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.

Persons With Spinal Cord Injury Report Peripherally Dominant Serotonin-Like Syndrome After Use of Serotonergic Psychedelics.

Psychedelic-assisted therapy (PAT) may treat various mental health conditions. Despite its promising therapeutic signal across mental health outcomes, less attention is paid on its potential to provide therapeutic benefits across complex medical situations within rehabilitation medicine. Persons with spinal cord injury (SCI) have a high prevalence of treatment-resistant mental health comorbidities that compound the extent of their physical disability. Reports from online discussion forums suggest that those living with SCI are using psychedelics, though the motivation for their use is unknown. These anecdotal reports describe a consistent phenomenon of neuromuscular and autonomic hypersensitivity to classical serotonergic psychedelics, such as psilocybin and lysergic acid diethylamide (LSD). Persons describe intense muscle spasms, sweating, and tremors, with an eventual return to baseline and no reports of worsening of their baseline neurological deficits. The discomfort experienced interferes with the subjective beneficial effects self-reported. This phenomenon has not been described previously in the academic literature. We aim to provide a descriptive review and explanatory theoretical framework hypothesizing this phenomenon as a peripherally dominant serotonin syndrome-like clinical picture-that should be considered as such when persons with SCI are exposed to classical psychedelics. Raising awareness of this syndrome may help our mechanistic understanding of serotonergic psychedelics and stimulate development of treatment protocols permitting persons with SCI to safely tolerate their adverse effects. As PAT transitions from research trials into accepted clinical and decriminalized use, efforts must be made from a harm reduction perspective to understand these adverse events, while also serving as an informed consent process aid if such therapeutic approaches are to be considered for use in persons living with SCI.

Psychedelic therapy in the treatment of addiction: the past, present and future.

Psychedelic therapy has witnessed a resurgence in interest in the last decade from the scientific and medical communities with evidence now building for its safety and efficacy in treating a range of psychiatric disorders including addiction. In this review we will chart the research investigating the role of these interventions in individuals with addiction beginning with an overview of the current socioeconomic impact of addiction, treatment options, and outcomes. We will start by examining historical studies from the first psychedelic research era of the mid-late 1900s, followed by an overview of the available real-world evidence gathered from naturalistic, observational, and survey-based studies. We will then cover modern-day clinical trials of psychedelic therapies in addiction from first-in-human to phase II clinical trials. Finally, we will provide an overview of the different translational human neuropsychopharmacology techniques, including functional magnetic resonance imaging (fMRI) and positron emission tomography (PET), that can be applied to foster a mechanistic understanding of therapeutic mechanisms. A more granular understanding of the treatment effects of psychedelics will facilitate the optimisation of the psychedelic therapy drug development landscape, and ultimately improve patient outcomes.

The value of real world evidence: The case of medical cannabis.

Randomised controlled trials (RCTs) have long been considered the gold standard of medical evidence. In relation to cannabis based medicinal products (CBMPs), this focus on RCTs has led to very restrictive guidelines in the UK, which are limiting patient access. There is general agreement that RCT evidence in relation to CBPMs is insufficient at present. As well as commercial reasons, a major problem is that RCTs do not lend themselves well to the study of whole plant medicines. One solution to this challenge is the use of real world evidence (RWE) with patient reported outcomes (PROs) to widen the evidence base. Such data increasingly highlights the positive impact medical cannabis can have on patients' lives. This paper outlines the value of this approach which involves the study of interventions and patients longitudinally under medical care. In relation to CBMPs, RWE has a broad range of advantages. These include the study of larger groups of patients, the use of a broader range and ratio of components of CBMPs, and the inclusion of more and rarer medical conditions. Importantly, and in contrast to RCTs, patients with significant comorbidities-and from a wider demographic profile-can also be studied, so providing higher ecological validity and increasing patient numbers, whilst offering significant cost savings. We conclude by outlining 12 key recommendations of the value of RWE in relation to medical cannabis. We hope that this paper will help policymakers and prescribers understand the importance of RWE in relation to medical cannabis and help them develop approaches to overcome the current situation which is detrimental to patients.

Alcohol and the Brain.

Alcohol works on the brain to produce its desired effects, e.g., sociability and intoxication, and hence the brain is an important organ for exploring subsequent harms. These come in many different forms such as the consequences of damage during intoxication, e.g., from falls and fights, damage from withdrawal, damage from the toxicity of alcohol and its metabolites and altered brain structure and function with implications for behavioral processes such as craving and addiction. On top of that are peripheral factors that compound brain damage such as poor diet, vitamin deficiencies leading to Wernicke-Korsakoff syndrome. Prenatal alcohol exposure can also have a profound impact on brain development and lead to irremediable changes of fetal alcohol syndrome. This chapter briefly reviews aspects of these with a particular focus on recent brain imaging results. Cardiovascular effects of alcohol that lead to brain pathology are not covered as they are dealt with elsewhere in the volume.

Current controversies in medical cannabis: Recent developments in human clinical applications and potential therapeutics.

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.

Cannabis based medicines and cannabis dependence: A critical review of issues and evidence.

Cannabis has been legalised for medical use in an ever-increasing number of countries. A growing body of scientific evidence supports the use of medical cannabis for a range of therapeutic indications. In parallel with these developments, concerns have been expressed by many prescribers that increased use will lead to patients developing cannabis use disorder. Cannabis use disorder has been widely studied in recreational users, and these findings have often been projected onto patients using medical cannabis. However, studies exploring medical cannabis dependence are scarce and the appropriate methodology to measure this construct is uncertain. This article provides a narrative review of the current research to discern if, how and to what extent, concerns about problems of dependence in recreational cannabis users apply to prescribed medical users. We focus on the main issues related to medical cannabis and dependence, including the importance of dose, potency, cannabinoid content, pharmacokinetics and route of administration, frequency of use, as well as set and setting. Medical and recreational cannabis use differs in significant ways, highlighting the challenges of extrapolating findings from the recreational cannabis literature. There are many questions about the potential for medical cannabis use to lead to dependence. It is therefore imperative to address these questions in order to be able to minimise harms of medical cannabis use. We draw out seven recommendations for increasing the safety of medical cannabis prescribing. We hope that the present review contributes to answering some of the key questions surrounding medical cannabis dependence.

Clozapine Response in Schizophrenia and Hematological Changes.

BACKGROUND: Clozapine is the only effective medication for treatment-resistant schizophrenia; however, its mechanism of action remains unclear. The present study explored whether its effectiveness is related to changes in hematological measures after clozapine initiation. METHODS: Patients with treatment-resistant schizophrenia commenced on clozapine between January 2007 and December 2014 by the United Kingdom's largest mental health trust were identified from electronic patient records. Hematological data from these patients were obtained from a monitoring registry. White blood cell, neutrophil, and platelet count were assessed at baseline and during the early phase of clozapine treatment. Clozapine response at 3 months was defined as "much," or "very much" improved on the seven-point Clinical Global Impression-Improvement (CGI-I) subscale. RESULTS: In the total sample (n = 188), clozapine initiation was associated with a significant transient increase (peaking in weeks 3 to 4) in white blood cell, neutrophil, and platelet count (P < 0.001). There were 112 (59.6%) patients that responded to treatment; however, none of the hematological factors assessed at baseline, nor changes in these factors, were directly associated with treatment response. IMPLICATIONS: Clozapine treatment is associated with transient hematological changes during the first month of treatment; however, there was no evidence that these were related to the therapeutic response.