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By John M. McPartland, DO, MS
Cannabis is used as a recreational drug, a medicinal herb, and the original source of the pharmaceutical drug dronabinol, an appetite stimulant and antiemetic. The active constituents in cannabis are cannabinoids. Although, the best-known cannabinoid is tetrahydrocannabinol (THC), there are many types, including some that are in chocoate (see Alternative Therapies in Women’s Health, March 1999, pp. 28-29). Cannabinoids affect women’s health in several ways. This article will clarify the definition of cannabinoids and address a few concerns regarding endocrinology and reproductive physiology.
Initially, cannabinoids were defined as a group of C21 terpenophenolic compounds uniquely produced by cannabis plants.1 Later, chemists at Lilly, Pfizer, and Sterling created synthetic cannabimimetic analogs, some of which are 800 times more potent than THC. These super-THCs proved useful as powerful research tools. Devane, Howlett, and colleagues probed marijuana’s psychoactivity using the super-THC CP55940, and they proved that THC fits into a selective, high-affinity neuron receptor.2 Prior to Devane’s discovery, researchers thought THC worked as a non-specific cell membrane solvent, "sloshing" neurons in the same manner as ethanol.
After Devane discovered cannabinoid receptors, he moved to the lab of Raphael Mechoulam, the Israeli scientist who discovered THC nearly 30 years ago. The discovery of specific cannabinoid receptors was exciting, and these investigators knew that it was implausible that receptors in human tissue could only be filled by an exogenous substance. Together they searched for the "endogenous ligand" that our bodies make to fit the cannabinoid receptor. The "endocannabinoid" molecule they isolated was quite surprising; it looked nothing like THC and turned out to be an amide of arachidonic acid.3 They named the molecule "anandamide," derived from the Sanskrit word ananda for "bliss." (Anandamide is one of the cannabinoids found in chocolate.)
The next big discovery was a cannabinoid antagonist, SR141716A, synthesized by Sanofi Labs. SR141716A blocks the effects of marijuana, and reverses the effects of THC—it improves short-term memory; makes rats more sensitive to pain; and inhibits "the munchies," thus causing weight loss. Researchers found that the cannabinoid receptors indirectly affect numerous other neurotransmitters and their receptors (including serotonin, dopamine, norepinephrine, acetylcholine, the endorphins, GABA, NMDA, and glutamate).
The identification of a second type of cannabinoid receptor ("CB2") led to the discovery of additional endocannabinoids. CB2 receptors occur on white blood cells, splenocytes, and tissues associated with immune function. Thus the cannabinoid system weaves between the mind and body.
The cannabinoid receptor is a G protein-coupled, seven-helix transmembrane nucleotide, similar to receptors of other neurotransmitters. The distribution of cannabinoid receptors correlates with the effects of THC. Dense receptor concentrations are found in the hippocampus (affecting short-term memory), the limbic system (controlling mood and emotions), and the cerebellum and basal ganglia (involved in coordination of movement). Low receptor concentrations in the brain stem help explain the lack of lethal effects from marijuana overdose.
Outside the CNS, dense concentrations of cannabinoid receptors appear in the ovaries and endometrium.4 Although the discovery of receptors in the female reproductive tract is relatively recent, the use of cannabis to treat reproductive tract problems has a long history; many physicians (including Sir Russell Reynolds, physician to Queen Victoria) have prescribed cannabis for dysmenorrhea.5
This may well have been an effective treatment; THC exerts significant anti-inflammatory effects by blocking the synthesis of prostaglandin E2 from arachidonic acid. To wit, cannabinoids act as selective COX-2 inhibitors, similar to celecoxib.6 Anti-prostaglandin activity may also account for some of the negative effects of cannabinoids on reproduction in rats, ranging from poor embryo implantation7 to post-term delivery and an increase in the frequency of stillbirths.8
Cannabis is an effective antiemetic and has been used to treat nausea and vomiting of pregnancy. Given the reproductive toxicity shown in animal studies, neither marijuana nor its derivatives should be used for pregnancy-related morning sickness.
Cannabinoids have complex actions on the endocrine system, with conflicting reports appearing in the literature. In rats, THC and anandamide stimulate the hypothalamic-pituitary-adrenal axis. This cascade begins in the receptor-rich hypothalamus, where cannabinoids quickly stimulate the secretion of corticotropin-releasing factor (CRF), which causes the pituitary to produce ATCH, resulting in the release of corticosterone from the adrenal cortex.9 Cells in the limbic system also produce CRF, but these neurons increase CRF production during cannabinoid withdrawal from chronic use.10
Other pituitary hormones in rats are affected by cannabinoids. No changes are seen in serum levels of follicle stimulating hormone (FSH); but cannabinoids suppress luteinizing hormone (LH), growth hormone (GH), and thyrotropin. The prolactin response is biphasic; early stimulation is followed by suppression.11,12 Based on a study of 56 women and 93 men who used cannabis at least once weekly for the two previous years (women averaged 5.8 uses/week; men averaged 8.2 uses/week), cannabinoids appear to have fewer endocrine effects in humans.13 The study results indicate that humans who smoke marijuana on a chronic basis, compared to non-smoking controls, exhibit no differences in cortisol, prolactin, LH, or FSH.13
THC and other cannabinoids do not exhibit direct estrogenic activity in estrogen receptor assays,4 but marijuana smoke interacts weakly with estrogen receptors in vitro.14 Apparently, marijuana contains phytoestrogens, including the estrogenic flavonoid apigenin, and volatilized apigenin retains pharmacological activity.14 Is the estrogenic effect of apigenin worrisome? Probably not, but this may contribute to gynecomastia that sometimes arises in males who are heavy smokers of marijuana. Apigenin has a high affinity for estrogen receptors (especially beta-estrogen receptors), but low estrogenic activity in estrogen-binding assays.15 In vitro, apigenin actually inhibits estradiol-induced proliferation of breast cancer cells.16
Cannabinoids also inhibit the growth of human breast cancer cells in vitro.17 Apparently cannabinoid receptors in breast cells suppress the synthesis of prolactin receptors and subsequently prolactin action, thus resulting in the down-regulation of the breast cancer BRCA 1 gene.18 Thus, the anti-proliferative action of cannabinoids is due to inhibition of DNA synthesis rather than to cytotoxicity or apoptosis. These characteristics have interested researchers who are designing and testing cannabinoids as potentially novel breast cancer treatments.
The Institute of Medicine (IOM) just released a report on medical marijuana.18 Because the report was funded by the White House Office of National Drug Control Policy, it is not surprising that the IOM endorsed pharmaceutical cannabinoids, but criticized the delivery of cannabinoids through smoked marijuana. The objections to the latter delivery system were both cultural (as Eric Voth, one of the panel of reviewers, stated, "We do not smoke medicine anywhere in our society")19 and medical (unfiltered marijuana smoke is very high in tars).
Tars can be avoided, however, by utilizing vaporizer technology. Vaporizers heat marijuana to 180-190o C, which is sufficiently high to vaporize THC, but is below the burning point of combustible plant materials, so no smoke is generated.20 Although vaporizers have been used with marijuana for 20 years, the IOM panel ignored this technology.
In addition to cannabinoids and phytoestrogens, marijuana contains dozens of terpenoids, which are volatilized and inhaled, cross the blood-brain barrier, and may modulate the effects of THC.21 Limonene, carvacrol, and pulegone, for instance, inhibit acetylcholinesterase (a mechanism shared by tacrine), so these terpenoids reverse the cholinergic deficit created by THC. Tacrine has blocked THC-mediated memory loss behavior in rats, and the same may be true of acetylcholinesterase inhibitors intrinsic to cannabis plants.21 The modulating effect of non-cannabinoids may be why many patients claim that utilizing the polypharmaceutical herb marijuana is superior to pure, synthetic THC (dronabinol).21
In summary, as noted by the IOM report, marijuana and cannabinoids are not completely benign substances. They are powerful drugs with a variety of pharmacological effects. Some of these effects are potentially therapeutic, but the subject of medical use of marijuana (as opposed to the use of isolated cannabinoids) remains embedded in a web of social concerns.
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