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THC

Morgan Grey

Updated Sept. 26, 2020

Transcript

THC

Group 3

Brittany Ens, Sydney Fearnley,

Olivia Friesen, Robert Goldberg,

Morgan Grey, Jeremiah Hyslop,

Mia Lecky, Katie Spiess

Abstract

Figure 1. Cannabis being prepared for comsumption

(-) - Trans –delta 9 – tetrahydrocannabinol (THC) is the main psychoactive component of cannabis sativa. THC is a partial agonist to cannabinoid receptor CB1, causing feelings of relaxation, pain relief, and euphoria. THC is highly lipid-soluble, allowing it to cross the blood-brain barrier and bind to CB1 receptors in the central nervous system. Cannabinoid receptors are G-protein coupled receptors, and binding of THC causes inhibition of adenylate cyclase and reduction of cAMP production. This mechanism is largely responsible for the impaired memory and motor function that occurs with THC consumption. Tetrahydrocannabinol is most commonly used recreationally through smoking marijuana, because it causes a “high”. It may be used by prescription for chronic pain relief. THC is also administered in the form of Dronabinol, capsules containing only THC and no other cannabinoids normally present in cannabis. Dronabinol is used as an antiemetic for patients receiving chemotherapy, and as an appetite stimulant for patients with AIDS. Unwanted effects of THC are minor and not life-threatening, but include confusion, paranoia, dry mouth, and hallucinations.

THC is rapidly absorbed through inhalation, but slowly absorbed through ingestion. It is metabolized through hydroxylation and oxidation reactions. Hydroxylation produces 11-OH-THC, which is then oxidized to THC-COOH and conjugated to glucuronide, which is excreted through urine. If used for pain relief, alternative medications include ibuprofen and codeine. If used for antiemetic properties, Gravol and Zofran may be used instead. Because THC occurs naturally in cannabis sativa, it appears to be safe. Now that marijuana is legal in Canada, hopefully more research can be conducted to determine the true health hazards of (-) - Trans – delta 9 – tetrahydrocannibinol.

Figure 2. Cannabis edible

Introduction

Cannabis sativa, otherwise known as hemp or marijuana, has been used for thousands of years. It has been used as medical treatment for chronic pain, as well as industrial use in synthesizing products. Medicinal use became more prominent in 1964 with the discovery of the main psychoactive ingredient, (-) - Trans – delta 9 – tetrahydrocannabinol. THC is one of 113 cannabinoids in the marijuana plant. Other cannabinoids include cannabinol and cannabidiol (CBD). THC and CBD are often used interchangeably, but are quite different in their properties. Both compounds are used medically, but this presentation will be focusing exclusively on THC.

Figure 3. Chemical structure

Pharmacokinetics

The pharmacokinetics of THC varies with the route of administration

Figure 4. Pharmacokinetics of ∆9-THC

Absorption

A

Inhalation

-THC is rapidly absorbed

-The peak plasma concentration occurs within 3-10 minutes after inhalation

-Systemic bioavailability (percentage of drug entering circulation) is between 10-35% and varies with the depth of inhalation & amount of time held in the lungs

Ingestion

-THC is slowly absorbed

-The peak plasma concentration occurs within 2-4 hours after ingestion

-While 95% of ingested THC is absorbed by the GI tract, the amount of the drug that remains unchanged is unknown

-Low systemic bioavailability of ~5-20% due to degradation in the stomach acid

Distribution

-THC is a highly lipophilic drug and accumulates in fat tissues

-Distribution of THC is determined by is physicochemical properties, such as solubility, permeability, and chemical stability

-90-95% of circulating THC is bound to serum proteins, predominantly lipoproteins; therefore, only 5-10% of the drug is pharmacologically active

-THC is able to cross the placenta and enter the breast milk

D

Metabolism

-Degradation of THC is catalyzed by the cytochrome-P450 in the liver though hydroxylation and oxidation reactions

-Hydroxylation (Phase 1) of THC produces the main active metabolite, 11-OH-THC, which is oxidized (Phase 2) to THC-COOH, an inactive metabolite

-Further degradation produces glucuronic acid conjugates, such as glucuronide, which can be eliminated in the urine

M

Figure 5: Degradation of THC

Excretion

- Following degradation, THC metabolites are primarily eliminated from the body via urine and feces

- Excretion occurs within days to weeks after administration

- The elimination half-life of THC is between 25-36 hours due to the high lipophilicity and slow release from lipid stores

- Continued use of THC and larger doses results in a longer elimination half-life

E

Cannabinoid Receptors

Figure 6: Structure of a GPCR

-CB receptors are G-protein coupled receptors (GPCRs) found on the presynaptic membrane of many neurons

-Cannabinoid receptors include two classes: CB1 and CB2

-CB1 receptors predominantly are located in the central nervous system

-The psychoactive, mental and behavioural effects of

THC occur due to binding to CB1 receptors

-CB2 receptors are located in the peripheral tissues and cells of the immune system

-THC inhibits Interleukin-2 (IL-2) transcription, and

suppresses the function of T-cells and macrophages

-CB2 receptors are not involved in the production

psychoactive effects

-The physiological ligands to these receptors are anandamides, derivatives of arachidonic acid

Mechanism of Action

MOA

-THC acts a partial agonist on cannabinoid receptors CB1 located in the central nervous system and CB2 receptors in the peripheral lymphoid tissues

-CB1 receptors are linked to effectors via Gi and Go

-When bound to a ligand (THC or an endocannabinoid), CB1 receptors, via Gi, function to:

1)Inhibit adenylyl cyclase causing a decrease in the

cAMP formation and inhibition of acetylcholine and

glutamate; therefore, modulate the neurotransmitter

release

2)Suppresses voltage-gated Ca2+ channels; therefore,

inhibiting the release of neurotransmitters from the

presynaptic membrane

3)Activating the G-protein-sensitive inwardly rectifying

potassium (GIRK) channels, allowing K+ to exit the cell

resulting in hyperpolarization

-THC can over-activate the cannabinoid system in the body which causes addiction and behavioural abnormalities

-The specific mechanisms responsible for producing the psychoactive effects of THC is unknown

Figure 7 : Effects of CB1 when activated by an endogenous or exogenous cannabinoid

Effects

The location of CB receptors determines the effects of THC

Effects

- relaxation

- euphoria

- reduction of nausea

- increased appetite

Figure 8: Cannabinoid receptor location in the central nervous system and their effects.

Alternative Names

Chemical Name

(-) - Trans – delta 9 – tetrahydrocannabinol

Synthetic form (approved by FDA)

Dronabinol (no longer manufactured in Canada)

Brand Name (s)

Marinol (no longer manufactured in Canada)
Syndros

Street Name(s)

marijuana, pot, weed, grass, ganja, dope, cannabis, Mary Jane, hemp, Devil’s Lettuce, chronic, reefer, stinkweed, broccoli, Bud

Availability

Uruguay and Canada are currently the only countries to have completely legalized consumption and sale of recreational cannabis nationwide.

Canada: Legal, The Cannabis Act that came into effect on October 17, 2018 currently permits the sale of: cannabis oil, fresh cannabis, dried cannabis, cannabis plant seeds, and cannabis plants

*The sale of edibles (food and drinks with cannabis extracts) will be permitted within 1 year after the coming into force date of the Cannabis Act.

USA: Illegal, though legal for medical use in 33 states, and legal for recreational use in 10 states (Alaska, California, Colorado, Maine, Massachusetts, Michigan, Nevada, Oregon, Vermont, and Washington)

Mexico: Legal (decriminalized), for non-commercial recreational use on October 21, 2018. Although, the details of the ruling are still in progress as it was not fully legalized for recreational use. It is legal for medical use (THC content below 1%).

Europe: Illegal, though few countries have legalized medical use including Germany, Greece, Italy, and Netherlands

Clinical Indications

Major Clinical indications:

- Slow the progression of Alzheimer's disease

-THC was found to slow down the formation of amyloid plaques by blocking the enzyme in the brain that makes them

-Treatment for Glaucoma

-Marijuana decreases the intraocular pressure

-Help with inflammatory bowel disease

-THC interacts with cells in the body that play a significant role in immune responses

- PTSD (Post -Traumatic Stress Disorder)

helps regulate system that causes fear and anxiety in the body and the brain

-psychiatric conditions and mood disorders

- Multiple Sclerosis or spinal inflammation

- Reduce the reliance of opioids

- Reduce effects of cachexia

Minor Clinical Indications:

-Treating nausea and vomiting

- Cancer patients after chemotherapy

- Help with neuropathic pain

- Decrease seizures

- Helps soothe tremors for Parkinson's disease

- Help protect the brain from concussions and trauma

- Marijuana has neuroprotective capabilities

-Help increase appetite

Ex. increase the appetite in HIV patients

-Bronchial asthma

Figure 9. Cannabis in bud form and capsalated.

Dosage

For treatment of Symptoms

1. Nausea, take 5mg THC up to 4 times daily (20mg daily)

2. Appetite, take 2.5mg THC up to 6 times daily (15mg Daily)

3. Pain, take 5mg THC up to 4 times daily (20mg daily)

4. Adverse effects typically occur with single doses greater than

10mg, or exceeding a total of 30mg daily.

Oral Dosage

1. The oral bioavailability of THC is ~6% to 20%

Inhaled Dosage

1. The inhaled bioavailability of THC is ~10% to 35%

2. Roughly 40% of THC is destroyed during combustion

3. Roughly 2.5% of the dry weight of cannabis is absorbed as

THC

a. Thus 1.0grams of cannabis smoked relates to an ~25mg dose

Tolerance

1. THC tolerance has a large effect on dosage, if desired effects are not attained at the recommended dosage level, THC dosage my be incrementally increased by 2.5mg intervals until desired effects are attained.

2. Long term use may decrease effect at a certain dosage, thus constant adjustment of dosage may be required to maintain results.

Major contraindications

Alternative

Treatments

THC should not be used by individuals who:

a. Have history of psychosis including schizophrenia and bipolar disorder

b. Are under the age of 18

c. Are pregnant or breastfeeding

d. Are advised against by physician

e. Are allergic

f. Are taking sedative medications such as barbiturates & CNS depressants

Minor Contraindications

Minor Contra-indications

Caution should be taken by individuals who:

a. Are under the age of 25

b. Smoke tobacco

c. Have or are at risk of cardiovascular or Respiratory disease

d. Are planning to become pregnant

e. Have mood or anxiety disorders

f. Heavily consume alcohol, opioids, or Benzodiazepines

g. Have sever liver or renal disease

h. Have a history of substance abuse

i. Are taking one of the following drugs that Interacts with THC:

-Warfarin

-Theophylline

-Antabuse

-Tricyclic antidepressants

-Prozac

-Anticholinergic medications

Unwanted Effects

Unwanted

Effects

Minor:

Tiredness
Dizziness
Airway obstruction from chronic smoking
Dependence and withdrawal symptoms
Irritability
Uneasiness
Sleeplessness
Increased perspiration
Loss of appetite
Dryness of mouth
Vomiting
Constipation
Slurred speech

Major:

Psychological effects
Schizophrenic psychosis (mostly in adolescents)
Dysphoria
Anxiety
Impaired cognition
Mental clouding, fragment of thoughts
Memory impairment
Impaired perception
Distorted time and space sense
Hallucinations
Blurred vision
Decreased motor function
Trembly weakness, muscle twitching
Variations in heart rate
Tachycardia with acute dosage
Bradycardia with chronic use
Sedative effects
Drowsiness, sleep, generalized CNS depression
Tolerance

Alternative Treatments

a. For pain management:

-ibuprofen & acetaminophen

-codeine

b. For nausea treatment:

-prescription: Zofran

- fewer health risks but can cause anxiety

-non-prescription: ginger & lemon in teas, water, or eaten

c. For CB1 activation:

-endogenous cannabinoids in brain

-synthetic alternatives in clinical trials

-organophosphorous agents in animal trials

-prevent the degradation of neurotransmitters released from activated CB1 receptors

Alternative

Treatments

Fun Facts

- A case-control study associated THC with a 29% increase in unsafe driving, compared to 101% for alcohol!

- Some studies indicate that chronic use of marijuana may decrease plasma testosterone and decreases sperm count, concentration, and motility, thus decreasing male fertility!

- Marijuana was the first item sold over the internet, where students from Stanford purchased cannabis from the Massachusetts Institute of Technology.

- Children have a lower density of CB1 receptors in their brains, making them less susceptible to the psychoactive effects of THC than adults.

- In Denver, Colorado medical marijuana dispensaries out number Starbucks 3:1.

- Cannabis brownies were made famous by a woman named Mary Jane, who had baked and distributed cannabis brownies to increase appetite in patients with AIDS.

Fig. 10 A grouping of cannabis edibles

Stories

A lady named Michele Mangione, was diagnosed as terminally ill and told she had three months to live. Diagnosed with stage four liver cancer and cushing's disease. Three months after Michelle's journey with medical marijuana foods she was completely cancer free.

Allison Ray Benavides became an advocate for pediatric cannabis when her son, Robby, was diagnosed with an intractable seizure disorder at only 3 years old. The prescribed pharmaceutical medications Robby was still having up to a hundred seizures a day. Soon after Robby was further prescribed with a new medication, Depakote, which reduced the seizures down to approximately twenty a day, only elevating some of the pain from Michelle watching her child repeatedly getting beat up each day. It was when Robby was finally put on Charlotte's Web, a low THC from used to treat seizures in children, that he had his first day being seizure free. It was exactly a year later after Robby's diagnosis and the use of Charlotte's Web that Robby was seizure free.

A gentleman in his eighty’s diagnosed with Prostate Cancer. He had a prostate-specific antigen of 3300, normal PSA are much lower around 8, he also had a tumor the size of a lemon. He started taking THC orally at night but that was a slow process, to speed up the process he started to take THC in the form of suppositories. Two years later he is cancer free.

A lady had open sores on her chest that were cancerous, the doctors could not get her sores to close so she took it upon herself and started mixing THC liquid with CBD oil. She then rubbed it across her chest every day a few times within 5 months the sores closed up.

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