MARIJUANA

-A REVIEW=
WITH EMPHASIS ON
MEDICAL MARIJUANA
AND USE PATTERNS IN
THE USA
Phil Wolfson MD
San Francisco, California
 Costs of Prohibition
 The United States is now the world's largest jailer,
imprisoning nearly half a million people for drug offenses
alone. That's more people than Western Europe, with a bigger
population, incarcerates for all offenses. Roughly 1.5 million
people are arrested each year for drug law violations - 40% of
them just for marijuana possession.
 Illegalization funds the Taliban and other narco-terrorist
organizations, destroys whole countries and warps others,
corrupts the justice and police systems and bloats the state
with negative, punitive bureaucracies. It creates a vast drug
industry in which money is the attractant.
 Illegalization/prohibition intrudes on citizens’ rights to
privacy and punishes personal choices as crimes. It makes
100s of millions of people world-wide into criminals and does
not diminish the consumer draw.
 Legal Status Terms
1) Psychoactive Drug Prescription and Medical Marijuana—
by controlled Prescription. State medication regulation of
use, providers, distribution and manufacture—may
include all or some. Providers may be policed and
targeted.

2) Decriminalization—reduction or elimination of penalties

for possession, use, sale, horticulture/manufacture-may
include all or some.

3) Legalization—No penalties for specified levels of

possession, use, sale, horticulture/manufacture-may
include all or some.

4) Full Legalization—May Include State Provision of

Substances through State Outlets.
 Arguments For
 UN Office of Drugs and Crime Executive Director Antonio
Maria Costa acknowledges that controls have generated an
illicit black market of macro-economic proportions that
uses violence and corruption.
 “We are demanding that governments replace the failed
policy of prohibition with a system that actually regulates
and controls drugs, including their purity and prices, as
well as who produces them and who they can be sold to.
You can't have effective control under prohibition, as we
should have learned from our failed experiment with
alcohol in the U.S. between 1920 and 1933.”-Jack Cole,
Executive Director of Law Enforcement Against
Prohibition (LEAP) and a retired undercover narcotics
detective
 Arguments Against

 The only hope for drug policy is a concerted effort

of drug prevention which upholds the notion of no
drug use, drug interdiction, and drug treatment. If
we soften our hold on an already vexing problem,
we will lose the war--Chairman of the International
Drug Strategy Institute, Eric A. Voth, M.D 1995—
introduced into the US House of Representatives
 Decriminalization Internationally
 Portugal 2001—Abolished all criminal penalties for possession of
drugs—including mj, coke, heroin and meth—jail time replaced
with offer of therapy. Rsults—all metrics show improvement—
from use to new HIV Cases in drug users. Methadone and
buprenorphine treatment numbers incresased by over 200%
 Netherlands—Non-enforcement and harm reduction policies.

 Canada—medical marijuana—small numbers—3800- of certified

users. Non-enforcement with rampant often visible cannabis use.
 Latin America 2008—Peru: coca leaf use not criminalized.
Argentina—2.6% of population said to use cocaine compared to
USA 3%. Personal possession of small amounts of drugs not
punishable. Mexico—decriminalized possession of small amounts
of drugs. Chile and Brazil—decriminalized possession of small
amounts
 Rationales for Decriminalization/
Legalization of Marijuana Use
 Marijuana illegalization began in the US State by State because of concerns
for social unrest and who were the predominant users—Mexican laborers,
Southern Blacks and Filipinos. In 1894, the Encyclopedia Britannica
estimated the number of users world-wide at 300 million souls. As the
campaign to illegalize grew marijuana was lumped with other drugs as
equivalent—cocaine, opium and heroin. The US had a large population of
morphine dependent civil War Veterans estimated at over 400,000 with a
huge social cost as well as about 150,000 opium addicts, many of them
women—by Rx often. Prohibition was a growing fundamentalist issue.
Marijuana was branded for political reasons as causing insanity, lust,
violence and crime. California labeled mj as ‘poison’ in 1907, prohibited its
possession unless prescribed by a physician until 1915 and included it
among hard narcotics in 1929. Federal prohibition was enacted in 1937
during the Great Depression and amidst political and social unrest.
Suppression of contrary information such as the La Guardia report and the
AMA’s original opposition to loss of one of its main medicaments was
part of the political agenda.
REEFER MADNESS
 Rationales for Decriminalization/
Legalization of Marijuana Use
 Marijuana is an extraordinarily safe drug. Its LD 50 is un-
established in humans. It has a probably 10,000 year long history
of human use.
 Hundreds of millions of people use and have used marijuana for
its medical, health, well-being, psychological and pleasurable
influences and properties.
 Marijuana as a source of violence is unfounded. The contrary
appears to be the case.
 The distortions of the illegal status for marijuana—cash crop
economy-- include violence, crime, invasion of personal space and
individual rights, unjust, irrational and punitive incarcerations all
related to prohibition of a plant that grows naturally in human
space with which we have historically cohabited and co-evolved.
The Great Danger!!!
 Caveats
 Like all psychoactive substances, marijuana experience is affected by
set and setting.
 Marijuana is not for everyone. Individual experience varies
profoundly from person to person.
 Within an individuals history of use, there may well be variations in
experience that lead to cessation because of changes in the quality of
personal experience.
 Some individuals respond variously with paranoia, fear, withdrawal,
isolation, mutism, and the other side of the spectrum is hyperactivity,
restlessness and agitation. A naïve users response is not predictable,
but is helped by thoughtful preparation, the presence of an
experienced sitter or guide and by conducive set and setting.
 Unpredictability is the rule for the effectiveness of marijuana for
medical indications although there are patterns of successful treatment
that are indications of how to proceed. Empiricism is the name of all
psychoactive substance use from Prozac to Ecstasy, and really for all
substances in general. Variability makes for our art form.
 Marijuana—the General Aspects
 THC is the dominant psychoactive source. Generally all marijuana use results
in getting stoned/intoxicated, this being modified by countervailing factors
such as the presence of pain and fatigue, depressed, manic and hypomanic
states, other substance ingestion, and the development of tolerance due to
sustained use.
 Marijuana is one of the few available and effective aphrodisiacs, therefore
beneficial for human sexuality—initiation, dysfunctional repair, and pleasure
training-- with little hazard for associated aggressive behavior—contrast to
GHB for example.
 Marijuana- is often beneficial for social interaction and has an empathic
potentiality.
 Stimulation and intensification of the senses is part of the experience.
Dreaming may be stimulated and altered.
 Contrary to common opinion some users are more productive and more
focused, much like a desirable ADD treatment. Some users are just as
productive. However most users experience a diminution in productivity.
 The Downside
 Chronic Use may lead to an amotivational syndrome, and
decreased social and vocational participation. This may
mimic depression or conceal a clinical depression. Other
substance use may contribute.
 Some chronic users experience a withdrawal reaction after
abrupt cessation: agitation, anxiety, irritability, insomnia
which may last two weeks or more. Anxiolytics and
hypnotics may be of benefit. A graded exercise program is an
especially good addition. Most chronic users have a mild
withdrawal that does not require treatment, or no
withdrawal at all.
 Operation of machinery is not a good idea when intoxicated.
There is an argument that mj users drive slower and more
cautiously and have the same rate of accidents as non-users. I
recommend not driving when intoxicated! I recommend not
working when intoxicated!
 The Downside II

 CHRONIC MJ SMOKING MAY CAUSE IRRITATIVE

PULMONARY SYMPTOMS BUT NO STUDY HAS YET
TO SHOW COPD/EMPHYSEMA WITH LONG-TERM
USE.
 THERE IS NO EVIDENCE OF INCREASED LUNG AND
PHARYNGEAL CANCER RATES IN LONG TERM
HEAVY MJ USERS.
CF TASHKIN, D. FOR EXTENSIVE REVIEWS

 MARIJUANA INCREASES HEART RATE VARIABLY

AND THERE ARE SOME CAUTIONERY TALES
ABOUT HEART ATTACKS AS AN IMMEDIATE
RESULT OF USE, BUT NOTHING SUGGESTIVE.
 Medical Marijuana
 Marijuana used for thousands of years as a medicment—malaria, constipation,
rheumatism, convulsions, pain, tetanus, and muscle spasms.
 There are a rapidly increasing number of indications for marijuana as adjunctive or first-
line treatment:

1. Glaucoma--Marijuana decreases intra-ocular pressure. Numerous patient reports and

Tomida, et al 2006 Randomized, double blind, placebo controlled, 4 way crossover study
—6 patients with ocular hypertension and primary open angle glaucoma.

2. Multiple Sclerosis—Multiple good studies indicate efficacy for spasticity, pain, tremor,
and incontinence.

3. Pain—potential utility for neuropathic pain and fibromyalgia. Less utility for chronic pain
although there are a significant number of individuals who use mj successfully for this.

4. Wasting syndromes—as an appetite stimulant for weight loss associated with HIV/AIDS.

5. Nausea, vomiting and appetite- Cancer treatment; as an adjunct to odansetron.

Anecdotally, I have used mj in psychosis with loss of appetite- for stimulation.

6. Migraines—for treatment of nausea and for some patients, mj may reduce frequency of
migraines and severity.

For an excellent review of clinical studies, see: O’Shaughnessy’s Summer 2010

Medical Marijuana--USA

Box=current mmj state

Triangle=mmj law expansion pending
Star= new mmj law pending
Hex=current decrim state
 PSYCHIATRY AND MEDICAL MARIJUANA
 IN SURVEYS OF CALIFORNIA PHYSICIANS RECOMMENDING MJ UNDER THE
Prop 215 UMBRELLA, OVER 20% OF DIAGNOSES WERE PSYCHIATRIC AND A
SIGNIFICANT PERCENTAGE OF OTHERS WERE RELATED DIAGNOSES.
 STUDIES ARE NOT AVAILABLE BECAUSE OF ILLEGAL STATUS, GETTING
APPROVAL AND FUNDING AS A RESULT, AND BECAUSE PSYCHOACTIVITY IS
A MORE SENSITIVE SUBJECT THAN STUDYING PHYSICAL DISORDERS.
 INDICATIONS ARE:

INSOMNIA

CHRONIC ANXIETY

DEPRESSION—DYSTHYMIC AND MAJOR

ATTENTION DEFICIT DISORDER

PANIC DISORDER

POST-TRAUMATIC STRESS DISORDER

SUBSTANCE DEPENDENCE—ESPECIALLY ALCOHOLISM AND CHRONIC

OPIATE USE
 PSYCHIATRY AND MEDICAL
MARIJUANA
 OTHER CONDITIONS:

TOURETTES SYNDROME—DOUBLE BLIND STUDIES FROM GERMANY SUPPORT

EFFICACY
Muller-Vahl et al. 2003. Delta 9-tetrahydrocannabinol (THC) is effective in the treatment of tics in Tourette syndrome:
a 6-week randomized trial. Journal of Clinical Psychiatry 64: 459-65.

 SCHIZOPHRENIA—CONTROVERSY CONTINUES OVER POSSIBLE CAUSATIVE LINKAGE

BETWEEEN HEAVY MJ USE COMMENCING BEFORE AGE 15 AND PSYCHOSIS. DATA IS
UNCLEAR, AMBIVALENT AND NOT PROSPECTIVE. I BELIEVE A CAUTIONERY IS
WARRANTED AND NO ONE UNDER 15 SHOULD BE USING MJ HEAVILY IN ANY EVENT.

IN ESTABLISHED DIAGNOSED INDIVIDUALS THERE IS EVIDENCE THAT MJ IMPROVES

ACUTE COGNITIVE PERFORMANCE.

2 STUDIES: LEWEKE 2007 USED CBD IN A 4 WEEK DOUBLE BLIND CROSSOVER STUDY
IN ACUTE SCHIZOPHRENIA COMPARING CBD AND AMISULPRIDE IN 42 PATIENTS.
BOTH TXS WERE EFFECTIVE WITH LESS SEs OCCURRING IN THE CBD GROUP.
UTILITY IS QUESTIONABLE AS ISOLATED CBD IS NOT AVAILABLE.

D’SOUZA 2005: UP TO 5MGIV THC IN STABLE ANTI-PSYCHOTIC TREATED

SCHIZOPHRENIA PATIENTS. THCTRANSIENTLY EXACERBATED A RANGE OF POSITIVE
AND NEGATIVE SYMPTOMS, PERCEPTUAL ALTERATIONS, COGNITIVE DEFICITS
WITHOUT PRODUCING BENEFICIAL EFFECTS
 PSYCHIATRY AND MEDICAL
MARIJUANA
 SCHIZOPHRENIA—CONTINUED

THERE ARE NO CONCLUSIVE STUDIES ONCAUSATION OR EXACERBATION

OF S. DUE TO MJ USE. A LARGE PERCENTAGE OF DIAGNOSED
SCHIZOPHRENICS USE MJ REGULARLY AND IRREGULARLY. SOME
DIAGNOSED SCHIZOPHRENICS ATTRIBUTE A NEGATIVE EFFECT TO MJ
USE--RELATED TO ONSET OR EXACERBATION--AND AVOID MJ. AS WITH
BIPOLAR DISORDERS SEPARATING MJ CAUSATION FROM MJ USE
ASSOCIATION AND SELF-MEDICATION FROM PRE-MORBID SYMPTOMS
HAS YET TO BE ACCOMPLISHED.
 BIPOLAR DISORDERS—ANECDOTAL REPORTS LINK MJ USE TO ONSET OF
MANIC EPISODES AND EXACERBATIONS OF MANIA BUT RESEARCH IS
INCONCLUSIVE AS TO CAUSATION. MANY BIPOLAR PATIENTS USE MJ
PARTICULARLY FOR DEPRESSION AND SEEK IT OUT FROM MDs
EVALUATING FOR MMJ RECOMMENDATIONS. NO GOOD STUDIES ARE
AVAILABLE.
 RECOMMENDATION: THOROUGH HISTORY TAKING AND IN- DEPTH
DISCUSSION OF THE EFFECTS OF MJ USE ON AN INDIVIDUAL PATIENT ARE
ESSENTIAL FOR UNDERSTANDING MJ USE AND ITS POTENTIAL FOR
NEGATIVE EFFECTS. BLANKET WARNIGNS DO NOT WORK. CONNECTION
TO PATIENTS DOES.
 PSYCHIATRY AND MEDICAL
MARIJUANA
 Conditions of Interest:

1. Restless Legs Syndrome—In my experience, unusual

success with bed time use of mj. In general mj has an
anti-spasmodic effect on skeletal muscles and sometimes
on smooth muscles and can be useful in potentially any
condition in which spasms are a problem.

2. Fibromyalgia—may mitigate pain and fatigue.

3. Autism—New work indicates potentially significant

effects on social interaction and agitation in autism
spectrum children. As usual, Lester Grinspoon is due
credit for this ongoing investigation.
 MARIJUANA —THE PLANT
 SATIVAS - The polar opposite of indicas. Tall, thin
plants, narrow leaves, lighter green colors, grow quick,
extend to heights of 20 feet in some cases. Origins are
traced back to Mexico, Columbia and southeast Asia.
Flowering times vary from 10 to 16 weeks, normally
longer than indicas. Taste ranges from earthy to fruity. A
good head stone. A great outdoor favorite.
 INDICAS - Short thick plants, broad leaves, darker
green, flowering in 8 to 10 weeks with thick dense flower
tops. Flavors from stinky skunk to fruity sweet. Origins
traced back to Afghanistan, Morocco and Tibet. More of
a body stone. Indoor grower's favorite types.

WHITE WIDOW

—AN INDICA SATIVA MIX

SUPER HIGH THC

 INDICA AND SATIVA
The difference between Indica and Sativa?Scientifically (and legally), all
cannabis is Cannabis Sativa L.. In practice, Indica and Sativa are the names used t
o distinguish each end of the cannabis 'spectrum'. There are a multitude of differen
t growth-patterns, qualities and effects within this spectrum, most of which are a re
sult of cannabis' remarkable ability to adapt to its environment. Genetically, and in
terms of interbreeding, all cannabis is in the same family. The Sativa 'high' and th
e Indica 'stone' are difficult to compare in terms of power. The immediate hit and r
ich taste of an Indica may seem more powerful initially; a Sativa may have a subtle
r, yet far more profound effect.
 SEPARATE SPECIES?
 ALL CANNABIS ‘SPECIES’ CAN CROSS
FERTILIZE PRODUCING FULLY FERTILE
HYBRIDS
 DURING THE 10,000 YEARS OF CO-EVOLUTION
CANNABIS AND HUMANS HAVE HAD AN
IMPACT ON EACH OTHER
 THROUGH BREEDING AND NATURAL
SELECTION, CANNABIS HAS EVOLVED IN
MANY DIRECTIONS: MANY REGIONAL
VARIETIES OF HEMP BRED FOR OIL AND FIBER;
SATIVA AND INDICA STRAINS FOR
PSYCHOACTIVITY AND HEALING
 Preparations
 Smokeable Marijuana/ Sinsemilla—sin semillas THC range—less than 1% to 10%.
Hydroponically grown mj may reach levels of 25% THC
 Hashish—made from cannabinoid rich glandular hairs of the buds of mj, also known as
trichomes—resin reservoirs. Advantage is high potency and easy transportation, THC
levels reaching as high as 70%--usual range is 20-60%
 Kief—is the dry powder form of the resin often manufactured through sieving that is
compressed into hashish
 Hash Oil—made from evaporating the solvents used to extract the lipophilic resin—also
known as honey oil. THC content can be as high as 90%, usually somewhat less.

Trichromes below
 Smoking versus Eating
 Smoking has an immediate onset enabling control of
dose and some control of duration. With vaporizers,
much of the tar content of smoke is removed.
 Eating marijuana in its myriad forms avoids
inhalation and respiratory problems. But dosage and
onset are harder to control and oral bioavailability is
less predictable. Onset of intoxication may be as long
as an hour or more from ingestion, depending on
stomach contents and the nature of the preparation.
 With recent introduction of THC assays, the quantity
of THC is beginning to be specifed in various
preparations and cannabadiol assay is just
commencing.
 Some Apocrypha
 There is a switch going on amongst growers from indoors to the
orthodoxy of outdoor gardening.
 Aficionados claim they can taste different flavors of strains.
They claim that they can tell indoor grown mj from outdoor
grown mj and can specify even the fertilizers used, as well as
organic versus chemical.
 In California, despite the explosion of cannabis dispensaries—
which are licensed as non-profit organizations—the price of an
ounce of sinsemilla is about $400. Dispensaries as the market
outlets control pricing to the consumer but increase their profits
by reducing what they pay growers, or create their own ‘grows’.
For a time dispensaries were said to have been averaging about
$500,000 in profits per month—hence the overwhelming interest
in opening new dispensaries.
 Canabinoids and Endocannabinoids
 Now about 66 phytocannabinoids isolated from mj

 Priniciple cannabinoids are THC, cannabadiol, and cannabinol.

 Two Receptors identified: 1) CB1—found in brain—basal ganglia,

limbic system and male and female reproductive systems—not in
medulla, hence THC’s safety which interacts with CB1.
Anandamide is the naturally occurring agonist for this receptor. CB1
is responsible for the euphoric and anticonvulsant effects of THC.
2)CB2—found in the immune system, especially the spleen—
investigation of anti-inflammatory and other functions is ongoing.
Raphael Mechoulam is the great endocannabinoid receptor scientist.
 Most widely disseminated, abundant receptors in the brain with
basic inhibitory functions that both inhibit and dis-inhibit by
inhibition
 ENDOCANNABINOIDS
CB1 receptors are predominantly located in the brain, including the basal ganglia,
hippocampus, cerebral cortex, cerebellum; they are also found in the spinal cord & 
primary afferent nociceptors. CB1 receptors are extraordinarily abundant in the brain.In
fact they are 10 times more abundant than mu opioid receptors, the receptors
responsible for the effects of morphine. Importantly, few CB1 receptors are present in
the cardiorespiratory area of the brainstem, which makes cannabinoid drugs relatively
safe in overdose.CB2 receptors are predominantly located peripherally in immune cells
such as mast cells and macrophages and recently in the microglia and astrocytes in the
brain. CB1 and CB2 cannabinoid receptors are the primary targets of endocannabinoids.
Thecannabinoid system plays an important role in regulatig many physiological
processes, Including metabolic regulation, appetite, reward systems, pain, movement,
mood, bone growth, and immune function. Cannabinoid receptors can be engaged
directly byagonists or antagonists, or indirectly by manipulating endocannabinoid
metabolism. In  the past several years, it has become apparent from preclinical studies
that therapies  either directly or indirectly modulating cannabinoid activity may be
clinically useful. Reference:1. Mackie K. Annu Rev Pharmacol Toxicol. 2006;46:101-22.
 Cannabinoids and Endocannabinoids
 THC—analgetic and neuroprotective. Equal affinity for
CB1 and CB2. Mimics the effects of anandamide.
 Cannabadiol—Many medical effects.: Inhibits breast
cancer growth in vitro. May reduce schizophrenic
symptoms, and have anti-anxiety, anti-inflammatory,
anti-convulsant, and anti-nausea properties. no affinity for
CB1 and CB2 receptors but acts as an indirect antagonist
of cannabinoid agonists. Leweke et al. performed a double
blind, 4 week, explorative controlled clinical trial to
compare the effects of purified cannabidiol and the
atypical antipsychotic amisulpride on improving the
symptoms of 42 patienmts with acute paranoid
shcizophrenia. Both txs showed improvement at 2 and 4
weeks with no significant difference between both tx
groups. Cannabadiol induced significantly less SEs.
Structures
 CANNABIS BASED MEDICINES
 Marinol- Dronabinol—isomer of THC: (-)-trans-isomer.
2.5mg/capsule Approved by FDA for decreasing nausea and
increasing appetite. By Rx in USA—Schedule III. Patent expires
in 2011—generics?
 Nabilone—synthetic isomer of THC marketed in the US, Canada,
UK, Mexico—as Cesamet. Chemotherapy induced nausea and
vomiting that has not responded to conventional anti-emetics;
and other medical conditions.
 Sativex—1:1 THC and CBD—an oralmucosal spray. Marketed in
Canada for MS related neuropathic pain and cancer pain.
Registration pending in several European countries.
 Cannador—Germany. Contains whole plant extract balanced for
THC and CBD—2:1. Used in several clinical trials—reduction of
muscle stiffness, spasms and pain in MS, cachexia in cancer
patients and post-op pain management
 The California Medical Marijuana Law
 Public Referendum authorized Physician Recommendation for
MMJ for a broad range of medical indications:’treatment of cancer,
anorexia, AIDS, chronic pain, spasticity, glaucoma, arthritis,
migraine, or any other illness for which marijuana provides relief.’
 Perceived for years with hostility by a Republican Attorney
General, MDs were harassed and prosecuted as the means to
control the implementation of the law and the Medical Board was
used to this end.
 MDs examine, chart, keep appropriate records—all to general
standard of care and issue recommendations for specified periods
of time—up to one year.
 This allows a patient located anywhere in the State to possess up to
8 ozs of mj, and to grow for personal use up to six mature plants.
 Counties have the right to exceed these limits and in several up to
30 plants may be grown.
 The California Medical Marijuana Law
 Primary caregivers may be given recommendations by MDs to provide mmj to
their patients.
 Under this rubric, patient collectives or dispensaries as they have come to be
known represent the bulwark of mmj sales to those patients who do not grow their
own mmj. There are over 1000 dispensaries now in California and that number is
constantly growing lured by fabulous profits made under non-profit status.
 Regulation of dispensaries is a local issue and has varied and been irregular,
mostly absent. Localities can use business licensure, zoning regulations and other
local ordinances to control dispensaries. Taxation is just beginning and there has
been little monitoring of dispensaries.
 There are now over 400,000 mmj patients in CA and probably a million or so in the
USA.
 Because of an easing of monitoring by the Medical Board, there has been a
proliferation of MDs offering quick and cheap recommendations with little respect
for clinical validity.
 MMJ is now estimated to be an over $200,000,0000 industry in CA and $14 billion
dollars for mj as a whole.
The Real Risk