The Science Behind Medical Marijuana

An overview of history and scientific information and background about marijuana use:

Marijuana strains were grown from seed and used by humans for least 12,000 years, initially in Southern and Central Asia.  Holy men and women (shamans) prized the plant as a necessary ingredient to achieve spiritual transcendence. Its aromatic buds were used for perfumes, medicines, and intoxicants.  They transported the seeds of this indigenous plant from the foothills of the Himalayas to the rest of the world, ranging from China to Europe and eventually to the New World.

Clinical benefits (physical, psychological, and emotional) have been attributed to marijuana use since 2,600 BC, initially in the Chinese pharmacopoeia. After the Uniform State Narcotic Act in 1932, research and clinical use of marijuana in the U.S. was severely limited, and it was studied primarily through animal studies and human case reports.

In 1986, there were only eight articles listed in PubMed under the topic “medical marijuana,” but by 2019, more than 1,500 were published, a greater than 18,000% increase.  Due to the explosion of societal, political and legislative changes in the United States, medical marijuana has now become legalized at the state level for the majority of the population.  A Pew Research Center survey published in 2018 indicates that 62% of Americans polled support marijuana legalization.

Cannabis contains phytocannabinoids (cannabidiol (CBD), delta-9-tetrahydrocannabinol (Δ9-THC) and other extracts from the plant species cannabis sativa (from both hemp and marijuana subspecies).  These pharmacologic agents modulate and influence a variety of physiological system bodies through the endocannabinoid system, including appetite, pain, inflammation, thermoregulation, sensation, muscle control, energy balance, metabolism, sleep hygiene, stress responses, motivation/reward, mood, and memory.  Medical marijuana may benefit patients experiencing cancer as well as neurological, psychological, metabolic, and pain disorders.

Phytocannabinoids (cannabidiol (CBD), and delta-9-tetrahydrocannabinol (Δ9-THC) are currently the most studied extracts from the plant species cannabis sativa. Currently, cultivated cannabis sativa has a much higher level of THC than cannabis from even 10 years ago, which may lead to unanticipated over use and dysphoria.

Hemp and marijuana are subspecies of cannabis sativa and are bred separately, each having various amounts of CBD and Δ9-THC. Both CBD and Δ9-THC interact uniquely with the endocannabinoid system (ECS). These endocannabinoids modulate and influence a multitude of physiological systems:

• appetite
• pain
• inflammation,
• thermoregulation
• intra-ocular pressure
• sensation
• muscle control
• energy balance
• metabolism
• sleep health
• stress responses
• motivation/reward
• mood
• memory

Research into the neurological benefits of both CBD and Δ9-THC demonstrates neuroprotective effects against oxidative stress and inflammation associated with a variety of neurological diseases, including malignant brain tumors, Parkinson’s disease, Alzheimer’s disease, multiple sclerosis, neuropathic pain, and the childhood seizure disorders Lennox-Gastaut and Dravet Syndromes.  Some psychiatric and mood disorders (schizophrenia, anxiety, depression, addiction, post-concussion syndrome, and post-traumatic stress disorders) are being actively studied and currently being treated with these phytocannabinoids.

Endocannabinoid System (ECS):

The endocannabinoid system (ECS) plays an important role in your overall health and in maintaining homeostasis in your body. The endocannabinoid system enables the naturally occurring cannabinoids in medical marijuana to interact with your body and trigger the effects of cannabis. It’s a complex system responsible for regulating your body’s immune response, metabolism, memory, appetite, communication among cells and more.

The ECS is a group of cell receptors and activating molecules. Consider cell receptors like tiny locks on your cell surfaces. Activating molecules known as agonists provide the keys for these locks. When agonists bind to cells, they relay messages and give cells directions. The ECS’s two main cell receptors are CB1 and CB2. Each one responds in its own way to different cannabinoids.  Your body naturally produces endocannabinoids all the time, and consuming cannabis increases their concentration in your body.

CB1 Receptors

CB1 receptors are activated by THC. You have CB1 receptors throughout your body, particularly in your spinal cord and brain. They’re mainly located in areas associated with certain behaviours they impact, such as in your hypothalamus, which pertains to regulating your appetite, and the amygdala, which relates to emotional and memory processing. You also have CB1 receptors in your nerve endings, where they’re involved in reducing the sensation of pain. CB1 receptors are mostly found in your central nervous system and provide you with benefits such as:

• Decreased nausea
• Increased appetite
• Inhibition of tumours
• Modulation of anxiety and stress
• Sensory and time perception
• Concentration
• Thought
• Memory
• Pleasure
• Coordinated movement
• Balance of your immune system

Although CB1 receptors are found in the cardiopulmonary center, they are sparsely populated. This explains why THC has an analgesic property but lacks the cardiorespiratory depression like opioids.

CB2 Receptors

CB2 receptors are activated by CBD. You’ll find CB2 receptors mostly on immune system cells and your peripheral nervous system. Once the activation of these receptors occurs, they begin an immune response of working to reduce damage to tissue and inflammation thought to play a significant role in the immune response of your body to certain medical conditions and diseases. Some cells have both receptor types.

• Pain
• Inflammation
• Immune modulation

Homeostasis:

Endocannabinoid activity has the main role in maintaining a stable internal environment even with external environment changes. This stability is referred to as homeostasis. Using numerous mechanisms, such as facilitating intercellular communication between various types of cells, endocannabinoids regulate homeostasis.  Homeostasis is the process of actively regulating biological systems to keep conditions within a confined range. For instance, your body doesn’t want a too-cold or too-hot temperature. It doesn’t want a too-low or too-high blood pressure level, either. To maintain optimum cellular performance, conditions must be “just right.”

Synergy: Entourage, ratios, terpenes

Entourage effect:

Whole plant extractions involve CBD, THC, and more than 400 trace compounds. These compounds interact synergistically to create an “entourage effect” that magnifies the therapeutic benefits of the individual components:  100 milligrams of synthetic single-molecule CBD is not equivalent to 100 milligrams of a CBD-rich whole plant cannabis extract.

Epidiolex, a CBD isolate, is a federally approved pharmaceutical for pediatric intractable seizure disorders. Pharma-sponsored scientific studies have established that synthetic, single-molecule CBD has a narrow therapeutic window and requires precise, high doses for efficacy.  Single-molecule CBD is less effective therapeutically than whole plant CBD-rich oil extract.  Whole-plant regimens demonstrate efficacy at lower dosing levels, but the consistency of the product can be challenging.  Epidiolex lacks an entourage effect.

Synergy arises from interactions between its multiple components so that the medicinal impact of the whole plant is greater than the sum of its parts.

Marijuana contains both terpenoids and cannabinoids; it’s not just the ratio of CBD:THC that’s important.

Terpenes are volatile aromatic molecules that evaporate easily.  Marijuana’s fragrance and particular psychoactive flavor are determined by the predominate terpenes in a strain.  Approximately 200 terpenes have been found in cannabis, characterized by the number of repeating units of a 5-carbon molecule called isoprene.  Terpenes are not unique to marijuana, Beta-caryophyllene is a sesquiterpene found in the essential oil of black pepper, oregano, and other edible herbs, as well as cannabis.  It is gastro-protective and anti-inflammatory because it binds directly to peripheral CB2 receptors.

The cannabinoid-terpenoid synergy has beneficial effects for the treatment of pain, inflammation, depression, anxiety, addiction, epilepsy, cancer, fungal and bacterial infections.  The cannabinoid-terpenoid interactions amplify the beneficial effects of cannabis while mitigating THC-induced anxiety.  The terpenoid profile varies considerably from strain to strain, and patients mistakenly assume that a higher THC or CBD provide more relief.  The exact strain and its processing are key to maintaining the delicate cannabinoid-terpenoid profile.

Personalized Medicine:

Cannabis Therapeutics is truly personalized medicine, balancing conventional medical care with therapeutic cannabis usage.  The endocannabinoid system is the largest and most diverse receptor system in the human body. There is no single product, strain, ratio or delivery method that’s right for everyone. Individual sensitivity to THC is only one factor in determining the appropriate ratio and dosage of CBD:THC, avoiding the dysphoria.  It has been well described that THC can be extremely unpleasant for some individuals. CBD can lessen or neutralize the intoxicating effects of THC.  Cannabis oil concentrates contain varying ratios of CBD:THC and are available so users can adjust or minimize psychoactive effects to suit their needs and sensitivities.

Higher CBD ratio (with lower levels of THC) seems to be more beneficial for anxiety, depression, spasms, psychosis, and seizure disorders.  A 1:1 CBD:THC ratio seems to be more beneficial for cancer, autism, and neuropathic pain.  Circadian rhythm also impacts the endocannabinoid system, sometimes requiring different CBD:THC ratios at different times of the day (more CBD for sunlight hours, more THC at night). The terpenes add a significant additional layer of complexity.

Dosage guidelines for personalized medicine:

Effective dosage varies widely, from as little as a few milligrams of CBD-enriched cannabis oil to a gram or more. Begin with a small test dose of high CBD/low THC oil, especially if you have little or no experience with cannabis. Use small doses over the course of the day, rather than one big dose. Use the same dose and ratio for several days and adjust the ratio or amount slowly. Cannabis compounds have biphasic properties, so low and high doses of the same substance can produce opposite effects. Too much THC can amplify anxiety and mood disorders. Cannabis Hyperemesis Syndrome is another potential adverse effect with use of high THC products, with some cannabis oils and concentrates (“shatter”) containing more than 70% THC.

“Less is more” is the mantra in cannabis therapy.  Observe the effects, don’t overdo it.

Pharmaceutical interactions:

More than half of U.S. adults regularly take prescription medicines and at least 75 percent of Americans take at least one over-the counter drug. Over 87% of the U.S. adult population has at least one chronic disease, and less than 12.2% are metabolically healthy.  Most seniors and many others take multiple drugs, and many of these can affect the metabolism of each other. Seniors are also the fastest growing demographic of cannabis users.

Cannabis is one of the most widely consumed substances in the United States and a huge number of cannabis users also consume other pharmaceutical products.  There are three main ways drugs can interact:

• Metabolic interactions: One drug can affect the metabolism of another drug, prolonging or reducing the activity, intensity, and side effects.
• Drug distribution: A drug can change how a second drug is absorbed and distributed throughout the body.
• Convergent pathways: Two drugs may work through convergent or similar biological pathways, which could lead to antagonistic or synergistic effects.

THC can enhance the painkilling effects of opiates, while CBD can reduce withdrawal and dependence. Patients taking medications, prescribed or over the counter, should monitor clinical symptoms and if needed, adjust the dosage. Problematic interactions are more likely when consuming high doses of CBD isolate products.  CBD is a safe substance but can interact with common pharmaceuticals. The Cytochrome P450 enzymes may be inhibited or amplified by CBD, THC, and other plant cannabinoids.  This variability can reduce or prolong the activity of other drugs by altering the metabolism of P450 dependent medications such as opioids, statins, blood thinners, insulin, and many antidepressants. Some pharmaceuticals, known as “prodrugs,” don’t become functional until they are metabolized into an active component. If CBD or THC inhibits the breakdown of a prodrug, the drug will remain inactive.   However, inhibiting the metabolism of a regular drug will result in higher blood levels of the active substance.  The clinical use of Sativex (a 1:1 CBD:THC sublingual tincture) and Marinol (a pure, synthetic THC pill) has resulted in few, reported adverse events attributable to interactions with pharmaceuticals.  Reported problematic drug interactions with cannabinoids have involved high doses of nearly pure CBD isolates and not cannabis in general.

A common polymorphism (genetic variant) that encodes cytochrome P450 enzymes also decreases THC metabolism,  so it breaks down more slowly and stays active longer, which results in hypersensitivity to THC’s psychoactive effects.  That may explain why some individuals find THC-rich cannabis to be unpleasant, while most find it relaxing. This genetic variant exists in 20% of European & Middle Eastern populations, less than 10% of African populations, and less than 5% of Asians. Separately, there is also a genetic variation in brain dopamine receptors that may predispose some individuals (particularly adolescent males) to dose-dependent acute psychosis.

THC has a significant intrinsic psychoactive effect, and overconsumption quickly creates a dysphoric reaction inhibiting continued consumption, a self-regulatory mechanism.  This safety net can be bypassed by unintentional overconsumption in naïve individuals or impatient users who presume more is better, as is often seen in edibles. With CBD, there is no dysphoric feedback loop. When CBD is extracted from the plant and concentrated as an isolate, higher doses are necessary for therapeutic efficacy, which increases the metabolic drug interactions.

Ten milligrams of THC in a cannabis product is a significant dose for a naïve patient, and sufficiently psychoactive for the occasional recreational user.

Ten mgs of THC combined with an equal amount of CBD in a Sativex tincture was found to produce analgesic benefits in clinical trials.

These are moderate doses compared to the amount of single-molecule CBD administered to epileptic children in clinical trials, up to 50 mg per kilogram. CBD isolates from internet storefronts and other unregulated sources exceeding 2000 mg are not uncommon.

The method of cannabinoid administration (smoking, eating, transdermal, sublingual, etc.) also has an impact on drug interactions, speed of onset, duration of action, and potential dysphoric reaction. Clinical interactions are far more likely when drugs are taken orally and processed by the liver before being distributed through the body. Cannabinoid absorption increases on a full stomach. Ingested cannabinoids have higher peak liver concentrations than inhaled cannabinoids, thus more potent drug interactions.

Manufacturing and product purity:

Look for clear labels showing the quantity and ratio of CBD and THC per dose, a manufacturing date, a batch number, and a lab tested for consistency and verified as being free of mold, bacteria, pesticides, solvent residues, and other contaminants. Avoid all products containing corn syrup, trans fats, GMOs, artificial additives, thinning agents or preservatives. Avoid extracted products using solvents like BHO, propane, hexane or other hydrocarbons. Extraction methods such as supercritical CO2 or food-grade ethanol are safest.

Vape oil products include a thinning agent, which dilutes the oil that is heated and inhaled.  Vape oils may contain propylene glycol, which when overheated produces formaldehyde, a carcinogenic byproduct.  Other additives to avoid include polyethylene glycol and flavouring agents (cream and cinnamon flavours are particularly toxic).  Look for cartridges that contain only natural cannabis-derived terpenes from the cannabis flower from which it was extracted.

Terminology:

• Anandamide: The first known endocannabinoid.
• Cannabidiol (CBD): A major non-intoxicating plant cannabinoid with significant anti-epileptic and anti-inflammatory properties.
• Cannabinoid: Any of the chemically active compounds in marijuana. Cannabinoids include THC, THCa, CBD, CBDa, CBN, and other compounds.  Many of these cannabinoids are not well studied.
• Concentrate: Refers to any product that refines marijuana flower into something more potent. This umbrella term includes any type of has, solventless (kief), as well as any has oils (BHO, CO2 oil, shatter, wax, etc.) and indicates that these products are a concentrated form of cannabis, carrying a higher potency.
• Edible: Any marijuana product for which the intended use is oral consumption. Note that edibles do not include vape products.
• Infused product: A product infused with marijuana that is intended for use of consumption other than by smoking, such as edibles, ointments, and tinctures.
• Marijuana flower: The flowering buds of the female marijuana plant that are harvested and cured for sales to processors or dispensaries.
• Recreational marijuana: Marijuana sold for purposes other than medicinal doses.
• Sativex: A pharmaceutical cannabis extract with a 1:1 ratio of CBD to THC. Approved in many countries outside of the United States.
• Terpenes: Volatile hydrocarbon compounds produced by plants. They are responsible for the smells associated with many plants.
• Tetrahydrocannabinol (Delta-9-tetrahydrocannabinol, or Δ9-THC or THC): The major intoxicating plant cannabinoid. It is the main psychoactive compound, alleviates pain, and reduces nausea.

Modes of Administration

• Ingested cannabinoids are primarily absorbed through the intestines and then are processed by the liver before being distributed through the body. Cannabinoids are absorbed more if ingested on a full stomach, but the absorption is slower in this case. The time it takes to be processed by the liver and absorbed into the bloodstream ranges from 2 to 4 hours. Ingested cannabinoids will have higher peak liver concentrations than inhaled cannabinoids.
• Oral-Mucosal and Sublingual is a middle ground between inhalation and ingestion. If taken correctly, oral-mucosal drugs are absorbed through membranes in the mouth (under the tongue and along the cheek) without swallowing. These come in the form of tinctures and under-the-tongue sprays, among other delivery systems. When administered sublingually, cannabinoids aren’t immediately processed by the liver—like ingested drugs—but neither do they go directly to the brain and heart—like inhaled drugs.
• Smoking and Vaping: Inhaled cannabinoids will go through the lungs into the bloodstream, directly towards the brain and heart. Then they will slowly pass through the liver. Compared to smoking, vaporizing cannabis bud usually results in a slightly higher dose and slower absorption.
• Topical cannabinoids can be absorbed through the skin into joints. There is limited drug interaction.
• Transdermal administration of cannabinoids is quite different than a regular topical application. A transdermal patch will slowly release cannabinoids into the bloodstream, usually at a constant rate. As with sublingual and inhaled cannabinoids, the liver concentration of cannabinoids should roughly parallel their concentration in the blood.

Some praise for cannabis is as follows:

“The efficacy of cannabis, particularly when it is used as a component of a treatment plan for chronic pain and allodynia, makes it a strong choice”

“Cannabis has been shown to contribute, through cannabinoid-receptor and non–cannabinoid-receptor mechanisms, to anti-inflammatory and neuroprotective effects that may alleviate chronic pain. These effects appear to be dose-dependent with respect to synaptic transmission within the dorsal horn of the spinal cord, and inhibition of this communication may play a role in the development of chronic pain associated with local inflammation or nerve injury. For example, in a murine model of neuropathic pain, administration of cannabis significantly reduced allodynia in a dose-dependent manner. Furthermore, in a recent study of refractory pain, cannabis showed efficacy in patients for whom traditional treatment options had failed.“

“Certain plants, as well as products made from their derivatives, yield a variety of cannabinoid alkaloids that have diverse functions and uses. Different formulations can be administered orally, topically, or by vaporization, in measured doses that avoid potential toxins associated with smoke from combustion of the plant. High-quality evidence is limited, but the evidence that is available suggests no lasting illness from cannabinoid use or, at worst, temporary discomfort associated with excessive or extreme doses. There are, however, few clinical trials focused on pain control in humans that quantify the adverse effects of medical marijuana. Despite decades of campaigns that have limited the ability to conduct research in the field and federal restrictions on cannabis, trials in humans have shown measurable effects of cannabinoids in alleviating chronic pain, with an acceptable safety profile. Experimental research and research in animals provide reassuring support on safety.”

“Provided that the patient is informed about the risks of combustion-related toxins and educated about how to abate the potential discomfort of inadvertent overexposure to tetrahydrocannabinol (e.g., by administering cannabidiol), … treatment carries negligible risk.”

“can expect moderate analgesia, reduced allodynia, muscle relaxation, a reduced stress response to … disability, and an empowering level of control over mood in coping with … illness”

“cannabinoid compounds are almost certainly safer than long-term opioid therapy, studies in humans that suggest efficacy are limited in quality and scope”

Medical Marijuana for Chronic Pain.  Lisa Caulley, M.D., M.P.H., Benjamin Caplan, M.D., and Edgar Ross, M.D. N Engl J Med 2018; 379:1575-1577

https://www.nejm.org/doi/full/10.1056/NEJMclde1808149

Wilkie G, Sakr B, Rizack T. Medical marijuana use in oncology: a review. JAMA Oncol 2016 March 17

Ahrens J, Demir R, Leuwer M, et al. The nonpsychotropic cannabinoid cannabidiol modulates and directly activates alpha-1 and alpha-1-beta glycine receptor function. Pharmacology 2009;83:217-222.

Casey SL, Atwal N, Vaughan CW. Cannabis constituent synergy in a mouse neuropathic pain model. Pain 2017;158:2452-2460.

Mondello E, Quattrone D, Cardia L. et al. Cannabinoids and spinal cord stimulation for the treatment of failed back surgery syndrome refractory pain. J Pain Res 2018;11:1761-1767.

The medical value of marijuana and related substances. In: Joy JE, Watson SJ, Jr., Benson JA, Jr., eds. Marijuana and medicine: assessing the science base. Washington, DC: National Academies Press, 1999:137-191.