fMRI scanning (3-T) using the monetary incentive delay (MID) and Go/No-go (GNG) tasks. An a-priori region of interest approach was used to image BOLD response during the following contrasts: reward anticipation>neutral anticipation and no-go/go in the rIFG, OFC and caudate. Data was analysed using ANOVA or Kruskal- Wallis tests (with Tukey or Mann-Whitney U post-hoc tests respectively) and Pearson's or Spearman's rank correlations, as appropriate. Holm-Bonferroni correction was applied.Results: There were significant group differences in the BIS-11 (p<0.001), UPPS-P (p<0.001) and Kirby Delay Discounting task (p=0.002). Appropriate post-hoc
Mertens LJ, Wall MB, Roseman L, et al., 2020, Therapeutic mechanisms of psilocybin: Changes in amygdala and prefrontal functional connectivity during emotional processing after psilocybin for treatment-resistant depression, JOURNAL OF PSYCHOPHARMACOLOGY, Vol: 34, Pages: 167-180, ISSN: 0269-8811
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- Citations: 64
Grabski M, Curran HV, Nutt DJ, et al., 2020, The development and validation of a human screening model of tobacco abstinence, DRUG AND ALCOHOL DEPENDENCE, Vol: 206, ISSN: 0376-8716
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- Citations: 1
Nutt D, Bazire S, Phillips LD, et al., 2020, So near yet so far: why won't the UK prescribe medical cannabis?, BMJ OPEN, Vol: 10, ISSN: 2044-6055
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- Citations: 24
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