Human brain effects of DMT assessed via EEG-fMRI.

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.

A role for the serotonin 2A receptor in the expansion and functioning of human transmodal cortex.

Integrating independent but converging lines of research on brain function and neurodevelopment across scales, this article proposes that serotonin 2A receptor (5-HT2AR) signalling is an evolutionary and developmental driver and potent modulator of the macroscale functional organization of the human cerebral cortex. A wealth of evidence indicates that the anatomical and functional organization of the cortex follows a unimodal-to-transmodal gradient. Situated at the apex of this processing hierarchy-where it plays a central role in the integrative processes underpinning complex, human-defining cognition-the transmodal cortex has disproportionately expanded across human development and evolution. Notably, the adult human transmodal cortex is especially rich in 5-HT2AR expression and recent evidence suggests that, during early brain development, 5-HT2AR signalling on neural progenitor cells stimulates their proliferation-a critical process for evolutionarily-relevant cortical expansion. Drawing on multimodal neuroimaging and cross-species investigations, we argue that, by contributing to the expansion of the human cortex and being prevalent at the apex of its hierarchy in the adult brain, 5-HT2AR signalling plays a major role in both human cortical expansion and functioning. Owing to its unique excitatory and downstream cellular effects, neuronal 5-HT2AR agonism promotes neuroplasticity, learning and cognitive and psychological flexibility in a context-(hyper)sensitive manner with therapeutic potential. Overall, we delineate a dual role of 5-HT2ARs in enabling both the expansion and modulation of the human transmodal cortex.

Trial of Psilocybin versus Escitalopram for Depression.

BACKGROUND: Psilocybin may have antidepressant properties, but direct comparisons between psilocybin and established treatments for depression are lacking. METHODS: In a phase 2, double-blind, randomized, controlled trial involving patients with long-standing, moderate-to-severe major depressive disorder, we compared psilocybin with escitalopram, a selective serotonin-reuptake inhibitor, over a 6-week period. Patients were assigned in a 1:1 ratio to receive two separate doses of 25 mg of psilocybin 3 weeks apart plus 6 weeks of daily placebo (psilocybin group) or two separate doses of 1 mg of psilocybin 3 weeks apart plus 6 weeks of daily oral escitalopram (escitalopram group); all the patients received psychological support. The primary outcome was the change from baseline in the score on the 16-item Quick Inventory of Depressive Symptomatology-Self-Report (QIDS-SR-16; scores range from 0 to 27, with higher scores indicating greater depression) at week 6. There were 16 secondary outcomes, including QIDS-SR-16 response (defined as a reduction in score of >50%) and QIDS-SR-16 remission (defined as a score of ≤5) at week 6. RESULTS: A total of 59 patients were enrolled; 30 were assigned to the psilocybin group and 29 to the escitalopram group. The mean scores on the QIDS-SR-16 at baseline were 14.5 in the psilocybin group and 16.4 in the escitalopram group. The mean (±SE) changes in the scores from baseline to week 6 were -8.0±1.0 points in the psilocybin group and -6.0±1.0 in the escitalopram group, for a between-group difference of 2.0 points (95% confidence interval [CI], -5.0 to 0.9) (P = 0.17). A QIDS-SR-16 response occurred in 70% of the patients in the psilocybin group and in 48% of those in the escitalopram group, for a between-group difference of 22 percentage points (95% CI, -3 to 48); QIDS-SR-16 remission occurred in 57% and 28%, respectively, for a between-group difference of 28 percentage points (95% CI, 2 to 54). Other secondary outcomes generally favored psilocybin over escitalopram, but the analyses were not corrected for multiple comparisons. The incidence of adverse events was similar in the trial groups. CONCLUSIONS: On the basis of the change in depression scores on the QIDS-SR-16 at week 6, this trial did not show a significant difference in antidepressant effects between psilocybin and escitalopram in a selected group of patients. Secondary outcomes generally favored psilocybin over escitalopram, but the analyses of these outcomes lacked correction for multiple comparisons. Larger and longer trials are required to compare psilocybin with established antidepressants. (Funded by the Alexander Mosley Charitable Trust and Imperial College London's Centre for Psychedelic Research; ClinicalTrials.gov number, NCT03429075.).

Personality change in a trial of psilocybin therapy v. escitalopram treatment for depression.

BACKGROUND: Psilocybin Therapy (PT) is being increasingly studied as a psychiatric intervention. Personality relates to mental health and can be used to probe the nature of PT's therapeutic action. METHODS: In a phase 2, double-blind, randomized, active comparator controlled trial involving patients with moderate-to-severe major depressive disorder, we compared psilocybin with escitalopram, over a core 6-week trial period. Five-Factor model personality domains, Big Five Aspect Scale Openness aspects, Absorption, and Impulsivity were measured at Baseline, Week 6, and Month 6 follow-up. RESULTS: PT was associated with decreases in neuroticism (B = -0.63), introversion (B = -0.38), disagreeableness (B = -0.47), impulsivity (B = -0.40), and increases in absorption (B = 0.32), conscientiousness (B = 0.30), and openness (B = 0.23) at week 6, with neuroticism (B = -0.47) and disagreeableness (B = -0.41) remaining decreased at month 6. Escitalopram Treatment (ET) was associated with decreases in neuroticism (B = -0.38), disagreeableness (B = -0.26), impulsivity (B = -0.35), and increases in openness (B = 0.28) at week 6, with neuroticism (B = -0.46) remaining decreased at month 6. No significant between-condition differences were observed. CONCLUSIONS: Personality changes across both conditions were in a direction consistent with improved mental health. With the possible exception of trait absorption, there were no compelling between-condition differences warranting conclusions regarding a selective action of PT (v. ET) on personality; however, post-ET changes in personality were significantly moderated by pre-trial positive expectancy for escitalopram, whereas expectancy did not moderate response to PT.

Neuroimaging in psychedelic drug development: past, present, and future.

Psychedelic therapy (PT) is an emerging paradigm with great transdiagnostic potential for treating psychiatric disorders, including depression, addiction, post-traumatic stress disorder, and potentially others. 'Classic' serotonergic psychedelics, such as psilocybin and lysergic acid diethylamide (LSD), which have a key locus of action at the 5-HT2A receptor, form the main focus of this movement, but substances including ketamine, 3,4-Methylenedioxymethamphetamine (MDMA) and ibogaine also hold promise. The modern phase of development of these treatment modalities in the early 21st century has occurred concurrently with the wider use of advanced human neuroscientific research methods; principally neuroimaging. This can potentially enable assessment of drug and therapy brain effects with greater precision and quantification than any previous novel development in psychiatric pharmacology. We outline the major trends in existing data and suggest the modern development of PT has benefitted greatly from the use of neuroimaging. Important gaps in existing knowledge are identified, namely: the relationship between acute drug effects and longer-term (clinically-relevant) effects, the precise characterisation of effects at the 5-HT2A receptor and relationships with functional/clinical effects, and the possible impact of these compounds on neuroplasticity. A road-map for future research is laid out, outlining clinical studies which will directly address these three questions, principally using combined Positron Emission Tomography (PET) and Magnetic Resonance Imaging (MRI) methods, plus other adjunct techniques. Multimodal (PET/MRI) studies using modern PET techniques such as the 5-HT2A-selective ligand [11 C]Cimbi-36 (and other ligands sensitive to neuroplasticity changes) alongside MRI measures of brain function would provide a 'molecular-functional-clinical bridge' in understanding. Such results would help to resolve some of these questions and provide a firmer foundation for the ongoing development of PT.

LSD-induced changes in the functional connectivity of distinct thalamic nuclei.

The role of the thalamus in mediating the effects of lysergic acid diethylamide (LSD) was recently proposed in a model of communication and corroborated by imaging studies. However, a detailed analysis of LSD effects on nuclei-resolved thalamocortical connectivity is still missing. Here, in a group of healthy volunteers, we evaluated whether LSD intake alters the thalamocortical coupling in a nucleus-specific manner. Structural and resting-state functional Magnetic Resonance Imaging (MRI) data were acquired in a placebo-controlled study on subjects exposed to acute LSD administration. Structural MRI was used to parcel the thalamus into its constituent nuclei based on individual anatomy. Nucleus-specific changes of resting-state functional MRI (rs-fMRI) connectivity were mapped using a seed-based approach. LSD intake selectively increased the thalamocortical functional connectivity (FC) of the ventral complex, pulvinar, and non-specific nuclei. Functional coupling was increased between these nuclei and sensory cortices that include the somatosensory and auditory networks. The ventral and pulvinar nuclei also exhibited increased FC with parts of the associative cortex that are dense in serotonin type 2A receptors. These areas are hyperactive and hyper-connected upon LSD intake. At subcortical levels, LSD increased the functional coupling among the thalamus's ventral, pulvinar, and non-specific nuclei, but decreased the striatal-thalamic connectivity. These findings unravel some LSD effects on the modulation of subcortical-cortical circuits and associated behavioral outputs.

Cost-effectiveness of psilocybin-assisted therapy for severe depression: exploratory findings from a decision analytic model.

BACKGROUND: There is growing evidence to support the use of the psychedelic drug psilocybin for difficult-to-treat depression. This paper compares the cost-effectiveness of psilocybin-assisted psychotherapy (PAP) with conventional medication, cognitive behavioural therapy (CBT), and the combination of conventional medication and CBT. METHODS: A decision model simulated patient events (response, remission, and relapse) following treatment. Data on probabilities, costs and quality-adjusted life years (QALYs) were derived from previous studies or from best estimates. Expected healthcare and societal costs and QALYs over a 6-month time period were calculated. Sensitivity analyses were used to address uncertainty in parameter estimates. RESULTS: The expected healthcare cost of PAP varied from £6132 to £7652 depending on the price of psilocybin. This compares to £3528 for conventional medication alone, £4250 for CBT alone, and £4197 for their combination. QALYs were highest for psilocybin (0.310), followed by CBT alone (0.283), conventional medication alone (0.278), and their combination (0.287). Psilocybin was shown to be cost-effective compared to the other therapies when the cost of therapist support was reduced by 50% and the psilocybin price was reduced from its initial value to £400 to £800 per person. From a societal perspective, psilocybin had improved cost-effectiveness compared to a healthcare perspective. CONCLUSIONS: Psilocybin has the potential to be a cost-effective therapy for severe depression. This depends on the level of psychological support that is given to patients receiving psilocybin and the price of the drug itself. Further data on long-term outcomes are required to improve the evidence base.

Relationship between astrocyte reactivity, using novel 11C-BU99008 PET, and glucose metabolism, grey matter volume and amyloid load in cognitively impaired individuals.

Post mortem neuropathology suggests that astrocyte reactivity may play a significant role in neurodegeneration in Alzheimer's disease. We explored this in vivo using multimodal PET and MRI imaging. Twenty subjects (11 older, cognitively impaired patients and 9 age-matched healthy controls) underwent brain scanning using the novel reactive astrocyte PET tracer 11C-BU99008, 18F-FDG and 18F-florbetaben PET, and T1-weighted MRI. Differences between cognitively impaired patients and healthy controls in regional and voxel-wise levels of astrocyte reactivity, glucose metabolism, grey matter volume and amyloid load were explored, and their relationship to each other was assessed using Biological Parametric Mapping (BPM). Amyloid beta (Aß)-positive patients showed greater 11C-BU99008 uptake compared to controls, except in the temporal lobe, whilst further increased 11C-BU99008 uptake was observed in Mild Cognitive Impairment subjects compared to those with Alzheimer's disease in the frontal, temporal and cingulate cortices. BPM correlations revealed that regions which showed reduced 11C-BU99008 uptake in Aß-positive patients compared to controls, such as the temporal lobe, also showed reduced 18F-FDG uptake and grey matter volume, although the correlations with 18F-FDG uptake were not replicated in the ROI analysis. BPM analysis also revealed a regionally-dynamic relationship between astrocyte reactivity and amyloid uptake: increased amyloid load in cortical association areas of the temporal lobe and cingulate cortices was associated with reduced 11C-BU99008 uptake, whilst increased amyloid uptake in primary motor and sensory areas (in which amyloid deposition occurs later) was associated with increased 11C-BU99008 uptake. These novel observations add to the hypothesis that while astrocyte reactivity may be triggered by early Aß-deposition, sustained pro-inflammatory astrocyte reactivity with greater amyloid deposition may lead to astrocyte dystrophy and amyloid-associated neuropathology such as grey matter atrophy and glucose hypometabolism, although the evidence for glucose hypometabolism here is less strong.

Sodium Oxybate for Alcohol Dependence: A Network Meta-Regression Analysis Considering Population Severity at Baseline and Treatment Duration.

AIMS: The estimated effect of sodium oxybate (SMO) in the treatment of alcohol dependence is heterogeneous. Population severity and treatment duration have been identified as potential effect modifiers. Population severity distinguishes heavy drinking patients with <14 days of abstinence before treatment initiation (high-severity population) from other patients (mild-severity population). Treatment duration reflects the planned treatment duration. This study aimed to systematically investigate the effect of these potential effect moderators on SMO efficacy in alcohol-dependent patients. METHODS: Network meta-regression allows for testing potential effect modifiers. It was selected to investigate the effect of the above factors on SMO efficacy defined as continuous abstinence (abstinence rate) and the percentage of days abstinent (PDA). Randomized controlled trials for alcohol dependence with at least one SMO group conducted in high-severity and mild-severity populations were assigned to a high-severity and mild-severity group of studies, respectively. RESULTS: Eight studies (1082 patients) were retained: four in the high-severity group and four in the mild-severity group. The high-severity group was associated with larger SMO effect sizes than the mild-severity group: abstinence rate risk ratio (RR) 3.16, P = 0.004; PDA +26.9%, P < 0.001. For PDA, longer treatment duration was associated with larger SMO effect size: +11.3% per extra month, P < 0.001. In the high-severity group, SMO showed benefit: abstinence rate RR 2.91, P = 0.03; PDA +16.9%, P < 0.001. In the mild-severity group, SMO showed benefit only in PDA for longer treatment duration: +23.9%, P < 0.001. CONCLUSIONS: In the retained studies with alcohol-dependent patients, high-severity population and longer treatment duration were associated with larger SMO effect sizes.

Imidazoline-I2 PET Tracers in Neuroimaging.

Targeting neuroinflammation, and in particular, microglial activation and astrocytosis, is a current area of the focus of new treatment interventions for a number of neurodegenerative disorders. Probing the roles of microglia and astrocytes in human disease requires the development of useful tools, such as PET imaging tools that are specific for the cell type(s) of interest. This review concentrates on the recent advances in the development of Imidazoline2 binding site (I2BS) PET tracers, which are purported to target astrocytes, and hence could represent key clinical imaging tools for targeting astrocytes in neurodegenerative disease. Five PET tracers for the I2BS are described in this review, with only one (11C-BU99008) being currently validated to GMP for clinical use, and data reported from healthy volunteers, Alzheimer's disease patients, and Parkinson's disease patients. The clinical data utilising 11C-BU99008 have revealed the potential early involvement of astrogliosis in neurodegeneration that might precede the activation of microglia, which, if confirmed, could provide a vital new means for potentially targeting neurodegeneration earlier in the disease course.

Effect of lysergic acid diethylamide (LSD) on reinforcement learning in humans.

BACKGROUND: The non-selective serotonin 2A (5-HT2A) receptor agonist lysergic acid diethylamide (LSD) holds promise as a treatment for some psychiatric disorders. Psychedelic drugs such as LSD have been suggested to have therapeutic actions through their effects on learning. The behavioural effects of LSD in humans, however, remain incompletely understood. Here we examined how LSD affects probabilistic reversal learning (PRL) in healthy humans. METHODS: Healthy volunteers received intravenous LSD (75 µg in 10 mL saline) or placebo (10 mL saline) in a within-subjects design and completed a PRL task. Participants had to learn through trial and error which of three stimuli was rewarded most of the time, and these contingencies switched in a reversal phase. Computational models of reinforcement learning (RL) were fitted to the behavioural data to assess how LSD affected the updating ('learning rates') and deployment of value representations ('reinforcement sensitivity') during choice, as well as 'stimulus stickiness' (choice repetition irrespective of reinforcement history). RESULTS: Raw data measures assessing sensitivity to immediate feedback ('win-stay' and 'lose-shift' probabilities) were unaffected, whereas LSD increased the impact of the strength of initial learning on perseveration. Computational modelling revealed that the most pronounced effect of LSD was the enhancement of the reward learning rate. The punishment learning rate was also elevated. Stimulus stickiness was decreased by LSD, reflecting heightened exploration. Reinforcement sensitivity differed by phase. CONCLUSIONS: Increased RL rates suggest LSD induced a state of heightened plasticity. These results indicate a potential mechanism through which revision of maladaptive associations could occur in the clinical application of LSD.

GABA-A receptor differences in schizophrenia: a positron emission tomography study using [11C]Ro154513.

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.

Astrocyte reactivity with late-onset cognitive impairment assessed in vivo using 11C-BU99008 PET and its relationship with amyloid load.

11C-BU99008 is a novel positron emission tomography (PET) tracer that enables selective imaging of astrocyte reactivity in vivo. To explore astrocyte reactivity associated with Alzheimer's disease, 11 older, cognitively impaired (CI) subjects and 9 age-matched healthy controls (HC) underwent 3T magnetic resonance imaging (MRI), 18F-florbetaben and 11C-BU99008 PET. The 8 amyloid (Aß)-positive CI subjects had higher 11C-BU99008 uptake relative to HC across the whole brain, but particularly in frontal, temporal, medial temporal and occipital lobes. Biological parametric mapping demonstrated a positive voxel-wise neuroanatomical correlation between 11C-BU99008 and 18F-florbetaben. Autoradiography using 3H-BU99008 with post-mortem Alzheimer's brains confirmed through visual assessment that increased 3H-BU99008 binding localised with the astrocyte protein glial fibrillary acid protein and was not displaced by PiB or florbetaben. This proof-of-concept study provides direct evidence that 11C-BU99008 can measure in vivo astrocyte reactivity in people with late-life cognitive impairment and Alzheimer's disease. Our results confirm that increased astrocyte reactivity is found particularly in cortical regions with high Aß load. Future studies now can explore how clinical expression of disease varies with astrocyte reactivity.

The prescriber's guide to classic MAO inhibitors (phenelzine, tranylcypromine, isocarboxazid) for treatment-resistant depression.

This article is a clinical guide which discusses the "state-of-the-art" usage of the classic monoamine oxidase inhibitor (MAOI) antidepressants (phenelzine, tranylcypromine, and isocarboxazid) in modern psychiatric practice. The guide is for all clinicians, including those who may not be experienced MAOI prescribers. It discusses indications, drug-drug interactions, side-effect management, and the safety of various augmentation strategies. There is a clear and broad consensus (more than 70 international expert endorsers), based on 6 decades of experience, for the recommendations herein exposited. They are based on empirical evidence and expert opinion-this guide is presented as a new specialist-consensus standard. The guide provides practical clinical advice, and is the basis for the rational use of these drugs, particularly because it improves and updates knowledge, and corrects the various misconceptions that have hitherto been prominent in the literature, partly due to insufficient knowledge of pharmacology. The guide suggests that MAOIs should always be considered in cases of treatment-resistant depression (including those melancholic in nature), and prior to electroconvulsive therapy-while taking into account of patient preference. In selected cases, they may be considered earlier in the treatment algorithm than has previously been customary, and should not be regarded as drugs of last resort; they may prove decisively effective when many other treatments have failed. The guide clarifies key points on the concomitant use of incorrectly proscribed drugs such as methylphenidate and some tricyclic antidepressants. It also illustrates the straightforward "bridging" methods that may be used to transition simply and safely from other antidepressants to MAOIs.

Acute effects of cannabis on speech illusions and psychotic-like symptoms: two studies testing the moderating effects of cannabidiol and adolescence.

BACKGROUND: Acute cannabis administration can produce transient psychotic-like effects in healthy individuals. However, the mechanisms through which this occurs and which factors predict vulnerability remain unclear. We investigate whether cannabis inhalation leads to psychotic-like symptoms and speech illusion; and whether cannabidiol (CBD) blunts such effects (study 1) and adolescence heightens such effects (study 2). METHODS: Two double-blind placebo-controlled studies, assessing speech illusion in a white noise task, and psychotic-like symptoms on the Psychotomimetic States Inventory (PSI). Study 1 compared effects of Cann-CBD (cannabis containing Δ-9-tetrahydrocannabinol (THC) and negligible levels of CBD) with Cann+CBD (cannabis containing THC and CBD) in 17 adults. Study 2 compared effects of Cann-CBD in 20 adolescents and 20 adults. All participants were healthy individuals who currently used cannabis. RESULTS: In study 1, relative to placebo, both Cann-CBD and Cann+CBD increased PSI scores but not speech illusion. No differences between Cann-CBD and Cann+CBD emerged. In study 2, relative to placebo, Cann-CBD increased PSI scores and incidence of speech illusion, with the odds of experiencing speech illusion 3.1 (95% CIs 1.3-7.2) times higher after Cann-CBD. No age group differences were found for speech illusion, but adults showed heightened effects on the PSI. CONCLUSIONS: Inhalation of cannabis reliably increases psychotic-like symptoms in healthy cannabis users and may increase the incidence of speech illusion. CBD did not influence psychotic-like effects of cannabis. Adolescents may be less vulnerable to acute psychotic-like effects of cannabis than adults.

Blunted endogenous opioid release following an oral dexamphetamine challenge in abstinent alcohol-dependent individuals.

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.

Baseline severity and the prediction of placebo response in clinical trials for alcohol dependence: A meta-regression analysis to develop an enrichment strategy.

BACKGROUND: There is considerable unexplained variability in alcohol abstinence rates (AR) in the placebo groups of randomized controlled trials (RCTs) for alcohol dependence (AD). This is of particular interest because placebo responses correlate negatively with treatment effect size. Recent evidence suggests that the placebo response is lower in very heavy drinkers who show no "spontaneous improvement" prior to treatment initiation (high-severity population) than in a mild-severity population and in studies with longer treatment duration. We systematically investigated the relationship between population severity, treatment duration, and the placebo response in AR to inform a strategy aimed at reducing the placebo response and thereby increasing assay sensitivity in RCTs for AD. METHODS: We conducted a systematic literature review on placebo-controlled RCTs for AD.We assigned retained RCTs to high- or mild-severity groups of studies based on baseline drinking risk levels and abstinence duration before treatment initiation. We tested the effects of population severity and treatment duration on the placebo response in AR using meta-regression analysis. RESULTS: Among the 19 retained RCTs (comprising 1996 placebo-treated patients), 11 trials were high-severity and 8 were mild-severity RCTs. The between-study variability in AR was lower in the high-severity than in the mild-severity studies (interquartile range: 7.4% vs. 20.9%). The AR in placebo groups was dependent on population severity (p = 0.004) and treatment duration (p = 0.017) and was lower in the high-severity studies (16.8% at 3 months) than the mild-severity studies (36.7% at 3 months). CONCLUSIONS: Pharmacological RCTs for AD should select high-severity patients to decrease the magnitude and variability in the placebo effect and and improve the efficiency of drug development efforts for AD.

Therapeutic effects of classic serotonergic psychedelics: A systematic review of modern-era clinical studies.

OBJECTIVE: To conduct a systematic review of modern-era (post-millennium) clinical studies assessing the therapeutic effects of serotonergic psychedelics drugs for mental health conditions. Although the main focus was on efficacy and safety, study characteristics, duration of antidepressants effects across studies, and the role of the subjective drug experiences were also reviewed and presented. METHOD: A systematic literature search (1 Jan 2000 to 1 May 2020) was conducted in PubMed and PsychINFO for studies of patients undergoing treatment with a serotonergic psychedelic. RESULTS: Data from 16 papers, representing 10 independent psychedelic-assisted therapy trials (psilocybin = 7, ayahuasca = 2, LSD = 1), were extracted, presented in figures and tables, and narratively synthesized and discussed. Across these studies, a total of 188 patients suffering either cancer- or illness-related anxiety and depression disorders (C/I-RADD), major depressive disorder (MDD), obsessive-compulsive disorder (OCD) or substance use disorder (SUD) were included. The reviewed studies established feasibility and evidence of safety, alongside promising early data of efficacy in the treatment of depression, anxiety, OCD, and tobacco and alcohol use disorders. For a majority of patients, the therapeutic effects appeared to be long-lasting (weeks-months) after only 1 to 3 treatment session(s). All studies were conducted in line with guidelines for the safe conduct of psychedelic therapy, and no severe adverse events were reported. CONCLUSION: The resurrection of clinical psychedelic research provides early evidence for treatment efficacy and safety for a range of psychiatric conditions, and constitutes an exciting new treatment avenue in a health area with major unmet needs.

The dopamine theory of addiction: 40 years of highs and lows.

For several decades, addiction has come to be viewed as a disorder of the dopamine neurotransmitter system; however, this view has not led to new treatments. In this Opinion article, we review the origins of the dopamine theory of addiction and discuss the ability of addictive drugs to elicit the release of dopamine in the human striatum. There is robust evidence that stimulants increase striatal dopamine levels and some evidence that alcohol may have such an effect, but little evidence, if any, that cannabis and opiates increase dopamine levels. Moreover, there is good evidence that striatal dopamine receptor availability and dopamine release are diminished in individuals with stimulant or alcohol dependence but not in individuals with opiate, nicotine or cannabis dependence. These observations have implications for understanding reward and treatment responses in various addictions.

Dynamical exploration of the repertoire of brain networks at rest is modulated by psilocybin.

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.