Marijuana (also spelled marihuana) is a word derived from maraguanquo, meaning “intoxicating plant”. Marijuana refers to a mixture of dried leaves, stems, and flowering tops of a weed-like plant, which was given the name Cannabis sativa by Linnaeus in 1753. Cannabis is a flowering hemp used for thousands of years as a fiber source for producing rope, clothing, and paper (among other uses). 

The term Cannabinoid describes the basic chemical structure shared by 70 or so unique compounds identified in the cannabis plant.

It wasn’t until the 1960s when Israeli researchers Yehiel Gaoini and Raphael Mechoulam identified one of these cannabinoid compounds, Δ-9-tetrahydrocannabinol (THC), as the major psychoactive ingredient in Cannabis. Another important phytocannabinoid (“phyto” means plant) with relatively low affinity for neuronal cannabinoid receptors is cannabidiol (CBD).

CBD is not considered psychoactive and research suggests considerable therapeutic potential for CBD in treating epilepsy, neurodegenerative disorders, anxiety, psychosis, and substance abuse. 

Marijuana can be obtained and prepared in a variety of ways for consumption. While marijuana can be consumed orally (e.g., cookies, brownies), the most common method of consumption is smoking the plant in rolled cigarettes called “joints” or in pipes and bongs. Tobacco and marijuana can be consumed together in hollowed-out cigars, or blunts, or in spliffs, which are joints/cigarettes containing a mixture of tobacco and marijuana.

Common street slang for marijuana include pot, reefer, grass, weed, dope, ganja, and mary jane. Terms used for the intoxicating experience of THC include “stoned” or “high”. 

The THC content of the cannabis plant depends on the strain, growing conditions, and pollination. The most common method of increasing marijuana’s THC potency is by preventing pollination and seed production by female plants. This is called sinsemilla (“without seeds”) and is now the most popular type of cannabis in circulation. 

The amount of THC can be increased by various methods that involve extracting the cannabinoids from the cannabis plant. Hashish is an example of a concentrated extract found in many parts of the Middle East and East Asia.

Recently, “dabbing” has become popular. Dabbing involves extraction of cannabinoids with butane. The solvent is then evaporated leaving behind a waxy sticky residue that is very high in THC. The waxy resin is smoked using a torch lighter or vaporizing device (i.e., vape pen). 

Not surprisingly, the THC content in consumed cannabis plants has risen over the past 20 years. The yearly mean THC content of marijuana seized by the drug enforcement agency (DEA) in 1995 was about 4%. In 2014 this number was as high as 12%. 

While medicinal and recreational use of marijuana dates back over 8,000 years in East Asia, the practice of marijuana smoking was introduced into the United States in the early 1900s. An anti-marijuana campaign in the 1930s led to the first federal regulations controlling cannabis and in 1937 marijuana became illegal in the United States with the passage of the Marijuana Tax Act. Recently, marijuana has been legalized in many states for medicinal use only but many are beginning to legalize the purchasing and recreational consumption of this intoxicating plant. 

Pharmacology of THC

Routes of Administration, Absorption, and Dosing

Marijuana is consumed orally (brownies, cookies, candies, tinctures) or smoked (inhaled into the lungs). An average joint contains about 0.5 grams to 1.0 grams of cannabis and approximately 40mg of THC. Smoking marijuana is the most rapid method of delivering THC to the brain as THC absorbed by the lungs bypasses the metabolizing enzymes in the liver. After inhaling marijuana smoke, about 20%-30% of the THC content in the smoke is rapidly absorbed in the lungs where it quickly enters the pulmonary circulation and travels to the brain. The amount of THC absorbed depends on the initial THC content in the plant and the pattern of smoking. The dose and time to effect are influenced by puff volume, puff frequency, inhalation depth, and the length of time the breath is held.

After smoking marijuana, THC levels peak in the blood after about 20 to 30 minutes and decline rapidly over the course of 1-2 hours. However, complete elimination from the body can take much longer as the lipophilic properties of THC means it can easily accumulate in fat tissue. The slow release of THC stored in fat is the reason THC metabolites can be detected weeks after a single use. 

Oral consumption of THC leads to prolonged but poor absorption of THC compared to inhalation. The bioavailability of THC is markedly reduced with oral consumption as a result of first-pass metabolism in the liver. This means oral consumption leads to unpredictable and variable THC levels. After consuming THC orally, THC levels peak in about 2-3 hours. 

Metabolism of THC and CBD

THC is metabolized initially in the lungs and liver. There are over 80 THC metabolites identified. Two major metabolites are 11-hydroxy-THC (11-OH-THC) and 11-nor-9-carboxy-THC (THC-COOH). Interestingly, 11-OH-THC crosses the blood-brain-barrier more readily than THC and is more effective in producing psychological effects in man. About 60%-70% of THC metabolites are excreted in feces and 20%-30% are excreted in the urine. Some metabolites may remain in the body for several weeks (metabolites may be detected in urine and feces for more than a week). As mentioned previously, THC and its metabolites accumulate in tissues (fat and brain) with repeated administration. Chronic users metabolize THC more rapidly than others. 

Cannabinoid Receptors

There are two major types of cannabinoid receptors identified to date: CB1 receptors and CB2 receptors. Generally, activation of CB receptors inhibits neurotransmission.

CB1 Receptors

The CB1 receptor is the principal cannabinoid receptor in the brain, where it is expressed at a high density in areas such as the basal ganglia, cerebellum, hippocampus, and cerebral cortex. 

CB1 receptors are typically located on axon terminals, where they act to inhibit the release of many different neurotransmitters. THC administration to mice causes classical CB1 receptor–mediated effects. These include reduced motor activity, hypothermia (reduced body temperature), catalepsy (rigidity/freezing behavior), and decreased response to painful stimuli (hypoalgesia). CB1 agonists also impair learning and memory consolidation via inhibition of long term potentiation (LTP) in the hippocampus. CB2 receptor activation in the immune system causes cytokine release and changes in immune cell migration necessary for an appropriate inflammatory response.

CB2 Receptors

The CB2 receptor was first identified in the immune system, but it is also found in a number of other tissues, including the brain, where it is mainly localized in microglial cells, which are immune cells that help fight off foreign invaders (among other roles). 

Endocannabinoids (The cannabinoids we make ourselves)

Our brain synthesizes several substances, called endocannabinoids, that are neurotransmitter-like retrograde messengers that stimulate CB1 receptors on presynaptic neurons (and other nearby cells) and modulate the release of numerous neurotransmitters. Anandamide was the first endocannabinoid to be discovered followed by 2-arachidonylglycerol (2-AG). 

The endocannabinoid system plays a complex role in learning, memory, and extinction of already learned tasks. Enhancing endocannabinoid signaling has anxiolytic effects in both stressed and unstressed laboratory animals, and it also leads to an antidepressant profile in standard rodent tests of depressive-like behavior. In contrast, reduced endocannabinoid levels are associated with increased anxiety- and depressive-like behaviors.

How Marijuana (THC) Affects Us

Acute (short-term) Physiological effects

• Conjunctival injection (red eyes)
• Tachycardia
• Orthostatic hypotension
• Hyperreflexia
• Sedation
• Hallucinations
• Increased appetite

The Marijuana “High”

AT LOW DOSES

• sense of well-being
• mild enhancement of senses (smell, taste, hearing)
• subtle changes in thought and expression
• talkativeness
• giggling
• increased appreciation of music
• increased appetite
• mild closed-eye visual distortions

AT HIGHER DOSES

• visual distortions may become more prominent
• sense of time is altered (overestimation of time)
• attention span is reduced
• short-term memory (seconds to minutes) is impaired (confabulation may occur)
• thought processes and mental perception may be significantly altered

Toxicity

• Lung damage (1 smoked joint = 5 cigarettes)
• Memory lapses
• Inability to concentrate
• Possible decreased resistance to diseases (impaired immune mechanisms)
• Exacerbation of psychosis
• Decreased testosterone levels (plasma) with chronic high doses
• Impairment of driving judgment with regard to speed; motor coordination not necessarily impaired; compensation for drug effect may occur in some subjects (behavioral tolerance); motor incoordination and ataxia at high doses; additive or synergistic effects of
• THC and alcohol on motor coordination
• Brain damage– evidence of neuronal damage in hippocampus after repeated administration of large doses in animals; no evidence of such damage substantiated in humans

Tolerance

Drug tolerance describes the reduced reaction to a drug following repeated use. Increasing the dosage of drug may or may not restore the drug’s effects. Tolerance is often reversible (e.g., through a drug holiday) and can involve both physiological and psychological factors. Tolerance to the psychological effect of THC has been demonstrated but is subject-dependent. There is some tolerance to physiological effects. Pharmacodynamic and behavioral tolerance also occurs. 

Therapeutic Roles for THC

Dronabinol (Marinol®)

Dronabinol is a THC analog approved for chemotherapy-induced nausea and as an appetite stimulant in patients with AIDS or cancer. Other potential therapeutic uses include glaucoma (by reducing ocular pressure) and analgesia (neuropathic pain, allodynia, hyperalgesia, peripheral pain).

Cannabinoids and Pain

Cannabinoid involvement in pain modulation is beyond the scope of this post, but it is worth mentioning that cannabinoids modulate pain pathways.

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