A critical assessment of the abuse, dependence and associated safety risks of naturally occurring and synthetic cannabinoids.

Various countries and US States have legalized cannabis, and the use of the psychoactive and non-psychoactive cannabinoids is steadily increasing. In this review, we have collated evidence from published non-clinical and clinical sources to evaluate the abuse, dependence and associated safety risks of the individual cannabinoids present in cannabis. As context, we also evaluated various synthetic cannabinoids.

Stimulant prodrugs: A pharmacological and clinical assessment of their role in treating ADHD and binge-eating disorder.

In this review, we critically evaluate the contribution of prodrugs to treating two related psychiatric disorders, attention-deficit hyperactivity disorder (ADHD) and binge-eating disorder (BED). ADHD is characterized by inattentiveness, distractibility, impulsiveness, and hyperactivity. BED is also an impulse-control disorder which leads to frequent, compulsive episodes of excessive eating (binges).

New Drugs to Treat ADHD: Opportunities and Challenges in Research and Development.

Since the landmark MTA (Multimodal Treatment of ADHD) trial unequivocally demonstrated the efficacy of methylphenidate, catecholaminergic drugs, especially stimulants, have been the therapeutic mainstay in treatment of Attention-Deficit Hyperactivity Disorder (ADHD). We review the new drugs which have entered the ADHD formulary. The lessons learned from drug-candidates that have succeeded in clinical trials together with those that have not have also been considered.

What pharmacological interventions are effective in binge-eating disorder? Insights from a critical evaluation of the evidence from clinical trials.

Binge-eating disorder (BED) is the commonest eating disorder and an important causal factor in obesity. Lisdexamfetamine is the only approved pharmacological treatment. Many drugs have been clinically evaluated and several were described as potentially promising treatments.

Evaluating the abuse potential of psychedelic drugs as part of the safety pharmacology assessment for medical use in humans.

Psychedelics comprise drugs come from various pharmacological classes including 5-HT agonists, indirect 5-HT agonists, e.g., MDMA, NMDA antagonists and κ-opioid receptor agonists.

Dopamine and μ-opioid receptor dysregulation in the brains of binge-eating female rats - possible relevance in the psychopathology and treatment of binge-eating disorder.

Adult, female rats given irregular, limited access to chocolate develop binge-eating behaviour with normal bodyweight and compulsive/perseverative and impulsive behaviours similar to those in binge-eating disorder. We investigated whether (a) dysregulated central nervous system dopaminergic and opioidergic systems are part of the psychopathology of binge-eating and (b) these neurotransmitter systems may mediate the actions of drugs ameliorating binge-eating disorder psychopathology. Binge-eating produced a 39% reduction of striatal D receptors with 22% and 23% reductions in medial and lateral caudate putamen and a 22% increase of striatal μ-opioid receptors.

Dopamine reuptake transporter (DAT) "inverse agonism"--a novel hypothesis to explain the enigmatic pharmacology of cocaine.

The long held view is cocaine's pharmacological effects are mediated by monoamine reuptake inhibition. However, drugs with rapid brain penetration like sibutramine, bupropion, mazindol and tesofensine, which are equal to or more potent than cocaine as dopamine reuptake inhibitors, produce no discernable subjective effects such as drug "highs" or euphoria in drug-experienced human volunteers. Moreover they are dysphoric and aversive when given at high doses.

Differences in the neurochemical and behavioural profiles of lisdexamfetamine methylphenidate and modafinil revealed by simultaneous dual-probe microdialysis and locomotor activity measurements in freely-moving rats.

Lisdexamfetamine dimesylate is a novel prodrug approved in North America, Europe and Brazil for treating attention deficit hyperactivity disorder (ADHD). It undergoes rate-limited hydrolysis by red blood cells to yield d-amphetamine. Following our previous work comparing lisdexamfetamine with d-amphetamine, the neurochemical and behavioural profiles of lisdexamfetamine, methylphenidate and modafinil were compared by dual-probe microdialysis in the prefrontal cortex (PFC) and striatum of conscious rats with simultaneous locomotor activity measurement.

A preclinical evaluation of the discriminative and reinforcing properties of lisdexamfetamine in comparison to D-amfetamine, methylphenidate and modafinil.

Lisdexamfetamine dimesylate, which consists of L-lysine covalently bound to D-amfetamine, is the first prodrug for treating ADHD. Its metabolic conversion to yield D-amfetamine by rate-limited, enzymatic hydrolysis is unusual because it is performed by peptidases associated with red blood cells. Other stimulants shown to be effective in managing ADHD include D-amfetamine, methylphenidate and modafinil.

Amphetamine, past and present--a pharmacological and clinical perspective.

Amphetamine was discovered over 100 years ago. Since then, it has transformed from a drug that was freely available without prescription as a panacea for a broad range of disorders into a highly restricted Controlled Drug with therapeutic applications restricted to attention deficit hyperactivity disorder (ADHD) and narcolepsy. This review describes the relationship between chemical structure and pharmacology of amphetamine and its congeners.

Metabolic consequences of antipsychotic therapy: preclinical and clinical perspectives on diabetes, diabetic ketoacidosis, and obesity.

Antipsychotic drugs, particularly second-generation antipsychotics (SGAs), have reduced the burden to society of schizophrenia, but many still produce excessive weight gain. A significant number of SGAs also act directly to impair glycemic control causing insulin resistance, impaired glucose tolerance and type 2 diabetes, and also rarely diabetic ketoacidosis (DKA). Schizophrenia itself is almost certainly causal in many endocrine and metabolic disturbances, making this population especially vulnerable to the adverse metabolic consequences of treatment with SGAs.

What is the prognosis for new centrally-acting anti-obesity drugs?

Obesity is a global problem that is predominantly caused by the increasing adoption of a low-cost, Westernised diet that is rich in fat and sugar and a more sedentary lifestyle. The costs of this epidemic are substantial increases in Type 2 diabetes, cardiovascular disease and some types of cancer that are certain to place a huge burden on individuals, healthcare providers and society. In this review, we provide an overview of the chequered history of pharmacotherapy for the treatment of obesity and an analysis of the regulatory and commercial challenges for developing new centrally-acting drugs in this metabolic indication.

Regulatory challenges for new drugs to treat obesity and comorbid metabolic disorders.

Obesity is a major cause of morbidity and mortality through cardio- and cerebrovascular diseases and cancer. The metabolic consequences of obesity include dyslipidaemia, hypertension, proinflammatory atherogenesis, pre-diabetes and Type 2 diabetes. For a significant proportion of patients, pharmacotherapy to tackle obesity is required as adjunctive support to diet, exercise and lifestyle modification.