Psychoactive Plants Hallucinogens - I: Marijuana

Marijuana  Cannabis sativa is one of the oldest cultivated plants in the world  Origin  Early history China Scythians Spread though Asia, Africa, and other area  Later History  North America  Recent History  New Laws in England

Botany of Cannabis sativa  Dioecious annual with male and female flowers on different individuals  Distinctive compound leaf with seven leaflets  The hallucinogenic properties concentrated in the resin which is produced by glandular trichomes  Maximum amount of resin on female plants, especially unfertilized female flowers

Female Plant Male Plant

Biochemistry  Hallucinogenic properties concentrated in the resin with the compound Delta-9-tetrahydrocannabinol (THC) the main psychoactive compound  THC belongs to a unique group of phenolic compounds called cannabinoids

THC  Concentration of THC varies greatly with the variety, sex, climate, growing conditions Sinsemilla varieties have highest THC Varieties cultivated for fiber (hemp varieties) have the lowest levels of THC  Potent varieties  Sensimilla hybrids result from crossing C. sativa and C. indica

Effects of Marijuana  Euphoria and calmness  Even moderate use impairs learning, short-term memory, and reaction time  THC is fat-soluble and accumulates in body tissues and may remain for days  One of the best studied effects is decreased sperm production  Decreased testosterone levels have also been reported

Cannabinoid Receptors  Humans have cannabinoid receptors in the brain, CNS, and other tissues  Functions of these receptors and the endogenous ligands not clear  At least two subtypes of these receptors exist - CB1 and CB2 - evidence also suggests other subtypes  G-protein linked receptors

Cannabinoid Receptors  CB1 cannabinoid receptors - most prominent in the brain and CNS and appears to mediate the psychoactive properties  CB2 cannabinoid receptors - appear to be almost exclusively expressed in the peripheral tissues - especially immune tissues and may modulate responses of the immune system

Natural Cannabinoids  First natural cannabinoid discovered in 1992  Anandamide is an endogenous ligand to the cannabinoid receptors in brain – function not completely determined – apparently binds to CB1  Other natural ligands have since been identified  When activated, CB1 receptors seem to suppress the release of one or more transmitters – glutamate, dopamine, GABA – this in turn may affect learning, movement, and memory  Show some interaction with opiate receptors

Cannabinoid Receptors

Cannabinoids  CB1 receptors are extremely abundant in the brain – more so than most other G-protein linked receptors – 10x more abundant that  opioid receptors (responsible for pain relief and euphoria from opiates)  Studied extensively in vertebrates and invertebrates – highly conserved molecule suggesting a long evolutionary history (500 million yrs) suggesting that cannabinoids play and important basic function in animal physiology

Medical Uses of Marijuana  Marijuana has been used as a medicinal plant by cultures throughout the world  In modern medicine, several well documented uses glaucoma treatment aid to chemotherapy increase appetite in AIDS patients and senior citizens reduce tremors in MS patients analgesic

Glaucoma Treatment  Glaucoma - eye disorder characterized by increased pressure This can damage the optic nerve and lead to blindness Leading cause of blindness in the U.S.  Marijuana - either smoking or ingesting oral preparations can decrease ocular pressure - smoke is especially effective

Aid to Chemotherapy  Chemotherapy for cancer often has side effects that result in nausea, vomiting, and loss of appetite - often results in severe weight loss - patients weaken considerable - often impairing recovery  Marijuana helps offset some of these effects - and especially increase appetite  Also growing evidence of anti-cancer activity

Other uses for appetite improvement  AZT and other drugs used to treat AIDS result in nausea and anorexia  Like use of chemotherapy in cancer patients, this commonly causes severe weight loss which impairs the bodies ability to fight  Marijuana helps nausea and increases the appetite thereby counteracting weight loss  Anorexia also a problem in some senior citizens

Multiple Sclerosis  Multiple sclerosis causes the destruction of patches of myelin in the brain and spinal cord  Demyelination produces many problems, so that victims eventually cannot walk, sit up, and become crippled and bedridden often with terrible muscle spasms  No effective treatment for MS - medications provide some relief from muscle spasms; however, the drugs lead to addiction  Marijuana reduce spasms in patients with MS  Individuals using marijuana have testified that sight and walking have been regained and spasms reduced or eliminated,  There is some evidence that the progress of MS is actually retarded

Analgesic Effects  In animal tests cannabinoids are analgesic and reduce neuropathic pain  Likely similar action in humans  Some studies show that cannabinoids are no more effective than codeine and have enough side effects to limit their use  Further studies needed to see about use for spasticity and neuropathic pain  Recent study CB2 receptors/endorphins

New Laws  Since 1996, nine states (Alaska, California, Colorado, Hawaii, Maine, Nevada, Oregon, Vermont, and Washington) have enacted laws or passed referenda that effectively allow patients to use medical marijuana.  These laws permit patients to use marijuana on the advise of their physicians.  In addition Arizona passed legislation, which allows physicians to write prescriptions for medical marijuana use  Federal Response to these laws aimed at physicians  Ten other states have symbolical medical marijuana laws (support use but have not legal protection)  Twelve states have medical marijuana research laws

States with effective medical marijuana laws Note: Arizona has a law but it is not effective because it only permits medical marijuana use when it is prescribed but physicians cannot legally prescribe

Editorial in NEJM  It was wrong to prohibit physicians from helping their patients.  It called for the reclassification of marijuana as a Schedule II drug so that physicians could prescribe it when needed.  Marijuana is currently classified as a Schedule I drug which is defined as a drug with no accepted medical use and a high potential for abuse.  Schedule II drugs can be prescribed for appropriate medical applications

NAS Study: Marijuana and Medicine  Cannabinoids likely have a natural role in pain modulation, control of movement, and memory.  The natural role of cannabinoids in immune systems is likely multi-faceted and remains unclear.  The brain develops tolerance to cannabinoids.  Animal research demonstrates the potential for dependence, but this potential is observed under a narrower range of conditions than with benzodiazepines, opiates, cocaine, or nicotine.  Withdrawal symptoms can be observed in animals but appear to be mild compared to opiates or benzodiazepines, such as diazepam (Valium).

Supreme Court  In May 2001 the U.S. Supreme Court unanimously ruled that medical use of marijuana is not a valid exception to the federal law that classifies marijuana as an illegal substance.  Justice Clarence Thomas: controlled substance statue “includes no exception at all for any medical use of marijuana”  Justices Sutter, Stevens, Ginsburg: Decision went too far!  In June 2005, Supreme Court ruled that the Federal Government can prosecute medical marijuana patients even in states that have laws allowing medical marijuana use.