Dr Daniel’s Guide to Balanced Cannabis Dosing

by in Medical Marijuana, Written by Dr. Daniel September 8, 2020

Dear Medical Cannabis Community,

I love you guys. You’re just frigging great. I owe a debt of gratitude to the medical cannabis community for giving me a voice and platform that, ultimately, has led to my success. So in the spirit of paying it forward, I’d like to share some of the knowledge I’ve gained as my clinical career in medicine has now morphed into a much more natural functional approach to whole-body optimization. Cannabis medicine is in its nascent stages in Western Medicine so establishing guidelines regarding whole-plant cannabis dosing and administration is also in its infancy.

Let’s start at 2700 B.C.E. with the first Chinese Pharmacopeia Pen Ts’ao (The Herbal). This early text warned that high doses of marijuana (Ma) seeds could cause a person to see demons, while moderate doses would enable users to communicate with the spirits. The modern translation in today’s peer-reviewed literature is that the threshold for the medical benefits of THC is far lower than many people think. Having a highly sensitive endocannabinoid system is extremely valuable for responding to illness, injury, and stress, and people can achieve that with low doses of cannabis.

Therefore, I’d like to address critical gaps in knowledge regarding dosing of various cannabis medicines.  Bringing some cohesion to the topic can guide both patients and clinicians to better shared clinical decisions regarding counseling on cannabis medicine dosing. When you finish reading this you will have a better understanding of how to dose your cannabis products to reach your maximal medicinal benefit while mitigating the less desirable effects of an incorrect balance of the endocannabinoid system (abbreviated ECS moving forward).

The Endocannabinoid System: Enter the Matrix

Recall that the ECS is an expansive neuromodulatory network that encompasses every organ system in the body. In its native physiologic state, the ECS exists to maintain homeostasis, or balance when the body encounters various shifts in equilibrium or insult. In times of stress or when the body’s reserve is not robust, we are said to be in endocannabinoid hypotonia. Understanding this aspect of natural balance will come into play as we formulate a practical guideline for tailored endocannabinoid system balance through administration of external cannabis preparations. My approach employs an individually tailored program to guide cannabis administration as a safe supplement to address natural deficits in endocannabinoid tone as they arise de novo. The ECS is a system that has been around long before cannabis (despite the name) and a healthy ECS can function well with only a minimal necessary dose of cannabis supplementation to achieve significant clinical benefit.

Cannabinoid (CB) receptors and their action

The cell membrane receives a stimulus signal which results in enzymatic production of AEA and 2-AG from the phospholipid cell membrane. They simply diffuse laterally like a float along the phospholipid membrane via carrier proteins to combine with the active site of the cannabinoid receptors CB1 and CB2. The CB1 receptor expression is widespread throughout the central nervous system (CNS) as well as peripherally in virtually every organ system. Although less research has been devoted to CB2 receptors, this class recognizes the same structural groups of cannabinoid agonists as CB1, with differing affinities in some cases. It is highly expressed throughout the immune system, modulating leukocyte migration, activation, and antigen processing. Unlike the CB1 receptor, which is highly conserved across human, rat and mouse, the CB2 receptor is much more divergent.

How does the Natural System react to external cannabinoids?

The primary constituents of cannabis are THC and CBD. The main constituents of the cannabis sativa plant are Delta-9-THC (tetrahydrocannabinol) and CBD (cannabidiol). These are known as phytocannabinoids because these are the plant derived molecules that combine with the same CB receptors as the endogenous anandamide and 2-AG. THC and CBD are not endocannabinoids and they do not have the same mechanism of action, nor are they governed by the same enzymatic controls as our native analogs. The body has adapted a workaround to short-circuit the receptor overactivation in the event of THC overtoxicity. Receptor down regulation because the natural enzymes that break down AEA and 2-AG can’t metabolize a supranormal dose of external cannabinoids as fast as they can a normal dose. The degradative enzymes FAAH and MAGL can be usurped very quickly to metabolize a supranormal cannabinoid dose that the body simply is not accustomed to.  Tolerance equals toxicity. Overmedication constitutes manual override of the internal control motherboard. FAAH and AMGL quickly reach their saturation point so receptors have to down regulate to deal with the excess that the enzymes can’t handle.

Therapeutic window

Determining the therapeutic window (where beneficial effects outweigh toxicity) is key to guiding the correct dose schedule.  Overmedicating the endocannabinoid receptors causes the receptors to react in a physiologic manner by retreating like a turtle head back into the cell so the THC molecule has no target to combine with. Another important facet to remember is the biphasic property of cannabis, vis-à-vis low and high doses having opposite effects. Small doses stimulate whilst larger doses sedate. After a certain point, dosage increases result in weaker therapeutic effects. This bell-shaped dose-response curve is characteristic of cannabinoid pharmacology and distinct from the linear dose response curve of most Western pharmacopeia (in which adding more drug will continue to effect change without maximum). This is likely an evolutionary protective effect to mitigate possible cannabis psychotoxicity that occurs with overdose. Fatal overdose is, however, impossible due to the scarcity of CB1 receptors in the respiratory center of the brainstem. Overdose of cannabis paradoxically leads to symptoms that cannabis would normally treat at lower physiologic doses. If patients run into this problem, a tolerance break of 48 hours is just the neural cleansing needed to upregulate CB receptors to their physiologic state.

Factors affecting THC bioavailability and Efficiency of administration

Not every patient uses THC as efficiently. Take relative amount (ratio) of smoke inhaled to fresh air for example. Users who take in less smoke per inhalation and more oxygen are going to require a smaller THC dose because their utilization is going to be more efficient. Cloud tokers are far less efficient and much more prone to tolerance. The body is being inundated with a very high concentration of THC relative to oxygen. Furthermore, a great proportion of the smoke is not getting to the bases of the lungs where there is the highest perfusion of blood. This means that these monster hits are missing out on better access to the bloodstream. Oftentimes, precious cannabinoid is wasted in dead space (nonvascularized areas) like the trachea when that smoke is coughed up immediately before ever making it to the bloodstream.

How does variablility in ECS makeup from one person to another determine ideal dose?

Diet, exercise, day-to-day stress, and genetics all play a role. Long story short, healthier people with better lifestyle habits will have a stronger basal endocannabinoid tone. We can deplete the endocannabinoid system through lifestyle choices by pathologically altering the microbiome of our gut (via a process called dysbiosis). Recall that the greatest concentration of cannabinoid receptors outside the central nervous system is in the immune system (which primarily resides in the gut). Micronutrient support of our gut cells can prevent the depletion of homeostatic reserve that we might need to employ during acute stress. Keeping the balance of the microbiome keeps the lines of communication between the pituitary gland, hypothalamus, and adrenal glands clear and functioning in a physiologic fashion.

Dosing: The long and short of how to dose your THC flower

Individualization of treatment is the answer. This means finding the optimal product and route of administration. All these issues will determine the answers to the three questions that patients should ask themselves when selecting a product and route of administration: how much cannabinoid is going to be incorporated into my body, how long before I feel the effects and how long are they going to last. Pharmacokinetics (PK) refers to the movement of drugs through the body, whereas pharmacodynamics (PD) refers to the body’s biological response to drugs. Understanding the exposure-response relationship (PK/PD) will help the patient understand the bioavailability (percent of active compound that reaches the bloodstream) of different cannabinoid preparations. Most literature and drug trials have landed on 5 milligrams of THC per dose, and up to a daily  maximum of 30 total mg of THC daily. These doses (and oftentimes much smaller) can potentiate a fast and durable response for a myriad of conditions without an uncomfortable level of psychoactivity.

Prescription cannabis products

These prescription drugs are pure isolates of cannabis compounds and do not contain the full suite of chemicals as in whole-plant preparations. Dronabinol is an isolated THC molecule marketed in oral pill form as Marinol. Clinical trials of Marinol showed effective doses at 2.5 milligrams for children and elderly, up to 10 mg per dose. Nabilone (Cesamet), a synthetic THC derivative which is 10 times more powerful than THC, is a powerful antiemetic used to combat chemotherapy-associated nausea and vomiting. Sativex® (nabiximols) is a combination sublingual spray. Each spray delivers a dose of 2.7 mg of THC with 2.5 mg of CBD into the oral mucous membrane. Their clinical trial on multiple sclerosis patients concluded eight sprays (puffs) per day (21.6 mg of THC and 20 mg of CBD per day) to be the optimal dosing regimen. Epidiolex® is a pure CBD hemp plant extract administered in the form of a syrup. The pure isolate compounds are plagued by slow pharmacokinetics and a very narrow therapeutic index. Big pharma failed at what nature perfected, and patients are far more inclined to use preparations of dried cannabis flowers, extracts, oils and tinctures.

Inhaled Preparations:

Smoking, the principal route of cannabis administration, provides a rapid and efficient method of drug delivery from the lungs to the brain. The smoking route is preferred by many cannabis users because of its rapid drug delivery and resultant fast onset of effects (peak concentration occurs at 9 min) but also for the ability to titrate dose to the desired degree of effect. The most useful method I have found for dosing inhaled cannabis is to take a single inhalation, breathe in deeply, and immediately exhale. Don’t resist the urge to cough and always keep hydration handy. New cannabis users should start with an even smaller dose at 2.5 mg THC before bedtime and carefully titrate up. The obvious disadvantage with combustive inhalation is the more than 2,000 compounds may be produced by pyrolysis.

Vaporisation:

These vaporizers employ dry heat to cannabis products up to temperatures at which the cannabinoids decarboxylate, but without reaching the point of combustion in which the toxic by-products are generated resulting from pyrolysis. Terpenes also have their individual volatile boiling point. Bioavailability of the major cannabinoids consumed by this method is very high (around 25%).The effects of cannabinoids are not prolonged in time, as changes in their plasma levels are very fast, both rising (which can be an advantage during acute pain crises, for example) and lowering. Thus, inhalation may be an interesting route of administration to deal with acute episodes that need immediate relief, but it would be the best option for chronic treatments, in which high levels of cannabinoids are looked for during prolonged periods of time and consistency in the dosage.

Concentrated resins are known for their much higher THC concentrations and are much harder to dose in small amounts. The other disadvantage with these extractions are the solvents used to prepare them (known as menstruum-Yum!)-hexane, butane, acetone, benzene, isopropanol, ethanol, etc. Food grade ethanol is the best option in this group, as some organic solvents can be toxic even in small amounts. Better choice is when supercritical fluid extraction using CO2 is employed, which leaves no toxic residues (but is more expensive to produce). Overall, these are not my favorite choice for medicinal applications of cannabis medicines.

Oral Administration

Slow rates of absorption and low THC concentrations occur in comparison with inhalation, orally administered THC or cannabis edibles can take 60-90 min to feel effects. THC Plasma concentrations peak at peaked ca. 4−6 h after ingestion. The psychoactivity also lasts longer and is less intense at equal doses versus the inhaled method.  This lower bioavailability (approximately 15%) is due to slow rates of absorption and the First Pass effect resulting from stomach acid and liver degradation of THC to 11-Hydroxy-THC metabolite prior to active THC absorption to the bloodstream. These aspects are the reason why edible products are more difficult to control in terms of their intensity and the time they take to appear. This is the reason oftentimes for overdosing on edibles (oftentimes referred to as a “cookie casualty.” 

On the other hand there are certainly situations that, from a clinical perspective, edibles can be used to clinical advantage. I’m quite preferential to them for elderly patients for a number of reasons. Fire is just bad for grandpa, okay? Especially if he is demented or is on supplementary oxygen. Secondly, if grandma is taking bladder incontinence medication then coughing is also not advisable. Incontinence can ruin any high, let me tell you. Lastly, I’m not counting calories in old folks man I won’t bullshit you. Brownies can be gummed out if dentures are an issue and liquid oil preparations are easily used on breads and muffins. Plus the longer duration of action makes it ideal for a bedtime snack to get them some good rest. Being old is tiring so getting a good night’s sleep comes at a premium.

The Entourage effect:

This further confounds the dosing regimen, as higher doses of pure THC preparations are required to achieve the same clinical benefit as lower doses of THC from full spectrum or “whole plant” preparations. Synergy between naturally occurring phytochemicals outlines the framework for the entourage effect-differing combinations of cannabinoids, terpenoids, and flavonoids producing unique and condition-specific effects.  It is important to note that the dose of THC needed for effect will differ based on whether this is THC isolated alone or in combination with whole plant extract with the entire suite of native cannabinoids. This is because a smaller dose of THC will be required to achieve the same effect due to the entourage effect of the other cannabinoids. 5 mg THC of two cultivars will have staggeringly different effects due to the both the synergistic and antagonistic effects of different chemical fingerprints. Individual variability in our endocannabinoid systems also contribute to the range of effects seen at equal doses of different cannabis cultivars.

THC/CBD ratio and dosing:

Here’s a big hurdle to get over when trying to employ medical marijuana in dispensaries that are co-adapted to serve recreational marijuana purposes. Since marijuana prohibition, growers have been crossbreeding high-octane thoroughbred cannabis strains (type 1 THC heavy strains) to steadily drive up THC content while breeding out an essential cannabinoid in CBD. Type 2 strains with a more balanced THC:CBD profile are prized in the medical cannabis world but are much harder to find than their diesel fuel cousins. This aspect of the unavoidable commercial nature of marijuana is unfortunate because adding CBD to THC widens the therapeutic window. The therapeutic effects of THC-dominant cannabis can be achieved at dosages lower than those required to produce euphoria or impairment. A 2011 reviewTrusted Source on the safety and side effects of CBD found that continuous use of CBD, even in high doses like 1,500 mg a day, is tolerated well by humans. CBD may modify the effects of THC and reportedly may inhibit cytochrome P450 (CYP 450)-mediated conversion of THC to 11-OH-THC [20][21]

Final thoughts Cannabis Administration

There are many things to consider in terms of product selection that are far beyond the scope of this blog. Let me just tie it up like this.  Check the label for the basic stuff. It is essential to know at least the amount of THC and CBD present in the products you consume to be able to systematically administer and be able to anticipate the effects after taking each dose. The correct dose is the lowest dose that produces a therapeutic benefit without the associated adverse events. The sweet spot is a dose large enough to feel effects but small enough to not cause unwanted psychoactivity. Marijuana is a safe enough drug to keep experimenting with until you find the sweet spot. Individualization of treatment is the answer. This means finding the optimal product and route of administration. Sometimes you might have to get your products from more than one place to get the true entourage effect on all the cannabinoids and terpenoids. A healthy approach to cannabis medication is to replace the endocannabinoid deficit without overshoot. Titrate to effect by starting low and going slow.

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