Endocannabinoids: Windows to the Brain
Katherine H. Taber, Ph.D. and Robin A. Hurley, M.D.
Cannabis sativa (hemp) is a flowering annual that has been in use as a structural material (cordage, cloth, paper) and in medicine for thousands of years.5–7 Reference to the psychoactive effects of its phytochemical products have been found in writing throughout the ancient world. Cannabis herb (marijuana) is made by drying the leaves and flowering tops. Cannabis resin (hashish) is made by collecting the fluid secreted by the plant during the flowering phase.
A recent review indicates that studies of this plant have identified more than 500 compounds within the plant.6 The principle psychoactive cannabinoids in Cannabis sativa are 8 and 9 tetrahydrocannabinol (THC)6,7 9 THC is considered the major psychoactive constituent as it is considerably more abundant in the plant and more potent in effect. The amount of 9 THC varies greatly across plant strains and is also affected by farming and preparation techniques.8Studies suggest an increasing content of 9 THC in street cannabis over the past few decades (e.g., 1.5% in 1980, 4.47% in 1997, 5.11% in 2002).8 9 THC is converted to 11-hydroxy-9 THC in the lungs and liver.7 Onset of action depends on both dose and method of administration. Following ingestion by smoking, initial effects may appear within the first minute, whereas following oral ingestion first effects may appear in 15–30 minutes.8,9 Onset, duration and nature of action (pleasant versus unpleasant) are affected by other factors, as well, such as individual differences in absorption, method of smoking, previous history, anxiety level, and environmental context.8,10Early acute effects commonly include light-headedness and euphoria, with some individuals experiencing tachycardia and hypotension. Later acute effects may include time dilation, relaxation, increased body awareness, increased appetite, sleepiness, impaired memory, and impaired concentration.7–9,11 Adverse reactions do occur (e.g., anxiety, panic, paranoia, psychotic symptoms), but are much less common.8,9,11,12 Functional imaging studies indicate that intoxication is associated with increased regional cerebral blood flow and metabolism, particularly in frontal and limbic regions as well as the cerebellum.8
Both tolerance and dependence can develop with chronic use.9,11–13 Withdrawal is characterized by nervousness, tension, anxiety, and sleep disturbances. While long-term cognitive impairment has been reported in some studies, the evidence for this is not strong.7–9,11,12 Some studies support an influence of cannabis use on the development of psychiatric disorders, particularly schizophrenia and mood disorders.11,12,14
A surge in research into the mechanism of action for 9 THC in the brain followed its isolation and identification in the 1960s.6 This led to the identification of endogenous cannabinoid (endocannabinoid) receptors in brain tissue. Research intensified following the cloning of these receptors (CB1 and CB2) in the early 1990s.6,7,15,16 Identification of the first endocannabinoid, N-arachidonoylethanolamine (anandamide, from the Sanskrit for “eternal bliss”) was achieved soon after.6 A decade later the modulatory action of endocannabinoids at synapses was discovered.17 Both the CB1 and CB2 receptors are cell surface proteins that span the membrane and are coupled intracellularly to one of the G-proteins.7,16–18 The distributions and actions of the CB1 and CB2 receptors are quite different.6,7,9,15–19 CB1 receptors are located predominately on axon terminals in both the central and peripheral nervous system and on some peripheral tissues (e.g., liver, gut, adrenal, muscle, fat). CB2 receptors are found principally peripherally on immune cells (e.g., spleen, macrophages, tonsils, monocytes, neutrophils), and were originally not thought to occur in the brain. More recently they have been identified on both neurons and glial cells, where they may participate in immune functions.6,7,9,17,20–22 This article will focus on the CB1 receptor and compounds that interact with it, as this system mediates most or all of the psychotropic actions of cannabinoids.
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