1. Factors that influence dosing of medical cannabis
This is Part 1 in a 5-part series on Dosing & Administration: There are many factors to consider when determining the correct dose of any medication, regardless of its potential for intoxication and impairment. Given that the first objective is to “do no harm”, the priority should be safety, soon followed by tolerability. These are different (See below). Once convinced that a given dose will do no harm, and that the patient will tolerate its effects, we shift towards clinical efficacy.
What is the minimum effective dose of a medication for a patient with a given clinical presentation? It depends.
1. Safety versus tolerability
Fortunately, Cannabis, or marijuana, has a long-standing, historical record of safety. There is anecdotal, epidemiologic and clinical trial data to substantiate that.1 Even the the United States Drug Enforcement Administration (DEA) states that, “No death from overdose of marijuana has been reported.”2
Tolerability is different than safety. Tolerability is more about a patient's perception of their experience, and less about biological harm. If, upon administration of a certain dose, a patient perceives the experience to be negative, they are unlikely to try Cannabis again, at any dose. To be clear, there is no true potential for harm in this scenario. The patient is safe, but the dose is intolerable because it creates excessive discomfort and dis-ease. For many, Cannabis produces a euphoric effect. For others, it produces a dysphoric effect (i.e. State of dis-ease).
2. Demographic factors Demographic factors are also important. What is the age of the patient? What is their weight? Is the patient pregnant or lactating? Is it safe, tolerable and prudent to give THC to a pediatric patient? Will it interfere with the normal growth and development of an immature brain? What about a geriatric patient? Will THC-induced ataxia or dizziness lead to a fall that might result in a hip fracture? These are serious considerations that deserve thought and conservative decision-making.
3. Lifestyle and health status Lifestyle factors are also important. Alcohol use is a consideration. Is there liver disease, or dysfunction, due to alcohol abuse? What about the amplification of impairment that may be due to using both Cannabis and alcohol concurrently? Will the combination of the two increase the risk of a serious, or non-serious, adverse effect?
Is there disease, or dysfunction, in other organ systems? Beyond metabolism in the liver, cannabinoids are eliminated thru the colon in feces and thru the kidneys in urine. The dosing approach may need to be adjusted if an individual has liver, kidney or gastrointestinal disease.
What about prescribed drugs? Is there a potential for a clinically significant drug-drug interaction between a cannabinoid and an patient's blood pressure medication? What about a history of psychiatric disorders? Is a high-dose of THC safe for a patient with a history of psychotic episodes or other mental health disorders?
Just because Cannabis has a favorable safety profile does not mean that these considerations are trivial.
4. Dose-dependent adverse effects The adverse effects of Cannabis are dose-dependent. This means the adverse effects are only present at a given threshold, and become more severe or frequent with higher dosages. On many occasions, tolerability and symptom relief can both be achieved with a low dose. It is important to understand that this is a moving target. Dose-dependence is unique to the patient. It takes a methodical approach to determine a clinically effective dose that is tolerable for a given patient. Working with a trained medical professional can help achieve this.
5. Dose administered versus the dose received Understanding the dose administered is easy. There are 10mg of THC in 1ml of liquid extract, for example. Understanding the dose actually received by the patient is more complicated. The dose received can only be estimated by referring to pharmacokinetic studies involving cannabinoids. In addition, there is tremendous biological variability between human beings. The dose received by one individual can be dramatically different from another, despite the fact that both were administered the same dose (You can learn more about the biological variability of cannabinoid pharmacokinetics here).
6. Pharmacokinetics Pharmacokinetics is a pharmacology term that refers to how the body processes drugs. There are four essential components to pharmacokinetics: Absorption of the drug, metabolism, distribution within, and elimination from, the body (You can learn more about the cannabinoid pharmacokinetics here)
Pharmacokinetic studies have documented the lower absorption of cannabinoids thru the gastrointestinal tract, as compared to the respiratory tract. The same dose may be administered to each system, but the dose received will be different due to differences in absorption and bioavailability.
When inhalation is the method of administration, a maximum of approximately 10-60% of a given dose of THC, or CBD, will be measured in blood at a given point in time (e.g. 30, 60, 90 minutes after administration). The percentage is much lower for cannabinoids administered by ingestion, 6-30%.3
The dose received varies depending on the method of administration. This is because the method of administration determines the pharmacokinetics, and the pharmacokinetics determines the dose received.
7. Therapeutic range The therapeutic range of a given drug in blood is also a consideration. Cannabinoid specific data is lacking here. Theoretically, there is a range of a given cannabinoid in blood which is correlated with a clinical endpoint (e.g. Symptom). This level is highly dependent on the individual and the clinical objectives.
In seizure disorders, for example, it is common for neurologists to measure blood levels of anti-convulsant drugs. They seek to maintain blood levels of the drug(s) within a range thought to be therapeutic (i.e. Reduce frequency, duration or severity of seizures). What is the therapeutics range of CBD in treating seizures? It varies, widely.4
8. Timing An important factor in pain control is timing. In patients with severe pain, a large loading dose may be required to establish a therapeutic blood level, say in the morning, while smaller maintenance doses may be given throughout the day. The is done to avoid breakthrough pain during the day. Breakthrough pain is pain that spikes as a result of inadequate therapeutic control. In patients with severe chronic pain, the timing of maintenance doses can be critical in order to avoid a breakthrough.
9. Tolerance Tolerance is the physiological process of adapting to a certain dose of a drug. Tolerance is not addiction, although it is sometimes confused with addiction. When a person develops a tolerance to THC, for example, a higher dose is required in order to achieve the same result as a prior dose. Tolerance is highly dependent on the dose and frequency of use. Based on suspected tolerance, a patient with a long history of recreational Cannabis use might receive a different starting dose than a patient with no history.
The bottom line In summary, there are a variety of factors to consider when determining the appropriate dose of cannabinoids to administer to a given individual for a given clinical situation. Understanding that person's health history and status (Presence or absence of disease) is critical, as is the method of administration. The method of administration determines the pharmacokinetics. The pharmacokinetics determines the dose that is actually received.
In health,
Despite the favorable safety profile, dosing and administration of cannabinoids is complicated. The process should be highly individualized and is best supervised by a trained health care professional. For more information, please consider booking a consultation (telephone or in-person) with Dr. Jamie Corroon, ND, MPH.
References
1. Wang T, Collet JP, Shapiro S, Ware MA. Adverse effects of medical cannabinoids: a systematic review. CMAJ. 2008;178(13):1669-1678. 2. DEA / Drug Fact Sheets - Marijuana/Cannabis. 2018. 3. Huestis MA. Pharmacokinetics and metabolism of the plant cannabinoids delta9-THC, cannabidiol and cannabinol. In: Handbook of Experimental Pharmacology. Vol 168. Springer-Verlag; 2005:657-690. 4. Sulak D, Saneto R, Goldstein B. The current status of artisanal cannabis for the treatment of epilepsy in the United States. Epilepsy & behavior : E&B. 2017;70(Pt B):328-333.
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