Publications
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Lord L-D, Expert P, Atasoy S, et al., 2019, Dynamical exploration of the repertoire of brain networks at rest is modulated by psilocybin, NeuroImage, Vol: 199, Pages: 127-142, ISSN: 1053-8119
Growing evidence from the dynamical analysis of functional neuroimaging data suggests that brain function can be understood as the exploration of a repertoire of metastable connectivity patterns ('functional brain networks'), which potentially underlie different mental processes. The present study characterizes how the brain's dynamical exploration of resting-state networks is rapidly modulated by intravenous infusion of psilocybin, a tryptamine psychedelic found in "magic mushrooms". We employed a data-driven approach to characterize recurrent functional connectivity patterns by focusing on the leading eigenvector of BOLD phase coherence at single-TR resolution. Recurrent BOLD phase-locking patterns (PL states) were assessed and statistically compared pre- and post-infusion of psilocybin in terms of their probability of occurrence and transition profiles. Results were validated using a placebo session. Recurrent BOLD PL states revealed high spatial overlap with canonical resting-state networks. Notably, a PL state forming a frontoparietal subsystem was strongly destabilized after psilocybin injection, with a concomitant increase in the probability of occurrence of another PL state characterized by global BOLD phase coherence. These findings provide evidence of network-specific neuromodulation by psilocybin and represent one of the first attempts at bridging molecular pharmacodynamics and whole-brain network dynamics.
Hayes AG, Nutt DJ, 2019, Compound asset sharing initiatives between pharmaceutical companies, funding bodies, and academia: Learnings and successes, PHARMACOLOGY RESEARCH & PERSPECTIVES, Vol: 7, ISSN: 2052-1707
Nestor LJ, Paterson LM, Murphy A, et al., 2019, Naltrexone differentially modulates the neural correlates of motor impulse control in abstinent alcohol-dependent and poly-substance dependent individuals, European Journal of Neuroscience, Vol: 50, Pages: 2311-2321, 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.
Jefsen O, Højgaard K, Christiansen SL, et al., 2019, Psilocybin lacks antidepressant-like effect in the Flinders Sensitive Line rat., Acta Neuropsychiatr, Vol: 31, Pages: 213-219
OBJECTIVE: Psilocybin is a serotonin receptor agonist with a therapeutic potential for treatment-resistant depression and other psychiatric illnesses. We investigated whether the administration of psilocybin had an antidepressant-like effect in a rat model of depression. METHODS: Using the Flinders Sensitive Line (FSL) rat model of depression, we assessed the antidepressant-like effect of psilocin and psilocybin, measured as a reduction in immobility time in the forced swim test (FST). We measured locomotor activity in an open field test (OFT) to control for stimulant properties of the drugs. We performed a set of experiments to test different doses, treatment paradigms, and timing of the tests in relation to the drug administration. RESULTS: Psilocin and psilocybin showed no effect on immobility, struggling, or swimming behaviour in the FST and no effect on locomotor activity in the OFT. FSL rats did show significantly more immobility than their control strain, the Flinders Resistant Line, as expected. CONCLUSION: Psilocin and psilocybin showed no antidepressant-like effect in the FSL rats, despite a positive effect in humans. This suggests that other animal models of depression and other behavioural tests may be more appropriate for translational studies in the effects of psilocybin.
Kuypers KPC, Ng L, Erritzoe D, et al., Microdosing psychedelics: More questions than answers? An overview and suggestions for future research, JOURNAL OF PSYCHOPHARMACOLOGY, ISSN: 0269-8811
Wilson S, Anderson K, Baldwin D, et al., 2019, British Association for Psychopharmacology consensus statement on evidence-based treatment of insomnia, parasomnias and circadian rhythm disorders: An update, JOURNAL OF PSYCHOPHARMACOLOGY, Vol: 33, Pages: 923-947, ISSN: 0269-8811
Meacher M, Nutt D, Liebling J, et al., 2019, Should the supply of cannabis be legalised now?, BMJ-BRITISH MEDICAL JOURNAL, Vol: 366, ISSN: 1756-1833
Bonomo Y, Norman A, Biondo S, et al., 2019, The Australian drug harms ranking study, JOURNAL OF PSYCHOPHARMACOLOGY, Vol: 33, Pages: 759-768, ISSN: 0269-8811
Wall MB, Pope R, Freeman TP, et al., 2019, Dissociable effects of cannabis with and without cannabidiol on the human brain's resting-state functional connectivity, JOURNAL OF PSYCHOPHARMACOLOGY, Vol: 33, Pages: 822-830, ISSN: 0269-8811
Colasanti A, Myers J, Helfer B, et al., 2019, Endogenous opioid release capacity in adult ADHD patients: a pilot study with PET and [C-11] carfentanil, 29th International Symposium on Cerebral Blood Flow, Metabolism and Function / 14th International Conference on Quantification of Brain Function with PET (BRAIN and BRAIN Pet), Publisher: SAGE PUBLICATIONS INC, Pages: 558-559, ISSN: 0271-678X
Wilson H, Dervenoulas G, Pagano G, et al., 2019, Evaluation of Imidazoline 2 binding sites reflecting astroglia pathology in Parkinson's disease: an in vivo [11C] BU99008 PET study, 5th Congress of the European-Academy-of-Neurology (EAN), Publisher: WILEY, Pages: 1005-1005, ISSN: 1351-5101
Roussakis A-A, Mohamed MA, Myers J, et al., 2019, Astrogliosis in Parkinson's disease dementia: a preliminary report with brain, 5th Congress of the European-Academy-of-Neurology (EAN), Publisher: WILEY, Pages: 890-890, ISSN: 1351-5101
Erritzoe D, Godlewska BR, Rizzo G, et al., 2019, Reduced serotonin release in patients with major depression: a PET study with [11C]Cimbi-36 and d-amphetamine challenge, 29th International Symposium on Cerebral Blood Flow, Metabolism and Function / 14th International Conference on Quantification of Brain Function with PET (BRAIN and BRAIN Pet), Publisher: SAGE PUBLICATIONS INC, Pages: 548-549, ISSN: 0271-678X
Kronenberg G, Desai D, Anghelescu I, et al., 2019, Tapering of SSRI treatment to mitigate withdrawal symptoms, LANCET PSYCHIATRY, Vol: 6, Pages: 560-562, ISSN: 2215-0374
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Wilson H, Niccolini F, Dervenoulas G, et al., 2019, Evaluation of imidazoline 2 binding sites reflecting astroglia pathology in Huntington's disease: an in vivo [11C] BU99008 PET study, 5th Congress of the European-Academy-of-Neurology (EAN), Publisher: WILEY, Pages: 317-318, ISSN: 1351-5101
Selvaraj S, Jauhar S, Baldwin DS, et al., 2019, Tapering of SSRI treatment to mitigate withdrawal symptoms., Lancet Psychiatry, Vol: 6, Pages: 560-561
Sessa B, Sakal C, O'Brien S, et al., 2019, First study of safety and tolerability of 3,4-methylenedioxymethamphetamine (MDMA)-assisted psychotherapy in patients with alcohol use disorder: preliminary data on the first four participants., BMJ Case Rep, Vol: 12
We present the preliminary data in an ongoing open-label safety and tolerability proof of concept study exploring the potential role for 3,4-methylenedioxymethamphetamine (MDMA)-assisted psychotherapy in treating patients with alcohol use disorder. At this stage, seven participants have completed the full 8-week MDMA-assisted psychotherapy course, including two therapy sessions each with MDMA. This paper focuses on the safety and tolerability of the therapeutic course for the first four participants to complete treatment. Longer-term outcomes of drinking behaviour will be presented later when the full project data are published. Results show all four participants have successfully tolerated the treatment. There have been no serious adverse events related to MDMA, no unexpected physiological responses to the MDMA sessions or changes to blood results or electrocardiograms, measured before and after the 8-week course. We conclude that the treatment is well- tolerated and are making plans to expand the project into a randomised placebo-controlled study.
Maron E, Baldwin DS, Balõtšev R, et 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.
Jauhar S, Hayes J, Goodwin GM, et al., 2019, Antidepressants, withdrawal, and addiction; where are we now?, JOURNAL OF PSYCHOPHARMACOLOGY, Vol: 33, Pages: 655-659, ISSN: 0269-8811
Nutt D, 2019, ESSAY Why medical cannabis is still out of patients' reach-an essay by David Nutt, BMJ-BRITISH MEDICAL JOURNAL, Vol: 365, ISSN: 1756-1833
Palmer E, Tyacke R, Sastre M, et 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.
Sessa B, Higbed L, Nutt D, 2019, A Review of 3,4-methylenedioxymethamphetamine (MDMA)-Assisted Psychotherapy, FRONTIERS IN PSYCHIATRY, Vol: 10, ISSN: 1664-0640
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Nutt DJ, Gual A, Anderson P, et al., 2019, Why Less Is Always More in the Treatment of Alcohol Use Disorders., JAMA Psychiatry
Goodwin GM, Nutt D, 2019, Antidepressants; what's the beef?, ACTA NEUROPSYCHIATRICA, Vol: 31, Pages: 59-60, ISSN: 1601-5215
Lingford-Hughes A, Durant C, Paterson L, et 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
Haijen ECHM, Kaelen M, Roseman L, et 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
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.
Roseman L, Demetriou L, Wall M, et 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.
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
Erritzoe D, Roseman L, Nour MM, et 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.
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