Toxicology of Tetrahydrocannabinol

(THC – The Active Ingredient in Marijuana)

History of Marijuana Use

• Marijuana use has been around since ancient times dating back in Chinese medical compendium traditionally dating from 2737 B.C.

• Following its use in China it spread to India and North Africa, and reached Europe as early as 500 A.D.

• During 1850 to 1942 A.D. it was prescribed by the United States Pharmacopeia for:– Labor Pains– Nausea– Rheumatism

• A campaign conducted in the 1930s sought to portray Marijuana as a powerful and addictive substance.

• Many considered it the gateway drug• In the 1960s the drug was used as a sign of rebellion against authority

History of Marijuana Use

• Controlled Substances Act of 1970 classified marijuana along with heroin and LSD as a Schedule I drug

– Schedule I Drug – Highest Abuse Potential and No Medical Use

• Most marijuana came from Mexico until 1975– This is when Mexico agreed to eradicate the crop by spraying it with an herbicide.

• Following this Columbia became the main supplier

• Following Reagan and Bush, harsher sentences and a crack down on importation across the border leads to increased domestic growth

– Especially in California and Hawaii

• There was a decreased smoking trend that didn’t start to increase until the 1990s, but leveled off at levels lower than previously seen

• The History of Marijuana Use is information collected from source 1.

THC Background

• Tetrahydrocannabinol (THC) – A compound, C21H30O2, obtained from

cannabis or made synthetically, that is the primary intoxicant in marijuana and hashish. (Source 6)

• It can be seen as a crystalline structure on the plant as seen on the right.

Pharmacology of THC• THC typically functions by binding a particular receptor in the brain, the

Cannabinoid Receptor (CB1).– The presence of this receptor indicates that there is a naturally occur

(endogenous) ligand, Anandimide, as well as other related compounds.

• The response can affect the hippocampus and hypothalamus– Hippocampus – A complex neural structure (shaped like a sea horse)

consisting of grey matter and located on the floor of each lateral ventricle; intimately involved in motivation and emotion as part of the limbic system; has a central role in the formation of memories.

– Hypothalamus – A region of the brain, between the thalamus and the midbrain, that functions as the main control center for the autonomic nervous system by regulating sleep cycles, body temperature, appetite, etc., and that acts as an endocrine gland by producing hormones, including the releasing factors that control the hormonal secretions of the pituitary gland.

• Pituitary Gland – The master endocrine gland affecting all hormonal functions.

• This information is from source 2, and the definitions are from source 4 (hippocampus) and source 5 (hypothalamus).

Neurological Effects of THC

• Endocannabinoid Synaptic Transmission1. Excitatory transmission of the neurotransmitter glutamate

causes an influx of Ca++ into the post-synaptic neuron.

2. The presence of Ca++ post-synaptically causes the production of endocannabinoids in the post-synaptic neuron.

• Endocannabinoids – Anandamide is an example. Anandamide is found in chocolate, along with inhibitors of the enzyme that breaks down Anandamide. This leads to a mild ‘euphoria’ feeling associated with chocolate consumption.

3. The endocannabinoid is then released into the synaptic cleft.

Neurological Effects Continued

• Endocannabinoid Synaptic Transmission Continued4. In the synaptic cleft the endocannabinoid binds to the

Cannabinoid Receptor of the pre-synaptic neuron.• This in turn modulates neurotransmission pre-synapticly

• Post-Synaptic Neuron Pre-Synaptic Neuron (Renegade Transmission)

– This mechanism is reverse of what is typically seen• Pre-Synaptic Neuron Post-Synaptic Neuron (Normal

Transmission)

• The Neurological Effects are from source 2.

Normal Functions Associated With Cannabinoid Receptor (CB1)

• Many Cannabinoid Recpetors are found in the parts of the brain that affect:– Pleasure

– Memory

– Thought

– Concentration

– Sensory and Time Perception

– Coordinated Movement

• This information is from source 3.

Toxicity of THC

• Merck Index (12th Edition) has indicated an LD50 value for THC as determined using rats– Male Rats were determined to have an LD50 of 1270 mg/kg

– Female Rats were determined to have and LD50 of 730 mg/kg

– Doing a direct scale up of this is 50g (female) and 86g (male) for a 68kg (150lbs) person.

• This does not, however, correlate directly with human toxicity and may be different.

• This information is from source 2.

Negative Effects of THC (pg. 1)

• Short-term effects can lead to problems with:– Memory and Learning

– Distorted Perception

– Difficulty in Thinking and Problem Solving

– Loss of Coordination

– Increased Heart Rate

• Long-term effects can lead to:– An increase in activation of the stress-response system

– Changes in activity of nerve cells containing dopamine• Dopamine – involved in regulation of motivation and reward

Negative Effects of THC Continued (pg. 2)

• Effect on Heart:– Risk of heart attack more than quadruple in first hour after smoking

marijuana.• Possibly from the effects on blood pressure, heart rate, and reduced oxygen-

carrying capacity.

• Effect on Lungs:– Infrequent abuse can cause burning and stinging of the mouth and throat,

often a cough accompanies this.– Similar respiratory problems to tobacco smokers:

• Daily Cough and Phlegm Production• Frequent Acute Chest Illness• Heightened Risk of Lung Infections• Greater Tendency to Obstructed Airways

– Increased likelihood of developing cancer of the head or neck• Evidence suggests that smoking marijuana doubles or triples the risk of these

cancers

Negative Effects of THC Continued (pg. 3)

• Effects on Lungs Continued:– Marijuana smoke contains 50 to 70 percent more carcinogenic

hydrocarbons than does tobacco smoke.

– Marijuana users usually inhale more deeply and hold their breath longer than tobacco smokers do.

• This increases the lungs’ exposure to the carcinogenic smoke.

• Effects on Immune System:– THC impairs the immune systems ability to fight disease

– In lab experiments that exposed animal and human cells to THC or other marijuana ingredients, normal disease-preventing reactions of key immune cells were inhibited

– Other studies indicated that mice exposed to THC or related substances were more likely to develop bacterial infections and tumors.

Negative Effects of THC Continued (pg. 4)

• Effects of Heavy Marijuana Use on Learning and Social Behavior– Can Cause:

• Depression

• Anxiety

• Personality Disturbances

– Can Lead To:• Falling Behind in Accumulating Intellectual, Job, or Social Skills

– Someone who smokes marijuana every day may be functioning at a reduced intellectual level all of the time.

– Research has shown that marijuana abusers remain impaired for a week after quitting, but could return to normal within 4 weeks.

• Some cognitive abilities may be restored, even after long-term heavy use.

Negative Effects of THC Continued (pg. 5)

• Working Associated Effects– Increased Absences– Increased Tardiness– Increased Accidents– Increased Worker Compensation Claims– Increased Job Turnover

• Important Measures of Life Achievements that are Effected– Cognitive Abilities– Career Status– Social Life– Physical Health– Mental Health

• The List of Negative Effects are all from the National Institute on Drug Abuse, National Institutes of Health, and the U.S. Department of Health and Human Services, Source 3.

Positive Effects of THC (pg. 1)

• Benefits– Cancer or AIDS treatment

• Ability to increase appetite and decrease nausea

• Possible tumor reduction

– Glaucoma• Decrease pressure in the eye

– Multiple Sclerosis• Can relieve spasms

Positive Effects of THC Continued (pg. 2)

• Benefits Continued– Tourette Syndrome

• Can reduce nervous tics and urges (using synthetic THC)

– Alzheimer’s Disease• Inhibition of Plaque Formation (using high in vitro concentrations of THC)

– Multiple Sclerosis, Parkinson's Disease, and Alzheimer’s Disease• Activation of CB1 receptors may facilitate neurogeneration and

neuroprotection.

– This information is from source 2.

References1. History of Marijuana Use. <

http://www.infoplease.com/ce6/sci/A0859487.html>2. Tetrahydrocannabinol. <http://en.wikipedia.org/wiki/

Tetrahydrocannabinol> Wikipedia3. Marijuana <http://www.drugabuse.gov/PDF/InfoFacts/Marijuana06.

pdf> National Institute of Drug Abuse4. Hippocampus <

http://dictionary.reference.com/browse/hippocampus> Dictionary.com

5. Hypothalamus <http://dictionary.reference.com/browse/hypothalamus> Dictionary.com

6. THC <http://dictionary.reference.com/browse/THC> Dictionary.com

• Information collected by and compiled by: Nicholas Card