Marijuana Chapter 11 Cannabis sativa Tetrahydrocannabinol THC History

Marijuana Chapter 11 Cannabis sativa Tetrahydrocannabinol (THC)

History of Marijuana Oldest non-food crop cultivated by man/woman Earliest archaeological records from Taiwan, 10, 000 yr (stone age) evidence of hemp fiber use Pottery, clothes, shoes, bow strings, paper (105 A. D. ) Ts’ai Lun ridicule! Use Spread throughout Asia, the mid East, and eventually. Europe.

History of Marijuana- Religious and Medical use Also originating in China…spread about 200 BC with Scythians warlike Middle Eastern tribe, gave us word “cannabis” used in cleansing ceremony after funerals threw hemp seeds on heated rocks inside tents & inhaled vapors

Early History India Bhang--tea Ganja—pipe Charas--hashish/hash

History of Marijuana Most infamous use by Muslim sect founded by Hasan-Sabbah (Hashishin) secret assassination gave us words hashish & assassin Hebrews also used cannabis (Old Testament in Exodus) God told Moses to make holy oil containing cannabis

History of Marijuana France in mid 1800 s with "Club des Hachichins" writer Gautier offered reward to anyone who invented a new pleasure – was given hashish by a doctor Victor Hugo, Alexander Dumas consumed large quantities of hash-like material wrote accounts of their experiences

History of Marijuana In Early U. S. , primarily for rope and canvas (George Washington), Minor medicinal use Prohibition increased use of MJ. . NYC “Tea Pads!”

The Bureau of Narcotics Commissioner of Narcotics, Harry Anslinger -crusade against marijuana 1920 s & 1930 s - major attention - drug of violent crime & danger to society

History of Marijuana 1937 Marijuana Tax Act made possession of marijuana without having paid special tax illegal classified marihuana as a controlled substance. Needless to say most doctors and dentists stopped using products covered by this law.

What we have lost

Various Uses Cannabis L. Stems Paper Plastics Fuels Textiles Animal Bedding Mulch Seeds Vegetable matter Bird seed Industrial hemp Flour and cereals Incense Body care products Non diary milk/cheese Nut butter Salad dressing Sports Bars/ Protein Powder Margarine Paints/ Varnishes Detergents

History of Marijuana Early 1940 s NYC Mayor Fiorello La Guardia set up commission of experts to determine consequences of marijuana use Final report - marijuana fairly minor intoxicant with few side effects even when used excessively Report ridiculed by Anslinger

A harder attitude- 1950’s-60’s VI. THE 1950's: HARSHER PENALTIES AND A NEW RATIONALE-THE "STEPPING STONE" THEORY 1951 Congress passed -the Boggs Act. . much harsher penalties for all drug violators. marijuana and other narcotics were lumped together First offense 2 - 5 years Second offense 5 - 10 years Third and subsequent offenses 10 - 20 years Fine for all offenses $2, 000. 00 Boggs stated: "We need only to recall what we have read in the papers in the past week to realize that more and more younger people are falling into the clutches of unscrupulous dope peddlers. . “ Perhaps Commissioner Anslinger best described the prevailing climate when he stated: Short sentences do not deter. In districts where we get good sentences the traffic does not flourish. . There should be a minimum sentence for the second offense. The commercialized transaction, the peddler, the smuggler, those who traffic in narcotics, on the second offense if there were a minimum sentence of 5 years without probation or parole, I think it would just about dry up the traffic

History of Marijuana comeback: late 1950 s to early 1960 s Now most broadly used illicit substance in U. S. 35 -40% of Americans having tried Numerous states have compassionate use laws

Marijuana use exploded in the 1960 s

And use continued at high rates into the 70’s through today

Time/CNN Poll 2006 80% approve of medical use of marijuana 72% say that marijuana possession should lead to fine, not jail 47% say that they have tried marijuana at least once

A changing Attitude? Law Reforms: 2006, Recreational Marijuana use on ballot in Colorado and Nevada Defeated in both cases January 02, 2009 Massachusetts On Nov. 4, a majority of voters in Massachusetts chose to decriminalize possession of small amounts of marijuana. Those in possession of less than an ounce of marijuana are no longer charged with a criminal offense, but instead face a $100 fine.

U. S. Drug laws TODAY

The International perspective-The Dutch Experience Marijuana is NOT legal, but laws are not enforced for Coffee shops in Amsterdam Over 1000 shops are now licensed in the Netherlands Cannot advertise Cannot sell to minors

Current MJ World Laws

The Future? / Politics of Marijuana

Preparations of Marijuana Leaves, stems and flowering buds of cannabis sativa Most of the THC is in the buds

Cannabis Preparations Name Part of Plant THC Marijuana Leaves, stems 1 -3 % Sinsemilla Sterile flower heads Ganja Hashish Cannabis resin 3 -8 % 10 -15 % Cannabis/ Resin concentrate 20 -60 % Hash Oil (alcohol extract)

Preparations of Marijuana Hash Oil - boil with solvent, solvent then strained out THC concentration as high as 60% - 70% Becoming more popular - ease of smuggling

Active Agents -9 -THC -8 -THC Cannabidiol Active Metabolites

Active Agents Cannabidiol - slows metabolism of THC increases duration converted to THC when burned may have neuroprotective, anticonvulsant and anti-psychotic effects

Pharmacokinetics Administration Inhalation – Smoke Oral – Tincture, Eating, Tea Marinol Oral-mucosal Sativex To meet demands for Sativex, GW Pharmaceuticals has increased production of cannabis at its fortified greenhouses to 60 t/y. (Source: ABPI) Distribution Everywhere as it is highly lipophilic Flies across BBB

Pharmacokinetics of THC Rapid absorption in lung 2 -4 hr duration of action Erratic absorption after oral admin. Great persistence in tissue: up to 30 days after a single dose Detection in urine 10 -14+ days after a single dose; >21 days after chronic use Distribution Everywhere as it is highly lipophilic Flies across BBB

Metabolism & Clearance • Binds to proteins and fats • Slow metabolism in liver • Metabolites remain detectable for a week – three weeks • Primary metabolic products may be more potent (11 -OH- 9 -THC)

Mechanism of Action Mostly unknown until the late 1980 s 1988 – Isolated the receptors 1992 – Discovered the first neurotransmitter for that receptor THC binds to and agonizes cannabinoid receptors Anandamide & 2 -AG are the NTs for cannabinoid receptors Anandamide : The brain’s own marijuana (from Ananda: Hindu word for bliss) Works as a neuromodulator/ and “retrograde NT”

Two Receptor Types CB-1 Receptor CB-2 Receptor Mostly in periphery Found primarily in immune system Found on heart – protects from inflammation? o. Located in CNS and PNS

CB 1 receptor hot spots

THC is a retrograde CB 1 agonist- works on the presynaptic terminal to modulate NT release

Physiological Effects of Marijuana Physiological effects Increase in HR & drop in BP Produces dry mouth & occasional dizziness Reddening of eyes (dilation of vessels in cornea) No permanent adverse cardiovascular effects People with heart disease should abstain Increased risk for heart attack four an hour after smoking Appetite increased May be related to actions on the Hypothalamus or nucleus accumbens- when stimulated by cannabinoids there is an increase in the reward value of natural rewards.

PSYCHOLOGICAL EFFECTS: Low - Moderate Doses Disinhibition STM impairment Relaxation Balance impaired Drowsiness Decreased muscle strength Exhilaration, euphoria sharpened humor Small tremor Sensory - perceptual changes Poor on complex Overestimate time passage tasks (e. g. , driving)

Higher Doses Psychotomimetic Pseudo hallucinations Synesthesias Paranoia Agitation/panic Disorganized thoughts Confusion Impaired executive function Increased impulsivity Impaired judgment, slower RT Pronounced motor deficits

Side Effects of Marijuana THC suppresses immune system, but not enough to increase risk of infection it appears. Lowers testosterone levels & sperm count as well as estrogen Crosses placental barrier ◦ Lower birth weight ◦ Some evidence suggests a relation between mother smoking while pregnant and childhood cancer Most severe side effects ◦ Respiratory - can lead to asthma & bronchitis ◦ Anxiety/panic in some users

THC Toxicity Almost impossible to OD THC not toxic in this sense Pot smoke contains more tar than cigarette smoke Data on cancer is very mixed – recent studies show no relationship Does one smoke the same? THC found to kill cultured hippocampal cells, but so far not in other cells high in CB receptor density Effect reversed with NSAIDS Possible mechanism for memory loss

THC – Tolerance & Dependence Tolerance develops with heavy long-term use Reverse tolerance in consistent users Cross tolerance with sedatives - alcohol Dependence – mild (like SSRIs) Mild withdrawal symptoms in humans, with irritability, depression, sleep disturbances, nausea, diarrhea, sweating, tremors, reduced food intake, and salivation 5% of heavy users may experience it 30 mg THC / 4 hrs / 10 -20 days 15+ joints per day (unusual levels of intake) Begin within 48 hours after cessation and lasts 2 – 10 days

Highly Debated Effects Amotivational Syndrome is a theoretical condition that proposes the heavy use of marijuana may alter a smoker’s motivations, goals, and possibly personality. Most research has not found this to be true When it appears to exist, It may be psychopathology independent of use

What is Amotivational Syndrome? Amotivational Syndrome is a theoretical condition that proposes the heavy use of marijuana may alter a smoker’s motivations, goals, and possibly personality. Better put, this syndrome may cause ". . . apathy, loss of effectiveness, and diminished capacity or willingness to carry out complex, longterm plans, endure frustration, concentrate for long periods, follow routines, or successfully master new material. Verbal facility is often impaired both in speaking and writing. Some individuals exhibit greater introversion, become totally involved with the present at the expense of future goals and demonstrate a strong tendency toward regressive, childlike, magical thinking. “ – Mc. Glothin, W. H.

History of Amotivational Syndrome The 1960’s are associated with an explosion of the use of marijuana. Peak use was surveyed in 1979 with 24 million smokers. Before this time, any record of amotivational syndrome was completely nonexistent.

Case Histories The concept of this syndrome first appeared in the 1960’s with a few case histories. However, these case histories were unable to show: a. How common amotivational syndrome is. b. Whether marijuana caused the change in motivation. c. If a change did occur, did it effect all facets of motivation or is it specific only to certain forms of motivation. What do you think?

What is the culprit? The big question is which comes first, the marijuana or the loss of motivation? Lets look at a few surveys conducted on college and high school students.

Evidence continued… A study among workers suggests that marijuana use can be hazardous to working or to a motivation to work Users had 55% more accidents, 85% more injuries, and a 75% increase in absenteeism (National Institute on Drug Abuse)

Survey Research A survey was conducted on 2000 college students in 1974 by Brill, N. et al. The researchers concluded that there was no difference in grade point average or academic success between smokers and non smokers. However, the marijuana smokers surveyed did have more trouble deciding on career goals and many did not pursue professional degrees.

Laboratory Studies Mendelson et al, 1974, conducted an experiment in which 10 casual and 10 heavy cannabis smokers were observed for 31 days. They were given access to as many marijuana cigarettes as they earned through a simple operant task which involved pressing a button to move a counter. The researchers found that all subjects earned the maximum amount of points each day and output was unaffected by marijuana smoking. Mendelson et al concluded that: "our data disclosed no indication of a relationship between decrease in motivation to work at an operant task and acute or repeat dose effects of marihuana"

The Jamaican Study ( 1976) A study performed by Rubin and Comitas 1976, examined the effects of marijuana on the performance of Jamaican farmers who regularly smoked marijuana in the belief that it enhanced their physical energy and work productivity. They used videotape to track the farmers movements and biochemical measures of exhaled breath to asses caloric expenditures before and after getting high. After smoking ganja the workers engaged in more intense and concentrated labor. but this was done less efficiently, especially by heavy users. Looking for your pencil when it’s behind your ear? "In all Jamaican settings observed, the workers are motivated to carry out difficult tasks with no decrease in heavy physical exertion, and their [mistaken] perception of increased output is a significant factor in bolstering their motivation to work. “ -Comitas

Debatable issues- Gateway Drug The gateway hypothesis holds that consumption of abusable drugs progresses in orderly fashion through several discrete stages Young et al. observed that marijuana was the first drug used by 42% of a sample of delinquent youths.

Debatable issues- Gateway Drug- Most well-designed studies suggest this is false. The entire sequence, which is exhibited by only a small minority of drug users, begins with beer or wine and moves progressively through hard liquor or tobacco, marijuana, and finally hard drugs. Each stage is thus a component of both a temporal sequence and a hierarchy. This claim has not been empirically supported, however. Researchers have reported that marijuana use is not a requirement for progression to hard drugs. Golub and Johnson (5) found that 75% of inner-city heavy drug users began using cocaine before using marijuana. These authors also report that 1%– 4% of hard drug users skipped both the alcohol/tobacco and marijuana stages (6). Mackesy-Amiti et al. (7) reported that 39% of their sample started using marijuana after they had used hard drugs. Blaze-Temple and Lo (8) reported that 29% of their sample began using marijuana after having used heroin, stimulants, or LSD. “Common liability model” is a better explanation Alcohol and cigarettes are stronger gateway drugs if one accepts the data

Debatable issues- Gateway Drug vs common liability model Alternatively, abuse of illicit drugs, whether or not preceded by use of licit compounds, may be more parsimoniously explained by their availability in the social environment and the level of the individual’s liability that is common to all abusable substances. For example, conduct problems in childhood presage consumption of all classes of abusable drugs. Genetic (9– 12), neurophysiological (13, 14), neurochemical (15, 16), and behavioral (17, 18) investigations have shown that the same factors are associated with consumption of licit and illicit drugs. Indeed, 100% of the genetic variance in the risk for diagnosis of substance use disorder is common acros

Medical Marijuana 1998 IOM (inst of Med. ) report concluded that there is scientific evidence for medical use Analgesic Anti-emetic Anti-spastic Appetite Stimulant Glaucoma-not particularly effective Tumor suppression? (lung cancer) Seizures? – THC & Cannibidiol protect against neurotoxicity

Medical Marijuana Many states have compassionate use laws ◦ California, Washington, Oregon, Nevada, Alaska, Vermont, Maine, Colorado, New Mexico, Montana, Rhode Island, Maryland Physicians “recommend” marijuana and patient buy it at buyers clubs. ◦ Would lose license if prescribed 2003 Gallup Pole – 75% for medical use, 66% against legalization 2005 study of physicians'’ attitudes ◦ 36 % were in favor of legal prescription ◦ 26% were neutral

The debate continues

Adverse Effects of Marijuana: Chronic Effects Lung damage-Bronchitis; Lung cancer?

Carcinogens in smoke Marijuana Tobacco Vinyl Chloride 5 ng D-M nitrosamine 75 ng M ethylnitrosamine 27 ng Benz-anthracene 75 ng Benz-pyrene 31 ng 12 ng D-M nitrosamine 84 ng M ethylnitrosamine 30 ng Benz-anthracene 43 ng Benz-pyrene 21 ng

Dependence on Marijuana Tolerance Withdrawal syndrome Irritability, mood changes Sleep disturbances Loss of appetite, nausea 5% heavy users: 15+ joints per day; “more or less permanently stoned” House of Lords Cannabis report (2000)

Adverse Effects of Marijuana: Chronic Effects Cognitive deficits?

Cognitive deficits Deficits on tests of memory, learning, word fluency (producing words in a particular category), and processing speed persist 48+ hours after last use in chronic marijuana users (Croft, et al. , 2001) Heavy users who begin smoking before age 17 show more severe deficits (Pope et al. , 2003)—but many accounts are possible

Costa Rican Study This study performed by Carter et al. 1980 that compared Costa Ricans’ employment history of heavy users to non-users. The comparison showed that non-users were more likely to have a stable employment history, have received promotions and raises, and to be in full-time employment Users were more likely to spend more than their incomes

Costa Rica cont. However, when comparing only users, a relationship between average daily marijuana consumption and employment presents a conflicting amotivational hypothesis. Those "who had steady jobs or who were self-employed were smoking more than twice as many marijuana cigarettes per day as those with more frequent job changes, or those who were chronically unemployed", indicating that "the level of consumption was related more to relative access than to individual preference"

What does this all mean? Evidence of Amotivational syndrome from these field studies are usually interpreted as failing to demonstrate the existance of an actual syndrome. Here a few problems with the evidence: 1. Sample sizes are too small to exclude the possibility of an effect occurring among a minority of heavy users. 2. Cohen (1982) argues that the heavy users come from socially marginal groups. Ø Therefore, the cognitive and motivational demands of their everyday lives were insufficient to detect any impairment caused by chronic cannabis use.

Laboratory Criticism There a few obvious weaknesses in Mendelson’s experiment. 1. The period of ‘heavy’ use was only 21 days, which is inconclusive with the amount of years that many of the subjects in the field studies endured. 2. The subjects were all healthy, young cannabis users with a mean IQ of 120 and nearly three years of college education. Ø During debriefing, many of the subjects reported that they were motivated to perform well to demonstrate that marijuana does not have any affect on their performance.

In Conclusion… The evidence of Amotivational Syndrome is extremely vague in all facets of research. The small number of field and experimental studies were unable to show convincing evidence to support such a syndrome. In conclusion, if there is such a syndrome, it is specific only to a few heavy users and is a very rare occurance.