The recent identification of cannabinoid receptors and their endogenous lipid ligands has triggered an exponential growth of studies exploring the endocannabinoid system and its regulatory functions in health and disease. Such studies have been greatly facilitated by the introduction of selective cannabinoid receptor antagonists and inhibitors of endocannabinoid metabolism and transport, as well as mice deficient in cannabinoid receptors or the endocannabinoid-degrading enzyme fatty acid amidohydrolase. In the past decade, the endocannabinoid system has been implicated in a growing number of physiological functions, both in the central and peripheral nervous systems and in peripheral organs. More importantly, modulating the activity of the endocannabinoid system turned out to hold therapeutic promise in a wide range of disparate diseases and pathological conditions, ranging from mood and anxiety disorders, movement disorders such as Parkinson9s and Huntington9s disease, neuropathic pain, multiple sclerosis and spinal cord injury, to cancer, atherosclerosis, myocardial infarction, stroke, hypertension, glaucoma, obesity/metabolic syndrome, and osteoporosis, to name just a few. An impediment to the development of cannabinoid medications has been the socially unacceptable psychoactive properties of plant-derived or synthetic agonists, mediated by CB 1 receptors. However, this problem does not arise when the therapeutic aim is achieved by treatment with a CB 1 receptor antagonist, such as in obesity, and may also be absent when the action of endocannabinoids is enhanced indirectly through blocking their metabolism or transport. The use of selective CB 2 receptor agonists, which lack psychoactive properties, could represent another promising avenue for certain conditions. The abuse potential of plant-derived cannabinoids may also be limited through the use of preparations with controlled composition and the careful selection of dose and route of administration. The growing number of preclinical studies and clinical trials with compounds that modulate the endocannabinoid system will probably result in novel therapeutic approaches in a number of diseases for which current treatments do not fully address the patients9 need. Here, we provide a comprehensive overview on the current state of knowledge of the endocannabinoid system as a target of pharmacotherapy.

http://www.phytecs.com/wp-content/uploads/2015/02/Pharmacol-Rev-2006-Pacher-389-462.pdf

The Endocannabinoid System as an Emerging Target of Pharmacotherapy

A model is proposed for integrating the neural and cognitive aspects of the positive symptoms of acute schizophrenia, using evidence from postmortem neuropathology and neurochemistry, clinical and preclinical studies of dopaminergic neurotransmission, anatomical connections between the limbic system and basal ganglia, attentional and other cognitive abnormalities underlying the positive symptoms of schizophrenia, specific animal models of some of these abnormalities, and previous attempts to model the cognitive functions of the septohippocampal system and the motor functions of the basal ganglia Anatomically, the model emphasises the projections from the septohippocampal system, via the subiculum, and the amygdala to nucleus accumbens, and their interaction with the ascending dopaminergic projection to the accumbens Psychologically, the model emphasises a failure in acute schizophrenia to integrate stored memories of past regularities of perceptual input with ongoing motor programs in the control of current perception A number of recent experiments that offer support for the model are briefly described, including anatomical studies of limbic-striatal connections, studies in the rat of the effects of damage to these connections, and of the effects of amphetamine and neuroleptics, on the partial reinforcement extinction effect, latent inhibition and the Kamin blocking effect; and studies of the latter two phenomena in acute and chronic schizophrenics

The neuropsychology of schizophrenia.

Δ9-Tetrahydrocannabinol (THC) is the main source of the pharmacological effects caused by the consumption of cannabis, both the marijuana-like action and the medicinal benefits of the plant. However, its acid metabolite THC-COOH, the non-psychotropic cannabidiol (CBD), several cannabinoid analogues and newly discovered modulators of the endogenous cannabinoid system are also promising candidates for clinical research and therapeutic uses. Cannabinoids exert many effects through activation of G-protein-coupled cannabinoid receptors in the brain and peripheral tissues. Additionally, there is evidence for nonreceptor-dependent mechanisms. Natural cannabis products and single cannabinoids are usually inhaled or taken orally; the rectal route, sublingual administration, transdermal delivery, eye drops and aerosols have only been used in a few studies and are of little relevance in practice today. The pharmacokinetics of THC vary as a function of its route of administration. Pulmonary assimilation of inhaled THC causes a maximum plasma concentration within minutes, psychotropic effects start within seconds to a few minutes, reach a maximum after 15–30 minutes, and taper off within 2–3 hours. Following oral ingestion, psychotropic effects set in with a delay of 30–90 minutes, reach their maximum after 2–3 hours and last for about 4–12 hours, depending on dose and specific effect. At doses exceeding the psychotropic threshold, ingestion of cannabis usually causes enhanced well-being and relaxation with an intensification of ordinary sensory experiences. The most important acute adverse effects caused by overdosing are anxiety and panic attacks, and with regard to somatic effects increased heart rate and changes in blood pressure. Regular use of cannabis may lead to dependency and to a mild withdrawal syndrome. The existence and the intensity of possible long-term adverse effects on psyche and cognition, immune system, fertility and pregnancy remain controversial. They are reported to be low in humans and do not preclude legitimate therapeutic use of cannabis-based drugs. Properties of cannabis that might be of therapeutic use include analgesia, muscle relaxation, immunosuppression, sedation, improvement of mood, stimulation of appetite, antiemesis, lowering of intraocular pressure, bronchodilation, neuroprotection and induction of apoptosis in cancer cells.

Pharmacokinetics and Pharmacodynamics of Cannabinoids

Re-evaluating the prevalence of and diagnostic composition within the broad clinical spectrum of bipolar disorders.

Toward a re-definition of subthreshold bipolarity: epidemiology and proposed criteria for bipolar-II, minor bipolar disorders and hypomania.

Psychedelic Drugs Reconsidered

Two researchers describe the medical benefits of marijuana, explain why it has been forbidden, and put forward arguments for legislation to make it available for patients who need it. Their argument is supported by accounts from individuals with various ailments.

Marihuana, the Forbidden Medicine

Introduction. Foreword. Section I: Bipolar Disorders. Foreword. Differential diagnosis, natural course, and epidemiology of bipolar disorders. Biological findings in bipolar disorders. Sleep and biological rhythms in bipolar illness. Treatment of bipolar disorders. Psychotherapeutic issues and suicide prevention in the treatment of bipolar disorders. Clinical approaches to treatment-resistant bipolar illness. Afterword. Section II: Neuroscience Techniques in Clinical Psychiatry. Foreword. Psychopharmacology in clinical psychiatry. Psychoendocrinology in clinical practice. Psychoimmunology in clinical psychiatry. The neurobiology of sleep: basic concepts and clinical implications. X-ray computed tomography and magnetic resonance imaging in psychiatry. Functional brain imaging techniques. Afterword. Section III: Differential Therapeutics. Foreword. The setting for psychiatric treatment. Differential therapeutics and treatment format. Strategies and techniques of prescriptive psychotherapeutic intervention. The choice of duration and frequency for outpatient psychotherapy. Differential therapeutics: psychopharmacology. Differential therapeutics: clinical, teaching, research, and administrative issues. Afterword. Section IV: Violence and the Violent Patient. Foreword. Determinants of human violence. Patterns in human violence. Evaluation of the violent patient. Emergency management of violent patients. The long-term treatment of the violent patient. Legal aspects of violence by psychiatric patients. Afterword. Section V: Psychiatric Epidemiology. Foreword. Epidemiology overview. The assessment of psychiatric diagnosis in epidemiological studies. Psychiatric disorders in the community: the epidemiologic catchment area study. Genetic epidemiology of psychiatric disorders. Parental mental disorder as a psychiatric risk factor. Toward the prevention of psychiatric risk disorders. Epidemiologic findings from disaster research. Afterword. Section VI: Psychopharmacology: Drug Side Effects and Interactions. Foreword. Antipsychotic drug side effects. Side effects of antidepressant drugs. Lithium carbonate and carbamazepine side effects. Benzodiazepine side effects. Clinically significant psychoactive drug interactions. Afterword. Index.

Psychiatry update : American Psychiatric Association annual review

Cocaine : a drug and its social evolution

Virtually all known human groups have devised and regularly used techniques for altering consciousness, among which alcohol and drugs are prominent. The authors offer a provocative analysis of the philosophical, sociological, and historical background of the attempt to control consciousness-altering drugs in modern industrial societies. In considering the right of individuals to diversify and enrich their experience versus the obligations of government to protect their citizens, they enable readers to step back for a moment and examine alternative ways of looking at what is usually called the drug problem.

/pdf/drug-control-in-a-free-society-tftqy037qa.pdf

Lester Grinspoon

Papers

Psychedelic Drugs Reconsidered

Marihuana, the Forbidden Medicine

Psychiatry update : American Psychiatric Association annual review

Cocaine : a drug and its social evolution

Drug Control in a Free Society