Marijuana Marijuana is a mixture of dried and crumbled leaves, small stems, and flowering tops from cannabis sativa, cannabis indica, cannabis ruderalis. It can be consumed orally, as in cookies or brownies, but is usually smoked in rolled cigarettes known as “joints,” various kinds of pipes, or in hollowed-out cigars called “blunts.” The psychoactive compound Δ9-tetrahydrocannabinol (THC), accounts for the use of cannabis as a drug and is concentrated in plant resin (most in flowering buds). Marijuana potency (in terms of THC content) varies widely, depending on the genetic strain of the plant and growing conditions. Potency can be increased by preventing pollination and seed production by the female plants. This marijuana is called sinsemilla (“without seeds”). Makes up 50% of confiscated marijuana. 11% considered “high grade” #1 most widely used illegal drug in US; It is classified as a mild hallucinogen Potency also depends on: frequency of use user characteristics setting expectations smoking behavior

Hashish Hashish is a cannabis derivative that can be smoked or eaten. It can refer to a relatively pure resin preparation with very high cannabinoid content, or a solvent extract of leaves or resin. Most potent form of marijuana Hash oil is an alcoholic extract. A drop is placed on a tobacco or marijuana cigarette. Use is fairly rare in US now less than 1% has been confiscated 2

History of Marijuana Marijuana remains a controversial subject in our society—castigated by many as a gateway to the so-called hard drugs, but praised by others as an unappreciated medical marvel. Marijuana is produced from flowering hemp (Cannabis sativa). Hemp has been a major source of fiber in many cultures for rope, cloth, and paper. Hemp seeds have been used for oil and bird food. Hemp also contains 70 unique compounds known as cannabinoids, plus more than 400 other identified compounds. 3

Early History of Marijuana 8000 BC: first archeological record 2700-1000 BC: Medical and religious use can be traced to ancient China, India, and the Middle East, spreading to the Arab world. 1800’s: Napoleon’s soldiers brought it to France from Egypt. It became popular with French writers and artists. Hemp was grown and used in colonial America. 1900’s: Marijuana smoking probably came to the U.S. with Mexican and Caribbean immigrants.

Modern History of Marijuana 1914: Harrison Act increased taxation for grower to seller 1926: Newspaper article links marijuana use to crime 1930s: US Bureau of Narcotics launched a public relations campaign to portray marijuana as a social menace that could destroy the youth of America. The propaganda included magazine articles and anti-marijuana films such as Reefer Madness. 1936: All states regulate use, sale, and possession. 1937: Marijuana Tax Act instituted a national registration and taxation system aimed at discouraging all use of cannabis. Made use illegal. 1944: La Guardia Report downplayed serious effects 1969: Marijuana Tax Act found to be unconstitutional 1970’s: Marijuana use peaks; drops in 1980’s; rises again in 1990’s 1996: First state laws legalizing Marijuana for medicinal use. 2012: First states laws legalizing Marijuana for recreational use.

Phytocannabinoids Marijuana has over 400 chemicals and ~ 70 phytocannabinoids 9-tetrahydro-cannabinol (THC) was identified as the major active ingredient in 1964. Is most pharmacologically active. Burning marijuana causes the THC to vaporize and enter the smoker’s lungs in small particles. THC is easily absorbed by the lungs, and blood plasma levels rise quickly. Effective dose and latency to onset of effects are influenced by the amount and potency of the plant used and patterns of smoking. Concentrations begin to decline as a result of metabolism in the liver and accumulation in the body’s fat stores (half life: ~19 hrs; complete elimination in 2-3 weeks). In oral use, poor absorption results in low and variable plasma levels, probably due to degradation in the stomach and first-pass metabolism (peak effect occurs ~90 mins after ingestion). THC synthetics: Dronabinol (Marinol) Nabilone (Esamet) 6

Phytocannabinoids Cannabigerol-type CBG Cannabichromene-type CBC Cannabidiol-type CBD Tetrahydrocannabinol- and Cannabinol-type THC, CBN Cannabielsoin-type CBE iso- Tetrahydrocannabinol- type iso-THC Cannabicyclol-type CBL Cannabicitran-type CBT

Endocannabinoids Arachidonoyl ethanolamide (AEA), Anandamide 2-arachidonoylglycerol (2-AG) Oleamide Endocannabinoid System Function: Reinforcement Dependence and/or Relapse Alcohol Other drugs

Endocannabinoid Physiology Retrograde messengers: carry information in the opposite direction

Cannabinoid Receptors A cannabinoid receptor in the CNS was identified in 1988. Receptors occur in many brain areas. Cannabinoid receptors are metabotropic work via G proteins to inhibit cAMP formation Inhibits adenylate cyclase inhibit voltage-sensitive Ca2+ channels open K+ channels. CB1 receptors CNS (reward via mesolimbic?) Located on axon terminals Inhibiting many neurotransmitters CB2 receptors immune system (could modulate response) Bone adipose (fat) cells GI tract. Rimonabant: CB1 antagonist CP-55,940: CB agonist

Cannabinoid Receptors in the Brain Cannabinoid receptors (CB1) cerebral cortex hippocampus basal ganglia cerebellum nucleus accumbens Receptor Autoradiography Brighter areas show greater receptor density

CB1 gene (CNR1) Expression

CB1 Receptors and Mood Prefrontal Cortex Hypothalamus Amygdala Hippocampus Raphe nucleus VTA Locus Coeruleus NPH

Marijuana use as a Function of Age Risk Factors: Emotional problems Family problems Drug use in household Drug us by peers Dislike of school Poor school performance Early age of first use Early positive increases dependency If not tried by 25 then typically never use

Negative Effects of Marijuana lung damage increased heart rate dry eyes and mouth impaired tracking ability memory loss reduced locomotor activity hypothermia hypoalgesia decreased sperm cell count decreased cognitive function decreased educational performance rejection of mainstream ideas anxiety or paranoia depersonalization derealization agitation altering of mood tolerance/addiction like properties marijuana madness desensitization of receptors Amotivational syndrome Gateway drug? Hippocampal CB1 receptors are responsible for memory impairment

Marijuana Madness Probability of Psychoses in Marijuana Users

Marijuana Madness Association Model: individuals who are already vulnerable to developing psychosis have an increased likelihood of using cannabis when they are young Causal Model: heavy use predisposes individuals to develop psychosis later in life. Indicator-Variable Model: one or more other factors lead jointly to cannabis use and psychosis proneness. 17

Marijuana Tolerance Develops after high levels or regular use May not develop uniformly to all effects Animals exposed to THC or CB1 agonists develop tolerance CB receptors are desensitized and downregulated following chronic THC exposure

Marijuana Dependence Dependence: Rehabilitation: Difficulty in stopping use Craving the drug Unpleasant withdrawal symptoms Most users do NOT become dependent Rehabilitation: Similar to other drug treatments Cognitive behavioral therapy Motivation enhancement therapy Patients are vulnerable to relapse

Marijuana Withdrawal Withdrawal: Symptoms: Increased irritability No DSM-V listing Not life threatening but unpleasant Some research supports notion Begins 1 day after last dose Lasts 4 – 12 days Symptoms: Increased irritability Increased Anxiety Decrease mood Increased sleep problems Increased aggressiveness Decreased appetite

Positive Effects of Marijuana reduced nausea reduced pain reduced MS spasticity reduced symptoms of GI tract disorders reduced cancer formation reduced symptoms of neurodegenerative disorders reduced symptoms of psychiatric disorders CB1 antagonists can reduce obesity Increased fear alleviation

History of Medicinal Marijuana 1937: after Marijuana Tax Act medicinal use of marijuana dropped so other medicines were developed 1970’s to present: increased interest in medicinal use for: Glaucoma Chemo-based Nausea (antiemetic) 1985: Synthetic THC, Marinol (Dronabinol) approved as antiemetic 1993: Marinol approved as appetite stimulant for AIDS patients 1999: Institute of Medicine – recommends medicinal use 2014: 23 states and DC allow medicinal use

The New Medicinal Marijuana * The New Medicinal Marijuana * Nabiximols THC CBD *FDA approved

Cannabis and Multiple Sclerosis Cannabidiol (CBD) Pain Shaking Spasms Spasticity Fatigue Sleep Quality Mobility Well Being

Cannabis and Cancer MMP-2: enzyme that promotes spread of cancer

Obesity Control CB1 antagonist: AM6545 Acts peripherally Reduces food consumption in humans and non-human animals May be useful in treating obesity