BACKGROUND Psilocybin may have antidepressant properties, but direct comparisons between psilocyb... more 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.
Repeated withdrawal from alcohol is clinically associated with progressive cognitive impairment. ... more Repeated withdrawal from alcohol is clinically associated with progressive cognitive impairment. Microglial activation occurring during pre-clinical models of alcohol withdrawal is associated with learning deficits. We investigated whether there was microglial activation in recently detoxified alcohol-dependent patients (ADP), using [ 11 C]PBR28 positron emission tomography (PET), selective for the 18kDa translocator protein (TSPO) highly expressed in activated microglia and astrocytes. We investigated the relationship between microglial activation and cognitive performance. Twenty healthy control (HC) subjects (45 ± 13; M:F 14:6) and nine ADP (45 ± 6, M:F 9:0) were evaluated. Dynamic PET data were acquired for 90 min following an injection of 331 ± 15 MBq [ 11 C]PBR28. Regional volumes of distribution (V T) for regions of interest (ROIs) identified a priori were estimated using a two-tissue compartmental model with metabolite-corrected arterial plasma input function. ADP had an~20% lower [ 11 C]PBR28 V T, in the hippocampus (F(1,24) 5.694; P = 0.025), but no difference in V T in other ROIs. Hippocampal [ 11 C]PBR28 V T was positively correlated with verbal memory performance in a combined group of HC and ADP (r = 0.720, P o 0.001), an effect seen in HC alone (r = 0.738; P = 0.001) but not in ADP. We did not find evidence for increased microglial activation in ADP, as seen pre-clinically. Instead, our findings suggest lower glial density or an altered activation state with lower TSPO expression. The correlation between verbal memory and [ 11 C]PBR28 V T , raises the possibility that abnormalities of glial function may contribute to cognitive impairment in ADP.
Drug and alcohol dependence are global problems with substantial societal costs. There are few tr... more Drug and alcohol dependence are global problems with substantial societal costs. There are few treatments for relapse prevention and therefore a pressing need for further study of brain mechanisms underpinning relapse circuitry. The Imperial College Cambridge Manchester (ICCAM) platform study is an experimental medicine approach to this problem: using functional magnetic resonance imaging (fMRI) techniques and selective pharmacological tools, it aims to explore the neuropharmacology of putative relapse pathways in cocaine, alcohol, opiate dependent, and healthy individuals to inform future drug development. Addiction studies typically involve small samples because of recruitment difficulties and attrition. We established the platform in three centres to assess the feasibility of a multisite approach to address these issues. Pharmacological modulation of reward, impulsivity and emotional reactivity were investigated in a monetary incentive delay task, an inhibitory control task, and an evocative images task, using selective antagonists for µ-opioid, dopamine D3 receptor (DRD3) and neurokinin 1 (NK1) receptors (naltrexone, GSK598809, vofopitant/aprepitant), in a placebo-controlled, randomised, crossover design. In two years, 609 scans were performed, with 155 individuals scanned at baseline. Attrition was low and the majority of individuals were sufficiently motivated to complete all five sessions (n=87). We describe herein the study design, main aims, recruitment numbers, sample characteristics, and explain the test hypotheses and anticipated study outputs.
Animal studies support the role of the dopamine D3 receptor (DRD3) in alcohol reinforcement or li... more Animal studies support the role of the dopamine D3 receptor (DRD3) in alcohol reinforcement or liking. Sustained voluntary alcohol drinking in rats has been associated with an upregulation of striatal DRD3 gene expression and selective blockade of DRD3 reduces ethanol preference, consumption, and cue-induced reinstatement. In vivo measurement of DRD3 in the living human brain has not been possible until recently owing to a lack of suitable tools. In this study, DRD3 status was assessed for the first time in human alcohol addiction. Brain DRD3 availability was compared between 16 male abstinent alcohol-dependent patients and 13 healthy non-dependent age-matched males using the DRD3-preferring agonist positron emission tomography (PET) radioligand [ 11 C]PHNO with and without blockade with a selective DRD3 antagonist (GSK598809 60 mg p.o.). In striatal regions of interest, where the [ 11 C]PHNO PET signal represents primarily DRD2 binding, no differences were seen in [ 11 C]PHNO binding between the groups at baseline. However, baseline [ 11 C]PHNO binding was higher in alcohol-dependent patients in hypothalamus (V T : 16.5±4 vs 13.7±2.9, p ¼ 0.040), a region in which the [ 11 C]PHNO signal almost entirely reflects DRD3 availability. The reductions in regional receptor binding (V T) following a single oral dose of GSK598809 (60 mg) were consistent with those observed in previous studies across all regions. There were no differences in regional changes in V T following DRD3 blockade between the two groups, indicating that the regional fractions of DRD3 are similar in the two groups, and the increased [ 11 C]PHNO binding in the hypothalamus in alcohol-dependent patients is explained by elevated DRD3 in this group. Although we found no difference between alcohol-dependent patients and controls in striatal DRD3 levels, increased DRD3 binding in the hypothalamus of alcohol-dependent patients was observed. This may be relevant to the development of future therapeutic strategies to treat alcohol abuse.
Pathological gambling is a psychiatric disorder and the first recognized behavioral addiction, wi... more Pathological gambling is a psychiatric disorder and the first recognized behavioral addiction, with similarities to substance use disorders but without the confounding effects of drug-related brain changes. Pathophysiology within the opioid receptor system is increasingly recognized in substance dependence, with higher mu-opioid receptor (MOR) availability reported in alcohol, cocaine and opiate addiction. Impulsivity, a risk factor across the addictions, has also been found to be associated with higher MOR availability. The aim of this study was to characterize baseline MOR availability and endogenous opioid release in pathological gamblers (PG) using [ 11 C]carfentanil PET with an oral amphetamine challenge. Fourteen PG and 15 healthy volunteers (HV) underwent two [ 11 C]carfentanil PET scans, before and after an oral administration of 0.5 mg/kg of d-amphetamine. The change in [ 11 C]carfentanil binding between baseline and post-amphetamine scans (ΔBP ND) was assessed in 10 regions of interest (ROI). MOR availability did not differ between PG and HV groups. As seen previously, oral amphetamine challenge led to significant reductions in [ 11 C]carfentanil BP ND in 8/10 ROI in HV. PG demonstrated significant blunting of opioid release compared with HV. PG also showed blunted amphetamine-induced euphoria and alertness compared with HV. Exploratory analysis revealed that impulsivity positively correlated with caudate baseline BP ND in PG only. This study provides the first evidence of blunted endogenous opioid release in PG. Our findings are consistent with growing evidence that dysregulation of endogenous opioids may have an important role in the pathophysiology of addictions.
Background: 3,4-Methylenedioxymethamphetamine (MDMA) is being actively researched as an adjunct t... more Background: 3,4-Methylenedioxymethamphetamine (MDMA) is being actively researched as an adjunct to psychotherapy. It may be beneficial to trust, empathy and cooperative behaviour due to its acute prosocial effects. Aim: To test (a) the acute effects of MDMA on measures of empathy, trust and cooperative behaviour, and (b) subacute changes in mood three days after MDMA administration. Methods: Twenty-five participants (n=7 female), participated in this double-blind, repeated-measures, placebo-controlled experiment. Participants attended two acute sessions, one week apart. Each acute session was followed by a subacute session three days later. Participants received placebo (100 mg ascorbic acid) during one acute session, and MDMA (100 mg MDMA-HCl) at the other, with order counterbalanced. Participants completed the following tasks assessing prosocial behaviour: a trust investment task, a trustworthy face rating task, an empathic stories task, a public project game, a dictator game and an ultimatum game. Participants reported subjective effects. Blood was taken pre-drug, 2 and 4 hours post-drug, and tested for plasma MDMA levels. Results: MDMA acutely increased self-reported 'closeness to others' and 'euphoria' and increased plasma concentrations of MDMA. MDMA did not significantly change task-based empathy, trust or cooperative behaviour. Using Bayesian analyses, we found evidence that MDMA and placebo did not differ in their effects on empathy and cooperative behaviour. MDMA did not significantly change subacute mood and this was supported by our Bayesian analyses. Conclusion: Despite augmentation in plasma MDMA levels and subjective drug effects, we found no increase in prosocial behaviour in a laboratory setting.
The International Journal of Neuropsychopharmacology, Dec 17, 2013
3,4-methylenedioxymethamphetamine (MDMA) is a potent monoamine-releaser that is widely used as a ... more 3,4-methylenedioxymethamphetamine (MDMA) is a potent monoamine-releaser that is widely used as a recreational drug. Preliminary work has supported the potential of MDMA in psychotherapy for post-traumatic stress disorder (PTSD). The neurobiological mechanisms underlying its putative efficacy are, however, poorly understood. Psychotherapy for PTSD usually requires that patients revisit traumatic memories, and it has been argued that this is easier to do under MDMA. Functional magnetic resonance imaging (fMRI) was used to investigate the effect of MDMA on recollection of favourite and worst autobiographical memories (AMs). Nineteen participants (five females) with previous experience with MDMA performed a blocked AM recollection (AMR) paradigm after ingestion of 100 mg of MDMA-HCl or ascorbic acid (placebo) in a double-blind, repeatedmeasures design. Memory cues describing participants' AMs were read by them in the scanner. Favourite memories were rated as significantly more vivid, emotionally intense and positive after MDMA than placebo and worst memories were rated as less negative. Functional MRI data from 17 participants showed robust activations to AMs in regions known to be involved in AMR. There was also a significant effect of memory valence: hippocampal regions showed preferential activations to favourite memories and executive regions to worst memories. MDMA augmented activations to favourite memories in the bilateral fusiform gyrus and somatosensory cortex and attenuated activations to worst memories in the left anterior temporal cortex. These findings are consistent with a positive emotional-bias likely mediated by MDMA's pro-monoaminergic pharmacology.
Positron emission tomography (PET) enables non-invasive estimation of neurotransmitter fluctuatio... more 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, [ 11 C]CIMBI-36, and a d-amphetamine challenge to evaluate synaptic 5-HT changes in the living human brain. Seventeen healthy male volunteers received [ 11 C]CIMBI-36 PET scans before and 3 h after an oral dose of d-amphetamine (0.5 mg/kg). Dynamic PET data were acquired over 90 min, and the total volume of distribution (V T) in the frontal cortex and the cerebellum derived from a kinetic analysis using MA1. The frontal cortex binding potential (BP ND frontal) was calculated as (V T frontal /V T cerebellum) − 1. ΔBP ND frontal = 1 − (BP ND frontal post-dose/BP ND frontal baseline) 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 [ 11 C]CIMBI-36 BP ND frontal. Following d-amphetamine administration, [ 11 C]CIMBI-36 BP ND frontal was reduced by 14 ± 13% (p = 0.002). Similar effects were observed in other cortical regions examined in an exploratory analysis. [ 11 C]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.
As a behavioural addiction, gambling disorder (GD) provides an opportunity to characterize addict... more As a behavioural addiction, gambling disorder (GD) provides an opportunity to characterize addictive processes without the potentially confounding effects of chronic excessive drug and alcohol exposure. Impulsivity is an established precursor to such addictive behaviours, and GD is associated with greater impulsivity. There is also evidence of GABAergic dysregulation in substance addiction and in impulsivity. This study therefore investigated GABAA receptor availability in 15 individuals with GD and 19 healthy volunteers (HV) using [11C]Ro15‐4513, a relatively selective α5 benzodiazepine receptor PET tracer and its relationship with impulsivity. We found significantly higher [11C]Ro15‐4513 total distribution volume (VT) in the right hippocampus in the GD group compared with HV. We found higher levels of the ‘Negative Urgency’ construct of impulsivity in GD, and these were positively associated with higher [11C]Ro15‐4513 VT in the amygdala in the GD group; no such significant correla...
Journal of psychopharmacology (Oxford, England), Jan 5, 2015
Drug and alcohol dependence are global problems with substantial societal costs. There are few tr... more Drug and alcohol dependence are global problems with substantial societal costs. There are few treatments for relapse prevention and therefore a pressing need for further study of brain mechanisms underpinning relapse circuitry. The Imperial College Cambridge Manchester (ICCAM) platform study is an experimental medicine approach to this problem: using functional magnetic resonance imaging (fMRI) techniques and selective pharmacological tools, it aims to explore the neuropharmacology of putative relapse pathways in cocaine, alcohol, opiate dependent, and healthy individuals to inform future drug development. Addiction studies typically involve small samples because of recruitment difficulties and attrition. We established the platform in three centres to assess the feasibility of a multisite approach to address these issues. Pharmacological modulation of reward, impulsivity and emotional reactivity were investigated in a monetary incentive delay task, an inhibitory control task, and ...
Background: The serotonin 5-HT2A receptor is suspected to be involved in a number of psychiatric ... more Background: The serotonin 5-HT2A receptor is suspected to be involved in a number of psychiatric disorders, including schizophrenia. In particular, atypical antipsychotics have antagonistic effects on the 5-HT2A receptors pointing at a specific role of the 5-HT2A receptor in the pathophysiology of this disease. The aim of this study is to investigate the 5-HT2A binding in neuroleptic-naive schizophrenic patients. Methods: Fifteen unmedicated subjects diagnosed with schizophrenic disorder (27.5 T 4.5), 11 males and 4 females, and 15 healthy control subjects matched for age (28.5 T 5.7) and gender underwent a 40 min PET study using the 5-HT2A antagonist, [F-18]altanserin, as a radioligand. PET images were co-registered to 3 T MRIs for each individual subject, and ROIs were applied automatically onto the individual MRIs and PET images. Cerebellum was used as a reference region. The binding potential of specific tracer binding (BP1) was used as the outcome measure. Results: An increase in 5-HT2A receptor binding in the caudate nucleus was detected in the group of schizophrenic patients (0.7 T 0.1) when compared to the healthy controls (0.5 T 0.3), P = 0.02. No significant between group difference was seen in cortical receptor distribution. Conclusion: Dysregulations of mesocorticostriatal pathways are known to be involved in the pathophysiology of schizophrenia, but in vivo dysregulation of serotonin 5-HT2A receptor has not previously been detected in basal ganglia. Whether the shown elevation of 5-HT2A binding in caudate of schizophrenic patients is a primary pathophysiological disturbance in this disorder or rather secondary to changes in endogenous serotonin levels will require further investigation.
Poor behavioral inhibition is a common feature of neurological and psychiatric disorders. Success... more Poor behavioral inhibition is a common feature of neurological and psychiatric disorders. Successful inhibition of a prepotent response in 'NoGo' paradigms requires the integrity of both the inferior frontal gyrus (IFG) and the serotonergic system. We investigated individual differences in serotonergic regulation of response inhibition. In 24 healthy adults, we used 18 F-altanserin positron emission tomography to assess cerebral 5-HT 2A receptors, which have been related to impulsivity. We then investigated the impact of two acute manipulations of brain serotonin levels on behavioral and neural correlates of inhibition using intravenous citalopram and acute tryptophan depletion during functional magnetic resonance imaging. We adapted the NoGo paradigm to isolate effects on inhibition per se as opposed to other aspects of the NoGo paradigm. Successful NoGo inhibition was associated with greater activation of the right IFG compared to control trials with alternative responses, indicating that the IFG is activated with inhibition in NoGo trials rather than other aspects of invoked cognitive control. Activation of the left IFG during NoGo trials was greater with citalopram than acute tryptophan depletion. Moreover, with the NoGo-type of response inhibition, the right IFG displayed an interaction between the type of serotonergic challenge and neocortical 5-HT 2A receptor binding. Specifically, acute tryptophan depletion (ATD) produced a relatively larger NoGo response in the right IFG in subjects with low 5-HT 2A BP P but reduced the NoGo response in those with high 5-HT 2A BP P. These links between serotonergic function and response inhibition in healthy subjects may help to interpret serotonergic abnormalities underlying impulsivity in neuropsychiatric disorders.
The International Journal of Neuropsychopharmacology, 2013
3,4-methylenedioxymethamphetamine (MDMA) is a potent monoamine-releaser that is widely used as a ... more 3,4-methylenedioxymethamphetamine (MDMA) is a potent monoamine-releaser that is widely used as a recreational drug. Preliminary work has supported the potential of MDMA in psychotherapy for post-traumatic stress disorder (PTSD). The neurobiological mechanisms underlying its putative efficacy are, however, poorly understood. Psychotherapy for PTSD usually requires that patients revisit traumatic memories, and it has been argued that this is easier to do under MDMA. Functional magnetic resonance imaging (fMRI) was used to investigate the effect of MDMA on recollection of favourite and worst autobiographical memories (AMs). Nineteen participants (five females) with previous experience with MDMA performed a blocked AM recollection (AMR) paradigm after ingestion of 100 mg of MDMA-HCl or ascorbic acid (placebo) in a double-blind, repeatedmeasures design. Memory cues describing participants' AMs were read by them in the scanner. Favourite memories were rated as significantly more vivid, emotionally intense and positive after MDMA than placebo and worst memories were rated as less negative. Functional MRI data from 17 participants showed robust activations to AMs in regions known to be involved in AMR. There was also a significant effect of memory valence: hippocampal regions showed preferential activations to favourite memories and executive regions to worst memories. MDMA augmented activations to favourite memories in the bilateral fusiform gyrus and somatosensory cortex and attenuated activations to worst memories in the left anterior temporal cortex. These findings are consistent with a positive emotional-bias likely mediated by MDMA's pro-monoaminergic pharmacology.
Background: We aimed to demonstrate a pharmacologically stimulated endogenous opioid release in t... more Background: We aimed to demonstrate a pharmacologically stimulated endogenous opioid release in the living human brain by evaluating the effects of amphetamine administration on [ 11 C]carfentanil binding with positron emission tomography (PET). Methods: Twelve healthy male volunteers underwent [ 11 C]carfentanil PET before and 3 hours after a single oral dose of d-amphetamine (either a "high" dose, .5 mg/kg, or a sub-pharmacological "ultra-low" dose, 1.25 mg total dose or approximately .017 mg/kg). Reductions in [ 11 C]carfentanil binding from baseline to post-amphetamine scans (⌬BP ND) after the "high" and "ultra-low" amphetamine doses were assessed in 10 regions of interest. Results: [ 11 C]carfentanil binding was reduced after the "high" but not the "ultra-low" amphetamine dose in the frontal cortex, putamen, caudate, thalamus, anterior cingulate, and insula. Conclusions: Our findings indicate that oral amphetamine administration induces endogenous opioid release in different areas of human brain, including basal ganglia, frontal cortex areas, and thalamus. The combination of an amphetamine challenge and [ 11 C]carfentanil PET is a practical and robust method to probe the opioid system in the living human brain.
The American Journal of Drug and Alcohol Abuse, 2013
Anxiety has been linked to initiation, maintenance and relapse of alcohol dependence. Neurobiolog... more Anxiety has been linked to initiation, maintenance and relapse of alcohol dependence. Neurobiological models of anxiety have proposed important roles for amygdala-insula and amygdala-medial prefrontal cortex interactions in the generation and regulation of anxiety states, respectively. This study tested the hypotheses that abstinent alcohol-dependent patients would show a disruption of synchrony in these circuits as measured by resting state functional MRI. The study examined recently abstinent (n = 13), longer-term abstinent (n = 16) alcohol-dependent patients and healthy controls (n = 22). Resting-state synchrony (RSS) was examined in specific circuits, where degree of synchrony has been found to correlate with state anxiety levels in previous studies. Alcohol-dependent patients showed significantly elevated scores on anxiety and depression inventories compared with controls. No significant group differences in synchrony were observed between right amygdala and right ventromedial prefrontal cortex (vmPFC), between left amygdala and left vmPFC, or, after correction for multiple comparisons, right amygdala and dorsomedial prefrontal cortex (dmPFC). However, significantly decreased positive synchrony was found between left basolateral amygdala and left anterior insula, in patients relative to controls. Both early and longer-term abstinent alcohol-dependent patients showed increased anxiety levels relative to controls and altered resting state synchrony in circuits previously linked to state anxiety. Notably, the significant group differences in synchrony were in the opposite direction to our predictions based on the literature. These results may point to a lack of generalizability of models derived from young healthy homogeneous samples.
We here describe a multimodality neuroimaging containing data from healthy volunteers and patient... more We here describe a multimodality neuroimaging containing data from healthy volunteers and patients, acquired within the Lundbeck Foundation Center for Integrated Molecular Brain Imaging (Cimbi) in Copenhagen, Denmark. The data is of particular relevance for neurobiological research questions related to the serotonergic transmitter system with its normative data on the serotonergic subtype receptors 5-HT1A, 5-HT1B, 5-HT2A, and 5-HT4 and the 5-HT transporter (5-HTT), but can easily serve other purposes. The Cimbi Database and Cimbi Biobank were formally established in 2008 with the purpose to store the wealth of Cimbi-acquired data in a highly structured and standardized manner in accordance with the regulations issued by the Danish Data Protection Agency as well as to provide a quality-controlled resource for future hypothesis-generating and hypothesis-driven studies. The Cimbi database currently comprises a total of 1.100 PET and 1.000 structural and functional MRI scans and it hold...
BACKGROUND Psilocybin may have antidepressant properties, but direct comparisons between psilocyb... more 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.
Repeated withdrawal from alcohol is clinically associated with progressive cognitive impairment. ... more Repeated withdrawal from alcohol is clinically associated with progressive cognitive impairment. Microglial activation occurring during pre-clinical models of alcohol withdrawal is associated with learning deficits. We investigated whether there was microglial activation in recently detoxified alcohol-dependent patients (ADP), using [ 11 C]PBR28 positron emission tomography (PET), selective for the 18kDa translocator protein (TSPO) highly expressed in activated microglia and astrocytes. We investigated the relationship between microglial activation and cognitive performance. Twenty healthy control (HC) subjects (45 ± 13; M:F 14:6) and nine ADP (45 ± 6, M:F 9:0) were evaluated. Dynamic PET data were acquired for 90 min following an injection of 331 ± 15 MBq [ 11 C]PBR28. Regional volumes of distribution (V T) for regions of interest (ROIs) identified a priori were estimated using a two-tissue compartmental model with metabolite-corrected arterial plasma input function. ADP had an~20% lower [ 11 C]PBR28 V T, in the hippocampus (F(1,24) 5.694; P = 0.025), but no difference in V T in other ROIs. Hippocampal [ 11 C]PBR28 V T was positively correlated with verbal memory performance in a combined group of HC and ADP (r = 0.720, P o 0.001), an effect seen in HC alone (r = 0.738; P = 0.001) but not in ADP. We did not find evidence for increased microglial activation in ADP, as seen pre-clinically. Instead, our findings suggest lower glial density or an altered activation state with lower TSPO expression. The correlation between verbal memory and [ 11 C]PBR28 V T , raises the possibility that abnormalities of glial function may contribute to cognitive impairment in ADP.
Drug and alcohol dependence are global problems with substantial societal costs. There are few tr... more Drug and alcohol dependence are global problems with substantial societal costs. There are few treatments for relapse prevention and therefore a pressing need for further study of brain mechanisms underpinning relapse circuitry. The Imperial College Cambridge Manchester (ICCAM) platform study is an experimental medicine approach to this problem: using functional magnetic resonance imaging (fMRI) techniques and selective pharmacological tools, it aims to explore the neuropharmacology of putative relapse pathways in cocaine, alcohol, opiate dependent, and healthy individuals to inform future drug development. Addiction studies typically involve small samples because of recruitment difficulties and attrition. We established the platform in three centres to assess the feasibility of a multisite approach to address these issues. Pharmacological modulation of reward, impulsivity and emotional reactivity were investigated in a monetary incentive delay task, an inhibitory control task, and an evocative images task, using selective antagonists for µ-opioid, dopamine D3 receptor (DRD3) and neurokinin 1 (NK1) receptors (naltrexone, GSK598809, vofopitant/aprepitant), in a placebo-controlled, randomised, crossover design. In two years, 609 scans were performed, with 155 individuals scanned at baseline. Attrition was low and the majority of individuals were sufficiently motivated to complete all five sessions (n=87). We describe herein the study design, main aims, recruitment numbers, sample characteristics, and explain the test hypotheses and anticipated study outputs.
Animal studies support the role of the dopamine D3 receptor (DRD3) in alcohol reinforcement or li... more Animal studies support the role of the dopamine D3 receptor (DRD3) in alcohol reinforcement or liking. Sustained voluntary alcohol drinking in rats has been associated with an upregulation of striatal DRD3 gene expression and selective blockade of DRD3 reduces ethanol preference, consumption, and cue-induced reinstatement. In vivo measurement of DRD3 in the living human brain has not been possible until recently owing to a lack of suitable tools. In this study, DRD3 status was assessed for the first time in human alcohol addiction. Brain DRD3 availability was compared between 16 male abstinent alcohol-dependent patients and 13 healthy non-dependent age-matched males using the DRD3-preferring agonist positron emission tomography (PET) radioligand [ 11 C]PHNO with and without blockade with a selective DRD3 antagonist (GSK598809 60 mg p.o.). In striatal regions of interest, where the [ 11 C]PHNO PET signal represents primarily DRD2 binding, no differences were seen in [ 11 C]PHNO binding between the groups at baseline. However, baseline [ 11 C]PHNO binding was higher in alcohol-dependent patients in hypothalamus (V T : 16.5±4 vs 13.7±2.9, p ¼ 0.040), a region in which the [ 11 C]PHNO signal almost entirely reflects DRD3 availability. The reductions in regional receptor binding (V T) following a single oral dose of GSK598809 (60 mg) were consistent with those observed in previous studies across all regions. There were no differences in regional changes in V T following DRD3 blockade between the two groups, indicating that the regional fractions of DRD3 are similar in the two groups, and the increased [ 11 C]PHNO binding in the hypothalamus in alcohol-dependent patients is explained by elevated DRD3 in this group. Although we found no difference between alcohol-dependent patients and controls in striatal DRD3 levels, increased DRD3 binding in the hypothalamus of alcohol-dependent patients was observed. This may be relevant to the development of future therapeutic strategies to treat alcohol abuse.
Pathological gambling is a psychiatric disorder and the first recognized behavioral addiction, wi... more Pathological gambling is a psychiatric disorder and the first recognized behavioral addiction, with similarities to substance use disorders but without the confounding effects of drug-related brain changes. Pathophysiology within the opioid receptor system is increasingly recognized in substance dependence, with higher mu-opioid receptor (MOR) availability reported in alcohol, cocaine and opiate addiction. Impulsivity, a risk factor across the addictions, has also been found to be associated with higher MOR availability. The aim of this study was to characterize baseline MOR availability and endogenous opioid release in pathological gamblers (PG) using [ 11 C]carfentanil PET with an oral amphetamine challenge. Fourteen PG and 15 healthy volunteers (HV) underwent two [ 11 C]carfentanil PET scans, before and after an oral administration of 0.5 mg/kg of d-amphetamine. The change in [ 11 C]carfentanil binding between baseline and post-amphetamine scans (ΔBP ND) was assessed in 10 regions of interest (ROI). MOR availability did not differ between PG and HV groups. As seen previously, oral amphetamine challenge led to significant reductions in [ 11 C]carfentanil BP ND in 8/10 ROI in HV. PG demonstrated significant blunting of opioid release compared with HV. PG also showed blunted amphetamine-induced euphoria and alertness compared with HV. Exploratory analysis revealed that impulsivity positively correlated with caudate baseline BP ND in PG only. This study provides the first evidence of blunted endogenous opioid release in PG. Our findings are consistent with growing evidence that dysregulation of endogenous opioids may have an important role in the pathophysiology of addictions.
Background: 3,4-Methylenedioxymethamphetamine (MDMA) is being actively researched as an adjunct t... more Background: 3,4-Methylenedioxymethamphetamine (MDMA) is being actively researched as an adjunct to psychotherapy. It may be beneficial to trust, empathy and cooperative behaviour due to its acute prosocial effects. Aim: To test (a) the acute effects of MDMA on measures of empathy, trust and cooperative behaviour, and (b) subacute changes in mood three days after MDMA administration. Methods: Twenty-five participants (n=7 female), participated in this double-blind, repeated-measures, placebo-controlled experiment. Participants attended two acute sessions, one week apart. Each acute session was followed by a subacute session three days later. Participants received placebo (100 mg ascorbic acid) during one acute session, and MDMA (100 mg MDMA-HCl) at the other, with order counterbalanced. Participants completed the following tasks assessing prosocial behaviour: a trust investment task, a trustworthy face rating task, an empathic stories task, a public project game, a dictator game and an ultimatum game. Participants reported subjective effects. Blood was taken pre-drug, 2 and 4 hours post-drug, and tested for plasma MDMA levels. Results: MDMA acutely increased self-reported 'closeness to others' and 'euphoria' and increased plasma concentrations of MDMA. MDMA did not significantly change task-based empathy, trust or cooperative behaviour. Using Bayesian analyses, we found evidence that MDMA and placebo did not differ in their effects on empathy and cooperative behaviour. MDMA did not significantly change subacute mood and this was supported by our Bayesian analyses. Conclusion: Despite augmentation in plasma MDMA levels and subjective drug effects, we found no increase in prosocial behaviour in a laboratory setting.
The International Journal of Neuropsychopharmacology, Dec 17, 2013
3,4-methylenedioxymethamphetamine (MDMA) is a potent monoamine-releaser that is widely used as a ... more 3,4-methylenedioxymethamphetamine (MDMA) is a potent monoamine-releaser that is widely used as a recreational drug. Preliminary work has supported the potential of MDMA in psychotherapy for post-traumatic stress disorder (PTSD). The neurobiological mechanisms underlying its putative efficacy are, however, poorly understood. Psychotherapy for PTSD usually requires that patients revisit traumatic memories, and it has been argued that this is easier to do under MDMA. Functional magnetic resonance imaging (fMRI) was used to investigate the effect of MDMA on recollection of favourite and worst autobiographical memories (AMs). Nineteen participants (five females) with previous experience with MDMA performed a blocked AM recollection (AMR) paradigm after ingestion of 100 mg of MDMA-HCl or ascorbic acid (placebo) in a double-blind, repeatedmeasures design. Memory cues describing participants' AMs were read by them in the scanner. Favourite memories were rated as significantly more vivid, emotionally intense and positive after MDMA than placebo and worst memories were rated as less negative. Functional MRI data from 17 participants showed robust activations to AMs in regions known to be involved in AMR. There was also a significant effect of memory valence: hippocampal regions showed preferential activations to favourite memories and executive regions to worst memories. MDMA augmented activations to favourite memories in the bilateral fusiform gyrus and somatosensory cortex and attenuated activations to worst memories in the left anterior temporal cortex. These findings are consistent with a positive emotional-bias likely mediated by MDMA's pro-monoaminergic pharmacology.
Positron emission tomography (PET) enables non-invasive estimation of neurotransmitter fluctuatio... more 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, [ 11 C]CIMBI-36, and a d-amphetamine challenge to evaluate synaptic 5-HT changes in the living human brain. Seventeen healthy male volunteers received [ 11 C]CIMBI-36 PET scans before and 3 h after an oral dose of d-amphetamine (0.5 mg/kg). Dynamic PET data were acquired over 90 min, and the total volume of distribution (V T) in the frontal cortex and the cerebellum derived from a kinetic analysis using MA1. The frontal cortex binding potential (BP ND frontal) was calculated as (V T frontal /V T cerebellum) − 1. ΔBP ND frontal = 1 − (BP ND frontal post-dose/BP ND frontal baseline) 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 [ 11 C]CIMBI-36 BP ND frontal. Following d-amphetamine administration, [ 11 C]CIMBI-36 BP ND frontal was reduced by 14 ± 13% (p = 0.002). Similar effects were observed in other cortical regions examined in an exploratory analysis. [ 11 C]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.
As a behavioural addiction, gambling disorder (GD) provides an opportunity to characterize addict... more As a behavioural addiction, gambling disorder (GD) provides an opportunity to characterize addictive processes without the potentially confounding effects of chronic excessive drug and alcohol exposure. Impulsivity is an established precursor to such addictive behaviours, and GD is associated with greater impulsivity. There is also evidence of GABAergic dysregulation in substance addiction and in impulsivity. This study therefore investigated GABAA receptor availability in 15 individuals with GD and 19 healthy volunteers (HV) using [11C]Ro15‐4513, a relatively selective α5 benzodiazepine receptor PET tracer and its relationship with impulsivity. We found significantly higher [11C]Ro15‐4513 total distribution volume (VT) in the right hippocampus in the GD group compared with HV. We found higher levels of the ‘Negative Urgency’ construct of impulsivity in GD, and these were positively associated with higher [11C]Ro15‐4513 VT in the amygdala in the GD group; no such significant correla...
Journal of psychopharmacology (Oxford, England), Jan 5, 2015
Drug and alcohol dependence are global problems with substantial societal costs. There are few tr... more Drug and alcohol dependence are global problems with substantial societal costs. There are few treatments for relapse prevention and therefore a pressing need for further study of brain mechanisms underpinning relapse circuitry. The Imperial College Cambridge Manchester (ICCAM) platform study is an experimental medicine approach to this problem: using functional magnetic resonance imaging (fMRI) techniques and selective pharmacological tools, it aims to explore the neuropharmacology of putative relapse pathways in cocaine, alcohol, opiate dependent, and healthy individuals to inform future drug development. Addiction studies typically involve small samples because of recruitment difficulties and attrition. We established the platform in three centres to assess the feasibility of a multisite approach to address these issues. Pharmacological modulation of reward, impulsivity and emotional reactivity were investigated in a monetary incentive delay task, an inhibitory control task, and ...
Background: The serotonin 5-HT2A receptor is suspected to be involved in a number of psychiatric ... more Background: The serotonin 5-HT2A receptor is suspected to be involved in a number of psychiatric disorders, including schizophrenia. In particular, atypical antipsychotics have antagonistic effects on the 5-HT2A receptors pointing at a specific role of the 5-HT2A receptor in the pathophysiology of this disease. The aim of this study is to investigate the 5-HT2A binding in neuroleptic-naive schizophrenic patients. Methods: Fifteen unmedicated subjects diagnosed with schizophrenic disorder (27.5 T 4.5), 11 males and 4 females, and 15 healthy control subjects matched for age (28.5 T 5.7) and gender underwent a 40 min PET study using the 5-HT2A antagonist, [F-18]altanserin, as a radioligand. PET images were co-registered to 3 T MRIs for each individual subject, and ROIs were applied automatically onto the individual MRIs and PET images. Cerebellum was used as a reference region. The binding potential of specific tracer binding (BP1) was used as the outcome measure. Results: An increase in 5-HT2A receptor binding in the caudate nucleus was detected in the group of schizophrenic patients (0.7 T 0.1) when compared to the healthy controls (0.5 T 0.3), P = 0.02. No significant between group difference was seen in cortical receptor distribution. Conclusion: Dysregulations of mesocorticostriatal pathways are known to be involved in the pathophysiology of schizophrenia, but in vivo dysregulation of serotonin 5-HT2A receptor has not previously been detected in basal ganglia. Whether the shown elevation of 5-HT2A binding in caudate of schizophrenic patients is a primary pathophysiological disturbance in this disorder or rather secondary to changes in endogenous serotonin levels will require further investigation.
Poor behavioral inhibition is a common feature of neurological and psychiatric disorders. Success... more Poor behavioral inhibition is a common feature of neurological and psychiatric disorders. Successful inhibition of a prepotent response in 'NoGo' paradigms requires the integrity of both the inferior frontal gyrus (IFG) and the serotonergic system. We investigated individual differences in serotonergic regulation of response inhibition. In 24 healthy adults, we used 18 F-altanserin positron emission tomography to assess cerebral 5-HT 2A receptors, which have been related to impulsivity. We then investigated the impact of two acute manipulations of brain serotonin levels on behavioral and neural correlates of inhibition using intravenous citalopram and acute tryptophan depletion during functional magnetic resonance imaging. We adapted the NoGo paradigm to isolate effects on inhibition per se as opposed to other aspects of the NoGo paradigm. Successful NoGo inhibition was associated with greater activation of the right IFG compared to control trials with alternative responses, indicating that the IFG is activated with inhibition in NoGo trials rather than other aspects of invoked cognitive control. Activation of the left IFG during NoGo trials was greater with citalopram than acute tryptophan depletion. Moreover, with the NoGo-type of response inhibition, the right IFG displayed an interaction between the type of serotonergic challenge and neocortical 5-HT 2A receptor binding. Specifically, acute tryptophan depletion (ATD) produced a relatively larger NoGo response in the right IFG in subjects with low 5-HT 2A BP P but reduced the NoGo response in those with high 5-HT 2A BP P. These links between serotonergic function and response inhibition in healthy subjects may help to interpret serotonergic abnormalities underlying impulsivity in neuropsychiatric disorders.
The International Journal of Neuropsychopharmacology, 2013
3,4-methylenedioxymethamphetamine (MDMA) is a potent monoamine-releaser that is widely used as a ... more 3,4-methylenedioxymethamphetamine (MDMA) is a potent monoamine-releaser that is widely used as a recreational drug. Preliminary work has supported the potential of MDMA in psychotherapy for post-traumatic stress disorder (PTSD). The neurobiological mechanisms underlying its putative efficacy are, however, poorly understood. Psychotherapy for PTSD usually requires that patients revisit traumatic memories, and it has been argued that this is easier to do under MDMA. Functional magnetic resonance imaging (fMRI) was used to investigate the effect of MDMA on recollection of favourite and worst autobiographical memories (AMs). Nineteen participants (five females) with previous experience with MDMA performed a blocked AM recollection (AMR) paradigm after ingestion of 100 mg of MDMA-HCl or ascorbic acid (placebo) in a double-blind, repeatedmeasures design. Memory cues describing participants' AMs were read by them in the scanner. Favourite memories were rated as significantly more vivid, emotionally intense and positive after MDMA than placebo and worst memories were rated as less negative. Functional MRI data from 17 participants showed robust activations to AMs in regions known to be involved in AMR. There was also a significant effect of memory valence: hippocampal regions showed preferential activations to favourite memories and executive regions to worst memories. MDMA augmented activations to favourite memories in the bilateral fusiform gyrus and somatosensory cortex and attenuated activations to worst memories in the left anterior temporal cortex. These findings are consistent with a positive emotional-bias likely mediated by MDMA's pro-monoaminergic pharmacology.
Background: We aimed to demonstrate a pharmacologically stimulated endogenous opioid release in t... more Background: We aimed to demonstrate a pharmacologically stimulated endogenous opioid release in the living human brain by evaluating the effects of amphetamine administration on [ 11 C]carfentanil binding with positron emission tomography (PET). Methods: Twelve healthy male volunteers underwent [ 11 C]carfentanil PET before and 3 hours after a single oral dose of d-amphetamine (either a "high" dose, .5 mg/kg, or a sub-pharmacological "ultra-low" dose, 1.25 mg total dose or approximately .017 mg/kg). Reductions in [ 11 C]carfentanil binding from baseline to post-amphetamine scans (⌬BP ND) after the "high" and "ultra-low" amphetamine doses were assessed in 10 regions of interest. Results: [ 11 C]carfentanil binding was reduced after the "high" but not the "ultra-low" amphetamine dose in the frontal cortex, putamen, caudate, thalamus, anterior cingulate, and insula. Conclusions: Our findings indicate that oral amphetamine administration induces endogenous opioid release in different areas of human brain, including basal ganglia, frontal cortex areas, and thalamus. The combination of an amphetamine challenge and [ 11 C]carfentanil PET is a practical and robust method to probe the opioid system in the living human brain.
The American Journal of Drug and Alcohol Abuse, 2013
Anxiety has been linked to initiation, maintenance and relapse of alcohol dependence. Neurobiolog... more Anxiety has been linked to initiation, maintenance and relapse of alcohol dependence. Neurobiological models of anxiety have proposed important roles for amygdala-insula and amygdala-medial prefrontal cortex interactions in the generation and regulation of anxiety states, respectively. This study tested the hypotheses that abstinent alcohol-dependent patients would show a disruption of synchrony in these circuits as measured by resting state functional MRI. The study examined recently abstinent (n = 13), longer-term abstinent (n = 16) alcohol-dependent patients and healthy controls (n = 22). Resting-state synchrony (RSS) was examined in specific circuits, where degree of synchrony has been found to correlate with state anxiety levels in previous studies. Alcohol-dependent patients showed significantly elevated scores on anxiety and depression inventories compared with controls. No significant group differences in synchrony were observed between right amygdala and right ventromedial prefrontal cortex (vmPFC), between left amygdala and left vmPFC, or, after correction for multiple comparisons, right amygdala and dorsomedial prefrontal cortex (dmPFC). However, significantly decreased positive synchrony was found between left basolateral amygdala and left anterior insula, in patients relative to controls. Both early and longer-term abstinent alcohol-dependent patients showed increased anxiety levels relative to controls and altered resting state synchrony in circuits previously linked to state anxiety. Notably, the significant group differences in synchrony were in the opposite direction to our predictions based on the literature. These results may point to a lack of generalizability of models derived from young healthy homogeneous samples.
We here describe a multimodality neuroimaging containing data from healthy volunteers and patient... more We here describe a multimodality neuroimaging containing data from healthy volunteers and patients, acquired within the Lundbeck Foundation Center for Integrated Molecular Brain Imaging (Cimbi) in Copenhagen, Denmark. The data is of particular relevance for neurobiological research questions related to the serotonergic transmitter system with its normative data on the serotonergic subtype receptors 5-HT1A, 5-HT1B, 5-HT2A, and 5-HT4 and the 5-HT transporter (5-HTT), but can easily serve other purposes. The Cimbi Database and Cimbi Biobank were formally established in 2008 with the purpose to store the wealth of Cimbi-acquired data in a highly structured and standardized manner in accordance with the regulations issued by the Danish Data Protection Agency as well as to provide a quality-controlled resource for future hypothesis-generating and hypothesis-driven studies. The Cimbi database currently comprises a total of 1.100 PET and 1.000 structural and functional MRI scans and it hold...
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Papers by David Erritzoe