BMED 443: Endocannabinoids and

Medical Marijuana
Instructor: Darrell A. Jackson, Ph.D.
What is Marijuana?
Sedative (Narcotic)
Pain Killer
Hallucinogen
Medicine
Active ingredients
400 chemicals
61 are unique to Cannabis (cannabinoids)
THC Isolated in 1964

THC and Effects
When smoked THC is readily absorbed into blood
Euphoria: 2 mg smoked; 5 mg oral
Changes in perceptual time and space: 7 mg smoked;
17 mg oral
Changes in body image: 15 mg smoked; 25 mg oral
Pharmacokinetics
THC Half life 19 hours
11-hydroxy-THC half life 50 hours
Complete elimination 2-3 weeks


Behavioral Effects
Low - moderate doses
Loss of inhibition, relaxation, drowsiness
feeling of well being, exhilaration, euphoria
sensory - perceptual changes
recent memory impairment (confusion, memory
lapses and difficulties in concentration)
balance/stability impaired
Behavioral Effects
High doses
Pseudo-hallucinations
Synesthesia
impaired judgment, reaction time
pronounced motor impairment
increasingly disorganized thoughts, confusion,
paranoia, agitation

Not lethal even at very high doses
Certain parts of the brain govern specific functions. Note the distribution of functions.
Movement is found in the Frontal Lobe.

Frontal Lobe
body
When a person smokes marijuana, the active ingredient, cannabinoids or THC, travels quickly
to the brain. Note the areas where THC (magenta) concentrates. The VTA, nucleus accumbens,
caudate nucleus, hippocampus, and cerebellum are highlighted. THC binds to THC receptors
that are concentrated in areas within the reward system as well as these other areas. The action
of THC in the hippocampus explains its ability to interfere with memory and actions in the
cerebellum are responsible for its ability to cause loss of balance and coordination.
Side Effects
Increased pulse rate
Caffeine, nicotine
Red eye
Decreased salivation
No pupil change
cardiovascular (tachycardia)
respiratory (bronchodilation)
musculoskeletal (muscle relaxation)
gastrointestinal (decreased motility)
ENDOCANNABINOID SYSTEM
The first
endocannabinoid
discovered was named
anandamide (AEA)
A second arachidonic-
acid derivative 2-
arachidonoylglycerol
(2-AG) that binds to
cannabinoid receptors
was subsequently
described
ENDOCANNABINOID SYSTEM FUNCTION
Postsynaptic neurons synthesize membrane-bound
endocannabinoid precursors and cleave them to release active
endocannabinoids following an increase of cytosolic free
Ca
2+
concentrations
Endocannabinoids act as retrograde messengers by binding to
presynaptic CB
1
cannabinoid receptors, which are coupled to
the inhibition of voltage-sensitive Ca
2+
channels and the
activation of K
+
channels.
This blunts membrane depolarization and exocytosis, thereby
inhibiting the release of NTs such as glutamate, dopamine
and GABA and affecting, in turn, processes such as learning,
movement and memory.
ENDOCANNABINOID SYSTEM
FUNCTION: Continued
Endocannabinoid neuromodulatory signaling is
terminated by an unidentified membrane-transport
system (T) and a family of intracellular degradative
enzymes, the best characterized of which is fatty acid
amide hydrolase (FAAH), which degrades AEA to AA
and Et.
The endogenous cannabinoid system might also exert
modulatory functions outside the brain, both in the
peripheral nervous system and in extra-neural sites,
controlling processes such as peripheral pain, vascular
tone, intraocular pressure and immune function.

Endocannabinoid System
Cannabinoids Receptors
Effect of THC on hippocampal function
Medical Uses of Cannabis
1839 On the preparations of the Indian
Hemp, or Gunjah was published by a
British physician (OShaughnessy) working
in India
cannabis preparations were safe (nontoxic)
effective anticonvulsant
muscle relaxant
relieve the pain rheumatisms
Medical Uses of Cannabis in the USA
1860 Ohio Medical Society
reported on the successful
treatment of stomach pain,
chronic cough, and
gonorrhea using C. I ndica
1890s medical text
included the statement
Cannabis is very valuable
for the relief of pain,
particularly that
depending on nerve
disturbances.
Early 20th century
Psychologists used
psychoactive agents to study
the workings of the mind
French physician, Moreau,
tried to treat a variety of
mental disorders with
hashish
Used to treat cholera,
tetanus, and rabies
Queen Victoria smoked
marijuana for painful
menstrual cramps
Medical Uses of Cannabis
Four factors contributed to declining
cannabis prescription rates :
development of new and better drugs
variability of cannabis preparations
cannabis is insoluble in water and cannot be
injected
oral dosages have a long latency to onset of
action
Medical Uses of Cannabis
(1972) report found marijuana smoking to
be effective in reducing the intraocular
pressure in a glaucoma patient
(1975) study showed THC was effective in
reducing the severe nausea caused by cancer
chemotherapeutic agents
Cachexia treatment
Increase appetite
THC FORMULATIONS
FDA has approved two
drugs, Marinol and
Cesamet, for therapeutic
uses in the U.S., which
contain active ingredients
that are present in
botanical marijuana.
On December 22, 1992,
FDA approved Marinol
Capsules for the treatment
of anorexia associated with
weight loss in patients with
AIDS.
THC FORMULATIONS
Bayers new cannabis
product in Europe
marijuana-extract
spray called Sativex
It provides immediate
symptomatic relief,
similar to smoking
cannabis, without the
health hazards associated
with smoking.
Rimonabant Rimonabant
CB
1
Adipocyte
Brain
CB
1
Adiponectin
FA oxidation FA oxidation

Body weight
Central
effects
Metabolic
peripheral effects
Rimonabant (CB1 Blocker): A Multi-Impact Drug

Hyperinsulinemia
Insulin sensitivity restored

TG

HDL - C
Control of nicotine
dependence
Decrease in food intake
(palatable and non -
palatable food)
Van Gaal et al; Lancet (2005) 365: 1389-97
The Endocannabinoid System
States where voter initiatives have allow for
medical use of marijuana
http://online.wsj.com/article/SB10001424052748703626604575011223512854284.html
Legal Status
Although the federal courts have ruled on a number of cases
involving medical marijuana, they have not directly addressed
the conflict between the Controlled Substances Act (CSA) and
state medical marijuana laws. Until the Supreme Court rules
on the constitutionality of state medical marijuana laws, the
status quo will remain. The federal government classifies
marijuana as a Schedule I controlled substance and outlaws its
use.

Federal agents, mainly the DEA, continue to investigate and
enforce violations of the CSA. States continue to work under
the assumption that their laws are constitutional and absolve
local law enforcement agents from criminalizing medical
marijuana. Meanwhile, patients and healthcare providers are
left with no clear guidance, direction, or logic.
The Legal Status of Medical Marijuana; Matthew J Seamon Ann Pharmacother 2006;40