The human body possesses specific binding sites on the surface of many cell types for cannabinoids, and our body produces several endocannabinoids, fatty acid derivatives that bind to these cannabinoid receptors (CB) and activate them. CB receptors and endocannabinoids together constitute the endocannabinoid system. Some phytocannabinoids, cannabinoids of the cannabis plant, and a multitude of synthetic cannabinoids produced in the laboratory mimic the effects of endocannabinoids. Δ9-THC (dronabinol), the pharmacologically most active cannabinoid of the cannabis plant, binds to both types of cannabinoid receptors that have been identified so far, the CB1 and the CB2 receptor. These receptors have been found in the central nervous system (brain and spinal cord) and many peripheral tissues and organs. Depending on the kind of cells, on dose and state of the body, activation of CB receptors may cause a multitude of effects including euphoria, anxiety, dry mouth, muscle relaxation, hunger and pain reduction. Besides activation of CB receptors several other approaches are under investigation to influence the cannabinoid system with therapeutic intent, including blockade of CB receptors (antagonism) and modulation of endocannabinoid concentrations by inhibition of their degradation. Currently, several preparations that stimulate cannabinoid receptors (dronabinol, nabilone and cannabis) and one compound that blocks the CB1 receptor (rimonabant) are used medicinally. Keywords: Cannabis, THC, cannabinoid, cannabinoid receptor, endocannabinoid, therapeutic use. This article can be downloaded, printed and distributed freely for any non-commercial purposes, provided the original work is properly cited (see copyright info below). Available online at www.cannabis-med.org Author's address: Franjo Grotenhermen, franjo-grotenhermen@nova-institut.de Introduction Δ9-tetrahydrocannabinol (THC) is thought to be the pharmacologically most active cannabinoid of the cannabis plant and its products marijuana (cannabis herb) and hashish (cannabis resin). The majority of THC effects are mediated through agonistic actions at cannabinoid receptors of the human or animal body. Agonistic action means that receptors are activated in contrast to antagonistic action, i.e. blockade of receptor effects. Cannabinoid receptors and endocannabinoids, compounds produced by the body that bind to these receptors, together constitute the endocannabinoid system. This system is of great importance for the normal function of the body and is millions of years old. It has been found in mammals, birds, amphibians, fish, sea urchins, molluscs and leeches. The mechanism of action of cannabinoids is best investigated for THC and other cannabinoids that bind to known cannabinoid receptors, while the mode of action of other cannabinoids of therapeutic interest, among them cannabidiol (CBD), is less well established. Extended reviews on the issues presented in this short article are available at [2,4,5,7,9]. Additional and upto- date information is available from the IACM-Bulletin [8]. Cannabinoids Cannabinoids were originally regarded as any of a class of typical C21 groups of compounds present in Cannabis sativa L.. The modern definition is termed with more emphasis on synthetic chemistry and on pharmacology, and encompasses kindred structures, or any other compound that affects cannabinoid receptors. Monoterpenoid numbering Dibenzopyran numberingTHC (dronabinol), the main cannabinoid in the cannabis plant, according to the monoterpenoid system (Δ1-THC) and dibenzopyran system (Δ9-THC). This has created several chemical sub-categories that take into consideration the various forms of natural and synthetic compounds. It has been proposed to use the term phytocannabinoid for the natural plant compounds and endocannabinoids for the natural animal compounds, the endogenous ligands of the cannabinoid receptors. Synthetic agonists of these receptors have been classified according to their degree of kinship (e.g. "classical" vs. "non-classical") with phytocannabinoids. Natural plant cannabinoids are oxygen-containing aromatic hydrocarbons. In contrast to most other drugs, including opiates, cocaine, nicotine and caffeine, they do not contain nitrogen, and hence are not alkaloids. Phytocannabinoids were originally thought to be only present in the cannabis plant (Cannabis sativa L.), but recently some cannabinoid type bibenzyls have also been found in liverwort (Radula perrottetii and Radula marginata). More than 60 cannabinoids have been detected in cannabis, mainly belonging to one of 10 subclasses or types [3], of whom the cannabigerol type (CBG), the cannabichromene type (CBC), the cannabidiol type (CBD), the Δ9-THC type, and the cannabinol type (CBN) are the most abundant. Cannabinoid distribution varies between different cannabis strains and usually only three or four cannabinoids are found in one plant in concentrations above 0.1%. Δ9-THC is largely responsible for the pharmacological effects of cannabis including its psychoactive properties, though other compounds of the cannabis plant also contribute to some of these effects, especially CBD, a non-psychoactive phytocannabinoid common in some cannabis strains that has anti-inflammatory, analgesic, anti-anxiety and anti-psychotic effects. 11-OH-Δ9-tetrahydrocannabinol (11-OH-THC) is the most important psychotropic metabolite of Δ9-THC with a similar spectrum of actions and similar kinetic profiles as the parent molecule. 11-nor-9-carboxy-THC (THC-COOH) is the most important non-psychotropic metabolite of Δ9-THC. Cannabinoid Receptors To date two cannabinoid receptors have been identified, the CB1, and the CB2 receptor. They differ in signaling mechanisms and tissue distribution. Activation of cannabinoid receptors causes inhibition of adenylat cyclase, thus inhibiting the conversion of ATP to cyclic AMP (cAMP). Other mechanisms have also been observed, e.g. interaction with certain ion channels. Both CB1 and CB2 receptors belong to the large family of the G-protein-coupled receptors (GPCR). GPCRs are the most common receptors, containing 1000-2000 members in vertebrates. Cannabinoid CB1 receptors are among the most abundant and widely distributed GPCRs in the brain. Activation of the CB1 receptor produces effects on circulation and psyche common to cannabis ingestion, while activation of the CB2 receptor does not. CB1 receptors are mainly found on nerve cells in the brain, spinal cord and peripheral nervous system, but are also present in certain peripheral organs and tissues, among them endocrine glands, salivary glands, leukocytes, spleen, heart and parts of the reproductive, urinary and gastrointestinal tracts. Many CB1 receptors are expressed at the terminals of central and peripheral nerves and inhibit the release of other neurotransmitters. Thus, CB1 receptor activation protects the nervous system from over-activation or over-inhibition by neurotransmitters. CB1 receptors are highly expressed in regions of the brain, which are responsible for movement (basal ganglia, cerebellum), memory processing (hippocampus, cerebral cortex) and pain modulation (certain parts of the spinal cord, periaqueductal grey), while their expression in the brainstem is low, which may account for the lack of cannabis-related acute fatalities. The brainstem controls, among others, respiration and circulation. www.hemp4cure.co.uk |
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