Marijuana – Potential for Therapeutic Benefit
There is currently a great deal of attention, both nationally and internationlly, on the potential medical benefits of marijuana (cannabis). The reasons for this attention are multiple, not the least of which is financial. That being said, however, there is a massive interest in therapeutic cannabis. One major reason for this is medical science’s interest in how cannabis offers medical benefits.
Patients have many reasons to advocate for use of cannabis and cannabinoids. These include the inadequate success of currently available pain therapies, skepticism about the pharmaceutical industry, anecdotal and media reports reporting the effectiveness of marijuana, familiarity with marijuana because of past recreational use and knowledge that marijuana has been used for millennia for medical purposes.
The evaluation of cannabis has led to a grand new arena of knowledge surrounding a new neuroendocrine system in humans and animals not previously known and even now still very poorly understood, But this new world surrounding cannabis is huge. The “endocannabinoid system,” explained further below, is present throughout the brain, central nervous system and all other organ systems. It represents an extremely important new field of study for understanding how our bodies work and it offers an excciting new world of therapeutic possibilities. It is a new frontier in medical science.
Our current understanding of medical uses of cannabis are, unfortunately, based on only a rudimentary beginning of research with little definitive knowledge established. The nature of the research currently available to the medical community to direct clinicians toward safe and effective therapeutic applications of cannabis is very limited and based mostly on observational studies which provide very limited useful information to guide cannabis prescribing.
Cannabis – Research Studies
Observational studies are those in which data is reviewed by an investigator who observes and evaluates test subjects without manipulation or intervention and draws inferences from a population where no independent variables are under the control of the researcher. Observational studies can determine if there are associations between an activity and an outcome but cannot identify or confirm cause and effect. This is in contrast to randomised controlled trials (RCTs) where investigators do intervene by establishing specific variables to study and evaluate the effects of the intervention on an outcome. Randomised controlled trials are useful in determining causal relationships between treatment and outcome such as whether a medication actually works for a particular conditi0n. There are few and inadequate randomised controlled trials (RCTs) regarding marijuana to provide specifics for establishing treatment protocols.
There are many preclinical studies (animal and labatory-based research) that have shown that modulating the endocannabinoid system (ECS) with cannabinoids may be effective for mood and anxiety disorders, movement disorders, neuropathic (nerve) pain, epilepsy, multiple sclerosis, spinal cord injury, cancer, atherosclerosis, myocardial infarction, stroke, hypertension, glaucoma, obesity/metabolic syndrome, insomnia, drug addiction, Alzheimer’s disease, and osteoporosis. Unfortunately, there remains a lack of good quality human-based research to confirm the specifics of what the preclinical studies suggest. Most human research has focused on chronic pain, muscle spasticity, nausea, vomiting and anorexia. Some conditions, such as migraine headaches, fibromyalgia, and Irritable Bowel Syndrome (IBS) have underlying physiological patterns that suggest an underlying endocannabinoid deficiency, suggesting they may be effectively treated with cannabinoid medicines.
The Endocannabinoid System (ECS): Endocannabinoids and Phytocannabinoids
There are a number of physiologically active constituents of the cannabis (marijuana) plant, some of which have shown therapeutic benefits in a broad range of conditions. The major group of compounds found to be uniquely abundant in cannabis is the “cannabinoids.” Originally thought to be unique to cannabis, naturally occuring cannabinoids (endocannabinoids) were subsequently discovered in humans and animals (all vertebrates). An entire endocannabinoid system consisting of multiple types of endocannabinoids and cannabinoid receptors is distributed throughout the body.
This endocannabinoid system (ECS) of endocannabinoid receptors and endocannabinoids is similar to the opioid system of opioid receptors and the naturally occuring opioids (endorphins) in the body. The ECS regulates many physiologic functions ranging from the immune system to the nervous system and impacts sleep, appetite, mood, pain and other functions. For this reason, marijuana has attracted a great deal of attention from a pharmacotherapy perspective for its potential to affect many physiologic functions with possible benefit.
The clinical benefits from marijuana are derived from the many chemical agents found in the plant, including more than 100 pharmacologically active constituents, including cannabinoids and terpenes. The two best understood and most common of the cannabinoids are THC (tetrahydrocannabinol) and CBD (cannabidiol). There is very limited scientific information on the pharmacology and toxicology of the other constituents found in cannabis. It is believed that the clinical effects of marijuana come from not just THC or CBD, but are determined by both the concentrations and ratios of these two constituents as well as influences from the many other cannabinoids and terpenes found in the plant.
See: The Endocannabinoid System (ECS)
THC use is applicable for many symptoms and conditions including pain, nausea, spasticity/spasms, appetite stimulation, anxiety, depression, post-traumatic stress disorder (PTSD) and insomnia. THC and its active metabolite, 11-Hydroxy-THC. produce the “high” or euphoria associated with use of marijuana.
CBD does not produce the mind-altering “high” effects like euphoria but it does reduce anxiety and enhance sleep. CBD is a versatile anti-inflammatory analgesic, operating through numerous distinct mechanisms. It has anti-convulsant, anti-psychotic, antioxidant, neuroprotective and immunomodulatory effects. CBD is also thought to reduce nausea, particularly related to chemotherapy. In combination with THC, CBD modulates some of the side effects of THC, including reducing THC-induced anxiety. CBD suppresses the “high” caused by THC when provided at an 8:1 CBD:THC ratio.
See: Cannabidiol (CBD) – Introduction
Marijuana – Potential for Harm
While there is great hope for the therapeutic potential of cannabis, it is not for everyone and certain groups have been identifid who should likely avoid use of cannabis. The following groups are believed to be potentially at increased risk of harm from use of cannabis:
- Children, adolescents, and young adults (<25 y/0)
- Women who are pregnant or breastfeeding
- Those with a personal or family history of psychotic disorders such as schizophrenia
- Those with a history of chronic lung disease, cardiovascular disease and/or kidney disease
See: Marijuana (Cannabis): Potential for Harm
Clinical Evidence for Effectiveness
Research on Medical Marijuana
Definitive research regarding the medical uses of marijuana and its constitutents remains limited and in only early stages. Observational studies are those in which data is reviewed by an investigator who observes individuals without manipulation or intervention and draws inferences from a population where no independent variables are under the control of the researcher. Observational studies can determine if there are associations between an activity and an outcome but cannot identify or confirm cause and effect. This is in contrast to randomised controlled trials (RCTs) where investigators do intervene and look at the effects of the intervention on an outcome. RCTs are useful in determining cause-effect relationships between treatment and outcome such as whether a medication actually works for a particular conditi0n.. The current state of medical marijuana research is based mostly in observational studies with very few RCTs to guide management of most medical conditions with specific cannabis-based treatments.
Based on the 2017 report from the National Academies of Sciences, Engineering, and Medicine there is conclusive or substantial evidence that cannabis or cannabinoids are effective for the treatment of:
- Chronic pain in adults
- Chemotherapy-induced nausea and vomiting
- Multiple sclerosis spasticity symptoms
The report also found moderate evidence that cannabis or cannabinoids are effective for:
- Improving short-term sleep outcomes in individuals with sleep disturbance associated with obstructive sleep apnea syndrome (See: Sleep Apnea)
- Fibromyalgia (See: Marijuana – Fibromyalgia)
- Spasticity associated with Multiple Sclerosis
Additionally, there is increasing but limited research showing that cannabinoids are safe and effective in the treatment of:
- Seizure disorders
- Increasing appetite and decreasing weight loss associated with HIV/AIDS
- Tourette syndrome
- Several geriatric conditions
- Anxiety, particularly in individuals with PTSD and social anxiety disorder
- Depression, associated with chronic pain
- Neurocognition in some cases of dementia
Relative Contraindications to Cannabis Use:
- Patients who are <25 years of age
- Patients who have a current, past, or strong family history of psychosis
- Patients who have a current or past cannabis use disorder (marijuana addiction)
- Patients who have a current substance use disorder (chemical or behavioral)
- Patients who have cardiovascular or respiratory disease
- Patients who are pregnant or planning to become pregnant
- Inhaled cannabis should be used with caution in patients who smoke tobaccco
- Patients who are at increased risk of cardiovascular disease
- Patients who have anxiety or mood disorders
- Patients who are taking opioids or benzodiazepines
- Do not operate dangerous equipment or perform potentially dangerous activities after cannabis use
- Do not use with alcohol, opioids, or sedating drugs, especially benzodiazepines (Valium, Xanax, Klonopin etc)
- Keep cannabis-based products safely stored under lock and key
Cannabis users should be advised not to drive for at least:
(1) Three to four (3 to 4) hours after smoking
(2) Four – six (4-6) hours after sublingual administration
(3) Six – eight (6-8) hours after oral ingestion
(4) Eight (8) hours if they experience a subjective “high”
THC serum concentrations of 2–5 μg/L have been shown to impair driving, and concentrations of 7–10 μg/L can produce impairment equivalent to a blood alcohol concentration of 0.05%. Sweden and Australia have zero tolerance for illegal drugs in drivers. Of those drivers convicted for impaired driving in Sweden, 90% had blood levels of THC <5-μg/L and 61% had blood levels of THC <1 μg/L.
Two states, Nevada and Ohio, have set blood limits of ≥2 μg/L for THC or ≥5 μg/L for THCCOOH (a primary metabolite of THC) and Colorado has set(?) a limit of 5.0 μg/L THC in blood.. The highest limits in Europe are 3 μg/L for THC in Portugal and 50 μg/L for THCCOOH in Poland. While existing laws focus on THC and THCCOOH concentrations, appropriate cutoffs might also be selected for 11-OH-THC (another primary metabolite of THC) due its shorter detection window. THC- glucuronide, cannabinol, and cannabidiol concentrations in blood may also indicate recent cannabis smoking.
Of note, cannabinoids may be detected in the blood of chronic daily cannabis smokers for greater than one month after sustained abstinence. This is consistent with the time course of persisting neurocognitive impairment reported in recent studies. There is a strong public safety need to reduce cannabis-impaired driving and reduce cannabis-related motor vehicle injuries and deaths.
See: Use and Dosing
Marijuana (Cannabis) – Inhalation: Smoking vs Vaping
Marijuana (Cannabis) – Oral Use (Edibles)
Marijuana *Cannabis) – Topicals
Marijuana (Cannabis) – Dosing
Marijuana (Cannabis) – Dosing: “Pot” vs. Pharmaceutical Products
With as many as 850 brands of marijuana-derived CBD products and 150 hemp-derived products on the market and an even greater number of various extracts of THC and marijuana plants cultivated to produce maximum THC concentration, universal dosing recommendations are nearly impossible.
The determination of dosing is one of the major stumbling blocks in the study of medical marijuana. This is because marijuana, a plant, varies widely in the amount and ratios of the pharmacologically active constituents present depending on a multitude of variables. Depending on the plant there may be over 100 pharmacologically active constituents all of which vary depending on the genetics of the plant, the conditions in which the plant was grown, how and when it was harvested and other variables. As such there is a huge variability in the potency and expected effects between different plants.
As noted above, the major pharmacologically active cannabinoids in marijuana are THC and cannabidiol (CBD). The average contents of THC and CBD in dried plant preparations of marijuana confiscated from 1993 to 2008 in the United States were 4.5 and 0.4, respectively, although these contents vary widely. In the last decade these percentages have increased in different strains to more than 3-5 times as potent or more:
- THC levels doubled (8.9% in 2008, 17.1% in 2017)
- CBD levels decreased from 0.37% in 2008 to 0.14% in 2017
- THC:CBD ratio increase from 23:1 in 2008 to 104:1 in 2017
The significance of these numbers is that they indicate a very different product from the marijuana older people may remember from the days they used marijuana recreationally 20-30 years ago and now are turning to contemporary marijuana use for medical purposes. The higher THC content is associated with more side effects such as anxiety, impaired thinking and other symptoms associated with higher THC dosing. Additionally, the reduced amount of CBD, which reduces THC side effects, further contributes to the greater likelihood of side effects. This calls for careful dosing, starting at low doses and increase dosing slowly as indicated.
Louisiana law has recently permitted the use of raw or dried marijuana plant for medical purposes, but product isn’t expected until January, 2022. Dosing guidelines will be provided at that time. In the meantime,
See: Marijuana (Cannabis): Dosing
Other countries guidelines are briefly reviewed below but may not be up to date:
Canadian Guidelines – 2014
Based on Canadian guidelines published in 2014, smoked cannabis might be indicated for patients with severe neuropathic pain conditions who have not responded to adequate trials of pharmaceutical cannabinoids and standard analgesics. Smoked cannabis is contraindicated in patients who: (1) are 25 years of age or younger; (2) have a current, past, or strong family history of psychosis; (3) have a current or past cannabis use disorder (marijuana addiction); (4) have a current substance use disorder (addiction to other drugs); (5) have cardiovascular or respiratory disease; or (6) are pregnant or planning to become pregnant. It should be used with caution in patients who smoke tobacco, who are at increased risk of cardiovascular disease, who have anxiety or mood disorders, or who are taking high doses of opioids or benzodiazepines.
Based on these Canadian guidelines, when smoking is advised (which it is generally not), initial dosing recommendations for smoked marijuana are usually for small amounts of lower-potency marijuana. For example, the starting recommended dosing is 1 inhalation of a 9% maximum THC “joint” once per day. This can be increased to a maximum recommended dose of 1 inhalation 4 times a day, resulting in approximately half a “joint” per day (or 400 mg). Patients should not operate dangerous equipment or perform potentially dangerous activities after use. This includes no driving for 3 to 4 hours after inhaled medical marijuana, 6 hours after oral ingestion, and for at least 8 hours if they experience a subjective “high.”
Higher doses are sometimes used. It should be noted that if patients use a 5 gram dose of 15% THC, this represents approximately a 20 times higher dose than the recommended 400 mg of 9% THC. Higher doses, especially at this level are associated with significantly higher risk of adverse side effects (see below). In marijuana resin (commonly referred to as hash or hashish), the average contents of THC, CBD, and CBN are 14.1, 2.5, and 1.9%, respectively. Other commercial products including oils and edibles may contain even higher potencies.
In Germany currently there are 14 types of cannabis flowers that can be prescribed, with THC concentrations varying between 1% and 22% and CBD concentrations varying between 0.05% and 9%. Dosing information for specific indications is not available but the German Narcotic Drugs Act sets the maximum amount that can be prescribed within a 30-day period at 100 g cannabis in form of flowers, regardless of THC content. While THC-containing capsules and oil are not permitted under the German Narcotic Drugs Act, they can be prescribed for individual therapeutic trials as compounded medications in the form of drops, capsules or inhalation solution. Apparently, their recommended daily doses of THC range between 5 and 30 mg.
Adverse Side Effects
Overall, the adverse side effects of medical cannabis are within the range tolerated for other common medications. Multiple studies have demonstrated that there is no higher incidence of serious adverse events in cannabis subjects following medical cannabis use compared with control subjects, although non-serious adverse events were significantly higher in cannabinoid groups. Dizziness is the most common non-serious adverse effect reported. Other common adverse effects include:
- Euphoria, altered consciousness
- Acute panic or paranoid reaction
- Altered motivation
- Impaired attention, memory, and psychomotor performance
- Tachycardia, orthostatic hypotension (drop in blood pressure associated with sitting to standing)
- Dry mouth
- Increased appetite
For more information about cannabinoids and their side effects:
Marijuana (Cannabis): Side Effects and Drug Interactions
Cognitive impairment, including the ability to learn and remember new information, has been associated with long term illicit cannabis use but has been shown to be reversible after a period of abstinence.
Long-term heavy cannabis smokers have increased risk of pulmonary symptoms such as chronic bronchitis and COPD but have no increased incidence of lung cancer
As expected, cannabis-naive patients tend to have more frequent adverse side effects compared with regular users. The effects of THC can change over time, with therapeutic effects more resistant to tolerance development than adverse side effects. Careful attention. to appropriate dosage, delivery method, and ratio of cannabinoids can reduce many of the adverse side effccts.
It is important to point out that the adverse effects of medical cannabis cannot be equated with the adverse effect of illicit marijuana use. The amounts and ratios of the different cannabinoid constituents vary dramatically between different marijuana plants, whereas medical marijuana is anticipated to be formulated with specific standardized doses and ratios of the different cannabinoid components. The use of illicit marijuana does not allow for any accurate prediction of dosing.
Interactions With Other Drugs and Herbal Preparations
Cannabinoids and Opioids
There appears to be a synergistic analgesic (pain-relieving) benefit when cannabinoids are added to opioids for treatment of pain in which there is a greater-than-additive benefical effect with the addition of cannabinoids. Studies indicate a trend towards reduced use of opioids when patients taking opioids add cannabinoids to their regimen. It is not uncommon for patients started on cannabinoids to be able to taper off opioids.
Additionally, animals studies suggest that cannabinoids may reduce the development of tolerance to the analgesic benefits of opioids, resulting in less need for opioid dose escalation.
There is no enhancement of cardiorespiratory suppression from opioids with the addition of cannabanoids due to the very low density of cannabinoid (CB) receptors in brainstem cardiorespiratory centers. Cannabinoids are not reported to have any significant effecct on opioid metabolism, however there does appear to be a potential to do so (See below).
See: Cannabinoids and Opioids
Alcohol and Benzodiazepines
The combination of cannabinoids with alcohol and benzodiazepines may increase sedation and cognitive impairment.
NSAIDS (Non-Steroid Anti-inflammatory Drugs)
NSAIDs such as ibuprofen and naproxen, particularly indomethacin, may suppress the effects of THC.
Anticholinergic drugs (Tricyclic antidepressants (TCAs) and some muscle relatxers)
Medications with anticholinergic activity such as amitriptyline (Elavil) and doxepin, and muscle relaxers such as cyclobenzaprine (Flexeril) may increase the psychoactive side effccts of cannabinoids.
Sedative agents such as sleep aids (includes supplements containing GABA, melatonin, 5-HTP, skullcap, or valerian) – Use caution when taking these products and cannabis products together because of the potential for increased drowsiness.
Drug Metabolic Interactions
The major cannabanoids, THC and CBD are both metabolized in the liver by the CYP450 enzymes 2C9 and 3A4. Drugs that inhibit these enzymes may enhance or prolong the effects of THC and CBD. Whether people with genetic variants of these enzymes may experience altered effects from cannabinoids is not certain.
For more information:
Marijuana (Cannabis): Side Effects and Drug Interactions
Blood and Plasma Levels
Blood consists of solid components including red and white blood cells and a liquid component, plasma. Because cannabinoids do not absorb significantly into blood cells, almost all cannabinoids found in blood are in plasma. Therefore, when assessing blood levels, a blood level will represent an amount representing only about 50% of plasma levels which should be taken into account when reading about blood levels vs plasma levels. Plasma levels are generally the preferred measurement.
The average contents of Δ9-THC, CBD, and CBN in dried plant preparations of marijuana are 3.1, 0.3, and 0.3%, respectively although these contents vary widely. In marijuana resin (hashish) the mean contents of Δ9-THC, CBD, and CBN are 5.2, 4.2, and 1.7%, respectively. Smoking a single marijuana cigarette containing 34 mg Δ9-THC (the content of a 3.55% plant preparation) results in a plasma peak level of Δ9-THC at 162 ng/ml (0.516 μM). A peak level of plasma concentration of CBD is been reported to be 114 ng/ml (0.363 μM) after smoking 20 mg of CBD. How these levels correlate with clinical effects varies from individual to individual, but it is not unexpected that blood levels of cannabanoids may have future legal implications.