Publications
1319 results found
Schlag AK, O'Sullivan SE, Zafar RR, et al., 2021, Current controversies in medical cannabis: recent developments in human clinical applications and potential therapeutics., Neuropharmacology
Knowledge about the therapeutic potential of medical cannabis has greatly improved over the past decade, with an ever-increasing range of developments in human clinical applications. A growing body of scientific evidence supports the use of medical cannabis products for some therapeutic indications, whilst for others, the evidence base remains disputed. For this narrative review, we incorporate areas where the current evidence base is substantial, such as intractable childhood epilepsy and multiple sclerosis, as well as areas where the evidence is still controversial, such as PTSD and anxiety. We provide a high-level summary of current developments using findings from recent major reviews, as well as real world evidence (RWE), including global database registries and other patient reported outcomes (PROs). On the one hand, our strongest empirical data supports the use of cannabis-based medicinal products (CBMPs) for conditions with relatively small patient numbers. Yet on the other hand, the conditions, where the highest patient numbers present, often have debatable clinical evidence but good RWE, incorporating PROs of 1000s of patients. The discord between PROs and the respective strength of the evidence from randomised controlled trials (RCTs) highlights the urgent need for further research. The scientific literature examining the efficacy of medical cannabis for many conditions is still developing, whilst large numbers of patients globally have been successfully using medical cannabis to treat a broad range of conditions. We conclude on the importance of systematically developing RWE databases to supplement RCTs and to bridge the current evidence gaps.
Carhart-Harris R, Giribaldi B, Watts R, et al., 2021, Trial of Psilocybin versus Escitalopram for Depression, NEW ENGLAND JOURNAL OF MEDICINE, Vol: 384, Pages: 1402-1411, ISSN: 0028-4793
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- Citations: 1
Rolles S, Nutt DJ, Schlag AK, 2021, Some Contributions on How to Formulate Drug Policies and Provide Evidence-Based Regulation, AMERICAN JOURNAL OF BIOETHICS, Vol: 21, Pages: 28-31, ISSN: 1526-5161
Szigeti B, Kartner L, Blemings A, et al., 2021, Self-blinding citizen science to explore psychedelic microdosing, ELIFE, Vol: 10, ISSN: 2050-084X
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- Citations: 1
Rolles S, Schlag AK, Measham F, et al., 2021, A multi criteria decision analysis (MCDA) for evaluating and appraising government policy responses to non medical heroin use., Int J Drug Policy
BACKGROUND: Globally, non-medical heroin use is generating significant public health and social harms, and drug policy about heroin is a controversial field that encompasses many complex issues. Policy responses to illegal heroin markets have varied from militarized eradication of the opium poppy and harsh punishment of users, to more tolerant harm reduction approaches with decriminalized possession and use. METHODS: This paper reports the outcomes of a multi-criteria decision analysis (MCDA) on four generic regulatory regimes of heroin: prohibition, decriminalisation, state control and free market. Invited experts on drug harms, addiction, criminology and drug policy developed a comprehensive set of 27 policy outcome criteria against which these drug policy regimes were assessed. RESULTS: State control of heroin was identified as the preferred policy option although other policy regimes scored better on specific outcome criteria. The free market model scored better than decriminalisation, with absolute prohibition scoring worst on every criterium. The ranking of the regimes was robust to variations in the criterion-specific weights. CONCLUSION: The implications of these findings for the development of future policy responses to heroin and opioids generally are discussed in detail. Despite increasing overdose deaths and an opioid epidemic in North America, prohibition remains the predominant policy approach to heroin regulation at present. It is hoped that the current paper adds to the discussion of finding a valid regulatory alternative.
Nutt D, Carhart-Harris R, 2021, The Current Status of Psychedelics in Psychiatry, JAMA PSYCHIATRY, Vol: 78, Pages: 121-122, ISSN: 2168-622X
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- Citations: 5
Mirzaei N, Mota B, Birch A, et al., 2021, Imidazoline ligand BU224 reverses cognitive deficits, reduces microgliosis and enhances synaptic connectivity in a mouse model of Alzheimer’s disease, British Journal of Pharmacology, Vol: 178, Pages: 654-671, ISSN: 0007-1188
Background and PurposeActivation of type‐2 Imidazoline receptors has been shown to exhibit neuroprotective properties including anti‐apoptotic and anti‐inflammatory effects, suggesting a potential therapeutic value in Alzheimer's disease (AD). Here, we explored the effects of the Imidazoline‐2 ligand BU224 in a model of amyloidosis.Experimental approach6‐month‐old female transgenic 5XFAD and wild‐type (WT) mice were treated intraperitoneally with 5 mg.kg‐1 BU224 or vehicle twice a day for 10 days. Behavioural tests were performed for cognitive functions and neuropathological changes were investigated by immunohistochemistry, Western blot, ELISA and qPCR. Effects of BU224 on APP processing, spine density and calcium imaging were analysed in brain organotypic cultures and N2a cells.Key ResultsBU224 treatment attenuated spatial and perirhinal cortex‐dependent recognition memory deficits in 5XFAD mice. Fear conditioning testing revealed that BU224 also improved both associative learning and hippocampal‐ and amygdala‐dependent memory in transgenic but not in WT mice. In the brain, BU224 reduced levels of the microglial marker Iba1 and pro‐inflammatory cytokines IL‐1β and TNFα, and increased the expression of astrocytic marker GFAP in 5XFAD mice. These beneficial effects were not associated with changes in amyloid pathology, neuronal apoptosis, mitochondrial density, oxidative stress or autophagy markers. Interestingly, ex vivo and in vitro studies suggested that BU224 treatment increased the size of dendritic spines and induced a 3‐fold reduction in Aβ‐induced functional changes in NMDA receptors.Conclusions and implicationsOur data indicate that sub‐chronic treatment with BU224 improves memory and reduces inflammation in transgenic AD mice, at stages when animals display severe pathology.
Sanz C, Pallavicini C, Carrillo F, et al., 2021, The entropic tongue: Disorganization of natural language under LSD, CONSCIOUSNESS AND COGNITION, Vol: 87, ISSN: 1053-8100
Andersen KAA, Carhart-Harris R, Nutt DJ, et al., 2020, Therapeutic effects of classic serotonergic psychedelics: A systematic review of modern-era clinical studies, ACTA PSYCHIATRICA SCANDINAVICA, Vol: 143, Pages: 101-118, ISSN: 0001-690X
Orban C, McGonigle J, Flechais RSA, et al., 2020, Chronic alcohol exposure differentially modulates structural and functional properties of amygdala: A cross-sectional study, ADDICTION BIOLOGY, ISSN: 1355-6215
Alamia A, Timmermann C, VanRullen R, et al., 2020, DMT alters cortical travelling waves, eLife, Vol: 9, Pages: 1-16, ISSN: 2050-084X
Psychedelic drugs are potent modulators of conscious states and therefore powerful tools for investigating their neurobiology. N,N, Dimethyltryptamine (DMT) can rapidly induce an extremely immersive state of consciousness characterized by vivid and elaborate visual imagery. Here, we investigated the electrophysiological correlates of the DMT-induced altered state from a pool of participants receiving DMT and (separately) placebo (saline) while instructed to keep their eyes closed. Consistent with our hypotheses, results revealed a spatio-temporal pattern of cortical activation (i.e. travelling waves) similar to that elicited by visual stimulation. Moreover, the typical top-down alpha-band rhythms of closed-eyes rest were significantly decreased, while the bottom-up forward wave was significantly increased. These results support a recent model proposing that psychedelics reduce the ‘precision-weighting of priors’, thus altering the balance of top-down versus bottom-up information passing. The robust hypothesis-confirming nature of these findings imply the discovery of an important mechanistic principle underpinning psychedelic-induced altered states.
Turton S, Myers J, Mick I, et al., 2020, Blunted endogenous opioid release following an oral dexamphetamine challenge in abstinent alcohol dependent individuals, Molecular Psychiatry, Vol: 25, Pages: 1749-1758, ISSN: 1359-4184
Addiction has been proposed as a ‘reward deficient’ state, which is compensated for with substance use. There is growing evidence of dysregulation in the opioid system, which plays a key role in reward, underpinning addiction. Low levels of endogenous opioids are implicated in vulnerability for developing alcohol dependence (AD) and high mu-opioid receptor (MOR) availability in early abstinence is associated with greater craving. This high MOR availability is proposed to be the target of opioid antagonist medication to prevent relapse. However, changes in endogenous opioid tone in AD are poorly characterised and are important to understand as opioid antagonists do not help everyone with AD. We used [11C]carfentanil, a selective MOR agonist positron emission tomography (PET) radioligand, to investigate endogenous opioid tone in AD for the first time. We recruited 13 abstinent male AD and 15 control participants who underwent two [11C]carfentanil PET scans, one before and one 3 h following a 0.5 mg/kg oral dose of dexamphetamine to measure baseline MOR availability and endogenous opioid release. We found significantly blunted dexamphetamine-induced opioid release in 5 out of 10 regions-of-interest including insula, frontal lobe and putamen in AD compared with controls, but no significantly higher MOR availability AD participants compared with HC in any region. This study is comparable to our previous results of blunted dexamphetamine-induced opioid release in gambling disorder, suggesting that this dysregulation in opioid tone is common to both behavioural and substance addictions.
Wardle H, Banks J, Bebbington P, et al., 2020, Open letter from UK based academic scientists to the secretaries of state for digital, culture, media and sport and for health and social care regarding the need for independent funding for the prevention and treatment of gambling harms, BMJ-BRITISH MEDICAL JOURNAL, Vol: 370, ISSN: 1756-1833
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- Citations: 1
Borissova A, Ferguson B, Wall MB, et al., 2020, Acute effects of MDMA on trust, cooperative behaviour and empathy: A double-blind, placebo-controlled experiment, JOURNAL OF PSYCHOPHARMACOLOGY, ISSN: 0269-8811
Schlag AK, Baldwin DS, Barnes M, et al., 2020, Medical cannabis in the UK: From principle to practice, JOURNAL OF PSYCHOPHARMACOLOGY, Vol: 34, Pages: 931-937, ISSN: 0269-8811
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- Citations: 3
Nutt D, Nestor L, Suckling J, et al., 2020, Disturbances across whole brain networks during reward anticipation in an abstinent addiction population., NeuroImage: Clinical, Vol: 27, Pages: 1-10, ISSN: 2213-1582
The prevalent spatial distribution of abnormalities reported in cognitive fMRI studies in addiction suggests there are extensive disruptions across whole brain networks. Studies using resting state have reported disruptions in network connectivity in addiction, but these studies have not revealed characteristics of network functioning during critical psychological processes that are disrupted in addiction populations. Analytic methods that can capture key features of whole brain networks during psychological processes may be more sensitive in revealing additional and widespread neural disturbances in addiction, that are the provisions for relapse risk, and targets for medication development. The current study compared a substance addiction (ADD; n = 83) group in extended abstinence with a control (CON; n = 68) group on functional MRI (voxel-wise activation) and global network (connectivity) measures related to reward anticipation on a monetary incentive delay task. In the absence of group differences on MID performance, the ADD group showed reduced activation predominantly across temporal and visual regions, but not across the striatum. The ADD group also showed disruptions in global network connectivity (lower clustering coefficient and higher characteristic path length), and significantly less connectivity across a sub-network comprising frontal, temporal, limbic and striatal nodes. These results show that an addiction group in extended abstinence exhibit localised disruptions in brain activation, but more extensive disturbances in functional connectivity across whole brain networks. We propose that measures of global network functioning may be more sensitive in highlighting latent and more widespread neural disruptions during critical psychological processes in addiction and other psychiatric disorders.
Mokrysz C, Shaban NDC, Freeman TP, et al., 2020, Acute effects of cannabis on speech illusions and psychotic-like symptoms: two studies testing the moderating effects of cannabidiol and adolescence., Psychol Med, Pages: 1-9
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.
Marques TR, Ashok AH, Angelescu I, et al., 2020, GABA-A receptor differences in schizophrenia: a positron emission tomography study using [C-11]Ro154513, Molecular Psychiatry, Vol: 2020, Pages: 1-10, ISSN: 1359-4184
A loss of GABA signaling is a prevailing hypothesis for the pathogenesis of schizophrenia. Preclinical studies indicate that blockade of the α5 subtype of the GABA receptor (α5-GABAARs) leads to behavioral phenotypes associated with schizophrenia, and postmortem evidence indicates lower hippocampal α5-GABAARs protein and mRNA levels in schizophrenia. However, it is unclear if α5-GABAARs are altered in vivo or related to symptoms. We investigated α5-GABAARs availability in antipsychotic-free schizophrenia patients and antipsychotic-medicated schizophrenia patients using [11C]Ro15-4513 PET imaging in a cross-sectional, case–control study design. Thirty-one schizophrenia patients (n = 10 antipsychotic free) and twenty-nine matched healthy controls underwent a [11C]Ro15-4513 PET scan and MRI. The α5 subtype GABA-A receptor availability was indexed using [11C]Ro15-4513 PET imaging. Dynamic PET data were analyzed using the two-tissue compartment model with an arterial plasma input function and total volume of distribution (VT) as the outcome measure. Symptom severity was assessed using the PANSS scale. There was significantly lower [11C]Ro15-4513 VT in the hippocampus of antipsychotic-free patients, but not in medicated patients (p = 0.64), relative to healthy controls (p < 0.05; effect size = 1.4). There was also a significant positive correlation between [11C]Ro15-4513 VT and total PANSS score in antipsychotic-free patients (r = 0.72; p = 0.044). The results suggest that antipsychotic-free patients with schizophrenia have lower α5-GABAARs levels in the hippocampus, consistent with the hypothesis that GABA hypofunction underlies the pathophysiology of the disorder.
Nutt D, Erritzoe D, Carhart-Harris R, 2020, Psychedelic Psychiatry's Brave New World, CELL, Vol: 181, Pages: 24-28, ISSN: 0092-8674
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- Citations: 19
Erritzoe D, Ashok AH, Searle GE, et al., 2020, Serotonin release measured in the human brain: A PET study with [11C]CIMBI-36 and d-amphetamine challenge, Neuropsychopharmacology, Vol: 45, Pages: 804-810, ISSN: 0893-133X
Positron emission tomography (PET) enables non-invasive estimation of neurotransmitter fluctuations in the living human brain. While these methods have been applied to dopamine and some other transmitters, estimation of 5-hydroxytryptamine (5-HT; Serotonin) release has proved to be challenging. Here we demonstrate the utility of the novel 5-HT2A receptor agonist radioligand, [11C]CIMBI-36, and a d-amphetamine challenge to evaluate synaptic 5-HT changes in the living human brain. Seventeen healthy male volunteers received [11C]CIMBI-36 PET scans before and 3 hours after an oral dose of d-amphetamine (0.5 mg/kg). Dynamic PET data were acquired over 90 minutes, and the total volume of distribution (VT) in the frontal cortex and the cerebellum derived from a kinetic analysis using MA1. The frontal cortex binding potential (BPNDfrontal) was calculated as (VTfrontal/VTcerebellum)-1. BPNDfrontal = 1- (BPNDfrontalpost-dose/ BPNDfrontalbaseline) was used as an index of 5-HT release. Statistical inference was tested by means of a paired Students t-test evaluating a reduction in post-amphetamine [11C]CIMBI-36 BPNDfrontal .Following d-amphetamine administration, [11C]CIMBI-36 BPNDfrontal was reduced by 14 ± 13 % (p = 0.002). Similar effects were observed in other cortical regions examined in an exploratory analysis.[11C]CIMBI-36 binding is sensitive to synaptic serotonin release in the human brain, and when combined with a d-amphetamine challenge, the evaluation of the human brain serotonin system in neuropsychiatric disorders, such as major depression and Parkinson’s disease is enabled.
Campeny E, Lopez-Pelayo H, Nutt D, et al., 2020, The blind men and the elephant: Systematic review of systematic reviews of cannabis use related health harms, EUROPEAN NEUROPSYCHOPHARMACOLOGY, Vol: 33, Pages: 1-35, ISSN: 0924-977X
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- Citations: 8
Nutt D, 2020, New psychoactive substances: Pharmacology influencing UK practice, policy and the law, BRITISH JOURNAL OF CLINICAL PHARMACOLOGY, Vol: 86, Pages: 445-451, ISSN: 0306-5251
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- Citations: 2
Hayes A, Wing V, McGonigle J, et al., 2020, The relationship between reward processing and impulsivity in addiction: a functional magnetic resonance imaging study, ECNP Workshop on Junior Scientists in Europe, Publisher: ELSEVIER, Pages: S70-S71, ISSN: 0924-977X
Introduction: Evidence suggests that abnormalities in reward processing and increased impulsivity contribute to the pathophysiology of addiction. However, the relationship between the two is currently not well characterised. This study used fMRI to investigate the BOLD response during reward and inhibitory control tasks and how such responses were associated with subjective and behavioural measures of impulsivity in abstinent alcohol, cocaine and polydrug addiction. We hypothesized a negative correlation between non-drug related reward anticipation and impulsivity measures in polydrug and alcohol dependence compared with healthy controls owing to increased impulsivity and thus more inhibitory control effort needed to maintain successful abstinence.Methods: Abstinent alcohol dependent (AD, n=27), polydrug dependent (PD, n=57) and healthy control (HC, n=65) participants were recruited [1] (REC number 11/H0707/9). Participants completed a battery of impulsivity measures; the Barratt Impulsiveness Scale (BIS-11) and the Urgency, Premeditation, (lack of), Perseverance (lack of), Sensation Seeking, Positive Urgency, Impulsive Behaviour Scale (UPPS-P) to measure trait impulsivity, the Kirby Delay Discounting task to measure choice impulsivity and the Stop Signal Task (SST) to measure impulsive action. Participants also underwent fMRI scanning (3-T) using the monetary incentive delay (MID) and Go/No-go (GNG) tasks. An a-priori region of interest approach was used to image BOLD response during the following contrasts: reward anticipation>neutral anticipation and no-go/go in the rIFG, OFC and caudate. Data was analysed using ANOVA or Kruskal- Wallis tests (with Tukey or Mann-Whitney U post-hoc tests respectively) and Pearson's or Spearman's rank correlations, as appropriate. Holm-Bonferroni correction was applied.Results: There were significant group differences in the BIS-11 (p<0.001), UPPS-P (p<0.001) and Kirby Delay Discounting task (p=0.002). Appropriate post-hoc
Mertens LJ, Wall MB, Roseman L, et al., 2020, Therapeutic mechanisms of psilocybin: Changes in amygdala and prefrontal functional connectivity during emotional processing after psilocybin for treatment-resistant depression, JOURNAL OF PSYCHOPHARMACOLOGY, Vol: 34, Pages: 167-180, ISSN: 0269-8811
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- Citations: 7
Nutt D, Bazire S, Phillips LD, et al., 2020, So near yet so far: why won't the UK prescribe medical cannabis?, BMJ OPEN, Vol: 10, ISSN: 2044-6055
Grabski M, Curran HV, Nutt DJ, et al., 2020, The development and validation of a human screening model of tobacco abstinence, DRUG AND ALCOHOL DEPENDENCE, Vol: 206, ISSN: 0376-8716
Mertens LJ, Wall MB, Roseman L, et al., 2019, Therapeutic mechanisms of psychedelic drugs: Changes in amygdala and prefrontal functional connectivity during emotional processing after psilocybin for treatment-resistant depression, 32nd Congress of the European-College-of-Neuropsychopharmacology (ECNP), Publisher: ELSEVIER, Pages: S416-S417, ISSN: 0924-977X
Erritzoe D, Godlewska BR, Rizzo G, et al., 2019, Brain serotonin release reduced among patients with severe depression: a pet study with [11c]cimbi-36 and d-amphetamine challenge, 32nd Congress of the European-College-of-Neuropsychopharmacology (ECNP), Publisher: ELSEVIER, Pages: S258-S258, ISSN: 0924-977X
Timmermann Slater CB, Roseman L, Schartner M, et al., 2019, Neural correlates of the DMT experience as assessed with multivariate EEG, Scientific Reports, Vol: 9, Pages: 1-13, ISSN: 2045-2322
Studying transitions in and out of the altered state of consciousness caused by intravenous (IV) N,N-Dimethyltryptamine (DMT - a fast-acting tryptamine psychedelic) offers a safe and powerful means of advancing knowledge on the neurobiology of conscious states. Here we sought to investigate the effects of IV DMT on the power spectrum and signal diversity of human brain activity (6 female, 7 male) recorded via multivariate EEG, and plot relationships between subjective experience, brain activity and drug plasma concentrations across time. Compared with placebo, DMT markedly reduced oscillatory power in the alpha and beta bands and robustly increased spontaneous signal diversity. Time-referenced neurophenomenological analyses revealed close relationships between changes in various aspects of subjective experience and changes in brain activity. Importantly, the emergence of oscillatory activity within the delta and theta frequency bands was found to correlate with the peak of the experience - particularly its eyes-closed visual component. These findings highlight marked changes in oscillatory activity and signal diversity with DMT that parallel broad and specific components of the subjective experience, thus advancing our understanding of the neurobiological underpinnings of immersive states of consciousness.
Lord L-D, Expert P, Atasoy S, et al., 2019, Dynamical exploration of the repertoire of brain networks at rest is modulated by psilocybin, NeuroImage, Vol: 199, Pages: 127-142, ISSN: 1053-8119
Growing evidence from the dynamical analysis of functional neuroimaging data suggests that brain function can be understood as the exploration of a repertoire of metastable connectivity patterns ('functional brain networks'), which potentially underlie different mental processes. The present study characterizes how the brain's dynamical exploration of resting-state networks is rapidly modulated by intravenous infusion of psilocybin, a tryptamine psychedelic found in "magic mushrooms". We employed a data-driven approach to characterize recurrent functional connectivity patterns by focusing on the leading eigenvector of BOLD phase coherence at single-TR resolution. Recurrent BOLD phase-locking patterns (PL states) were assessed and statistically compared pre- and post-infusion of psilocybin in terms of their probability of occurrence and transition profiles. Results were validated using a placebo session. Recurrent BOLD PL states revealed high spatial overlap with canonical resting-state networks. Notably, a PL state forming a frontoparietal subsystem was strongly destabilized after psilocybin injection, with a concomitant increase in the probability of occurrence of another PL state characterized by global BOLD phase coherence. These findings provide evidence of network-specific neuromodulation by psilocybin and represent one of the first attempts at bridging molecular pharmacodynamics and whole-brain network dynamics.
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