MarijuanaCannabis sativaTetrahydrocannabinol (THC)

Chapter 11

History of MarijuanaHistory of MarijuanaOldest non-food crop cultivated by man/womanEarliest archaeological records from Taiwan, 10,000 yr

(stone age) evidence of hemp fiber usePottery, clothes, shoes, bow strings, paper (105 A.D.)Ts’ai Lun ridicule!

Use Spread throughout Asia, the mid East, and eventuallyEurope.

History of Marijuana- Religious History of Marijuana- Religious and Medical useand Medical use

Also originating in China…spread about 200 BC with Scythianswarlike Middle Eastern tribe, gave us word “cannabis”used in cleansing ceremony after funeralsthrew hemp seeds on heated rocks inside tents &

inhaled vapors

Early HistoryIndia

Bhang--teaGanja—pipeCharas--hashish/hash

History of MarijuanaHistory of Marijuana

Most infamous use by Muslim sect founded by Hasan-Sabbah (Hashishin)secret assassinationgave us words hashish & assassin

Hebrews also used cannabis(Old Testament in Exodus)God told Moses to make holy oil containing cannabis

History of MarijuanaHistory of Marijuana

France in mid 1800s with "Club des Hachichins"writer Gautier offered reward to anyone who invented

a new pleasure – was given hashish by a doctorVictor Hugo, Alexander Dumas

consumed large quantities of hash-like materialwrote accounts of their experiences

History of MarijuanaHistory 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 NarcoticsCommissioner of Narcotics, Harry Anslinger -crusade against marijuana

1920s & 1930s - major attention - drug of violent crime & danger to society

History of MarijuanaHistory of Marijuana1937 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 Seeds Vegetable matter

PaperPlasticsFuelsTextilesAnimal BeddingMulch

Bird seedFlour and cerealsBody care productsNon diary milk/cheeseNut butterSalad dressingSports Bars/Protein PowderMargarinePaints/ VarnishesDetergents

Industrial hempIncense

History of MarijuanaHistory of MarijuanaEarly 1940sNYC 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 MarijuanaHistory of MarijuanaMarijuana comeback: late 1950s to early 1960sNow 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 1960s

Per

cent

Usi

ng

0

10

20

30

40

50

60

75 80 85 90 95 00

Percent High School Seniors reporting Marijuana use during their Senior year

05

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

Time/CNN Poll 200680% approve of medical use of marijuana72% say that marijuana possession should

lead to fine, not jail47% 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 advertiseCannot sell to minors

Current MJ World Laws

The Future?/ Politics of Marijuana

Preparations of MarijuanaPreparations of MarijuanaLeaves, 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

Ganja

Sterile flower heads

3-8 %

Hashish Cannabis resin 10-15 %

Cannabis/

Hash Oil

Resin concentrate

(alcohol extract)

20-60 %

Preparations of Preparations of MarijuanaMarijuana

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

Active AgentsActive Agents-9-THC

-8-THC

Cannabidiol

Active Metabolites

Active AgentsActive AgentsCannabidiol - slows metabolism of THC

increases durationconverted to THC when burnedmay have neuroprotective, anticonvulsant and

anti-psychotic effects

PharmacokineticsPharmacokineticsAdministration

Inhalation – SmokeOral – Tincture,

Eating, TeaMarinol

Oral-mucosal

Sativex

DistributionEverywhere as it is

highly lipophilicFlies across BBB

To meet demands for Sativex, GW Pharmaceuticals has increased production of cannabis at its fortified greenhouses to 60t/y. (Source: ABPI)

Pharmacokinetics of THCRapid absorption in lung2-4 hr duration of actionErratic 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 lipophilicFlies across BBB

Metabolism & ClearanceMetabolism & 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)(11-OH- 9-THC)

Mechanism of ActionMechanism of ActionMostly unknown until the late 1980s

1988 – Isolated the receptors1992 – 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 TypesTwo Receptor TypesCB-1 ReceptorCB-1 Receptor CB-2 ReceptorCB-2 Receptor

Mostly in periphery

Found primarily in immune system

Found on heart – protects from inflammation?oLocated in CNS and

PNS

CB1 receptor hot spots

THC is a retrograde CB1 agonist- works on the presynaptic terminal to modulate NT release

Physiological EffectsPhysiological Effectsof Marijuanaof 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 abstainIncreased risk for heart attack four an hour after smoking

Appetite increasedMay be related to actions on the Hypothalamusor nucleus accumbens- when stimulated by cannabinoids there

is an increase in the reward value of natural rewards.

PSYCHOLOGICAL EFFECTS:PSYCHOLOGICAL EFFECTS:Low - Moderate DosesLow - Moderate Doses

Disinhibition

Relaxation

Drowsiness

Exhilaration, euphoriasharpened humor

Sensory - perceptual

changesOverestimate time passage

STM impairment

Balance impaired

Decreased muscle strength

Small tremor

Poor on complex tasks (e.g., driving)

Higher DosesHigher DosesPsychotomimetic

Pseudo hallucinations

Synesthesias

Paranoia

Agitation/panic

Disorganized thoughts

Confusion

Impaired executive functionIncreased

impulsivity

Impaired judgment, slower RT

Pronounced motor deficits

Side Effects of MarijuanaSide 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 ToxicityTHC ToxicityAlmost impossible to OD

THC not toxic in this sensePot smoke contains more tar than

cigarette smokeData on cancer is very mixed – recent studies show no

relationshipDoes one smoke the same?

THC found to kill cultured hippocampal cells, but so far not in other cells high in CB receptor densityEffect reversed with NSAIDSPossible mechanism for memory loss

THC – Tolerance & THC – Tolerance & DependenceDependence

Tolerance develops with heavy long-term useReverse tolerance in consistent usersCross tolerance with sedatives - alcoholDependence – 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 it30 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 EffectsHighly Debated EffectsAmotivational SyndromeAmotivational 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 trueWhen 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, long-term 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.“ – McGlothin, 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 HistoriesThe 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 workUsers had 55% more accidents, 85% more

injuries, and a 75% increase in absenteeism(National Institute on Drug Abuse)

Survey ResearchA 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 that1%–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 MarijuanaMedical Marijuana1998 IOM (inst of Med.) report concluded that

there is scientific evidence for medical use

Analgesic Anti-emeticAnti-spasticAppetite StimulantGlaucoma-not particularly effectiveTumor suppression? (lung cancer)Seizures? – THC & Cannibidiol protect against

neurotoxicity

Medical MarijuanaMedical 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 continuesThe debate continues

Adverse Effects of Marijuana: Chronic Effects

Lung damage-Bronchitis; Lung cancer?

Carcinogens in smokeMarijuanaVinyl Chloride 5

ng D-M nitrosamine

75 ngM ethylnitrosamine

27 ng Benz-anthracene

75 ngBenz-pyrene

31 ng

TobaccoVinyl Chloride

12 ng D-M nitrosamine

84 ngM ethylnitrosamine

30 ng Benz-anthracene

43 ngBenz-pyrene

21 ng

Dependence on MarijuanaToleranceWithdrawal syndrome

Irritability, mood changesSleep disturbancesLoss 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 deficitsDeficits 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 employmentUsers 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 are 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. Therefore, the cognitive and motivational demands of

their everyday lives were insufficient to detect any impairment caused by chronic cannabis use.

Laboratory Criticism There are 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. 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.