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About the Manual

The purpose of this manual is to provide health care practitioners readily accessible guidance for dosing of medical cannabis for specific medical conditions and symptoms. Drug prescriptions inform the patient and the dispensing pharmacist the dose, route and schedule of administration of the specific drug.  However recommendation of medical cannabis is not so simple.  These plant-derived materials are composed of a complex mixture of cannabinoids and terpenoids and hence are more difficult for physicians to prescribe. This is because contemporary clinical pharmacology is based on prescribing a single active molecule derived from plants, or synthesized in the laboratory to mimic the active agent from the plant.  In addition modern clinical pharmacology is based on drug-receptor theory postulated in the late 19th and early 20th century.  

Background

Chemists in the 19th century who worked with vital dyes noted simple organic chemicals (dyes) would bind or stain some tissues but not others. They inferred that selectivity of binding to specific tissues depended on the presence or absence of “receptors” (macromolecules or proteins on the surface of cells). The next step after receptor binding and occupancy was the triggering of the specific biological effect(s). The receptor-occupancy model was the first to describe the activity of drugs at receptors and quantified the relationship between drug concentration and observed effect. The drug-receptor model follows mass-action kinetics and attempts to link the action of a drug to the proportion of receptors occupied by that drug at equilibrium. The magnitude of the biological response was supposed to be directly proportional to the amount of drug bound, and the maximum response would be elicited once all receptors were occupied at equilibrium. For many drugs, the relationship between drug concentration and biological effect corresponded to a hyperbolic curve that could be expressed as a  log concentration-effect (or a dose-response curve).  

 

Then there is the matter of drug distribution throughout the body and its metabolism.  Hence latency and duration of drug action (pharmacokinetics) all come into play when writing a schedule of drug administration.  Contemporary education of medical students and residents omits the study of study of the origins of drugs (pharmacognosy) and considers use of plant extracts as archaic medicine.  Hence, the vast majority of physicians have no knowledge or experience in recommending complex plant-derived extracts.  

 

There is an opinion among some practitioners of the medical profession that  “medical marijuana” is  a smokescreen for  recreational use of the plant.   They pose the question, “why push for medical marijuana when we already have the option to prescribe Δ9-tetrahydrocannabinol (Δ9-THC; Marinol)?“  Most physicians are not aware that Δ9-THC  monotherapy is not effective for many conditions for which cannabis preparations containing combinations of Δ9-THC and cannabidiol  (CBD) have been shown to be beneficial. These therapeutic effects were documented in class I studies (randomized double-blind, placebo-controlled studies) in multiple sclerosis patients with spasticity, and patients with chronic neuropathic pain, cancer pain, bladder hyperactivity, and urge incontinence. The cannabis preparations were taken orally as whole cannabis extracts, smoked or vaporized, or by oral–mucosal spray (Sativex) of an extract of the plant containing Δ9-THC and CBD in a 1:1 ratio.  Apparently Δ9-THC alone does not seem to be effective for these neurologic conditions.  Moreover, orally administered Δ9-THC has very long latency of onset and cannot be easily titrated to a therapeutic dose without eliciting adverse effects in some patients.

 

A more important explanation relates to the synergistic effects achieved when Δ9-THC is administered along with an “entourage” of phytocannabinoids found in the plant, especially CBD and terpenes. The entourage effect was first brought up in relation to the endocannabinoid system, with its combination of active and inactive synergists. The concept was refined and qualified by Mechoulam: “this type of synergism may play a role in the widely held view that in some cases, plants are better drugs than the natural products isolated from them.” A recent review of the phytocannabinoids supports the entourage concept that combinations of cannabinoids can in certain circumstances be more effective than Δ9-THC or CBD alone.

 

The entourage effect is not unique to the phytocannabinoids. Pharmaceutical monotherapies against human malaria are effective, but ephemeral, because of the inevitable evolution of resistant parasites. Dried whole-plant Artemisia annua has been reported to be more effective in slowing the evolution of malaria drug resistance than artemisinin, the pure drug isolated from the plant.  Rather than cast off medical marijuana as a ploy for recreational use, the medical profession would do well to seriously study the endocannabinoid system in health and disease. The federal government should reschedule cannabis and allow scientists to develop a rational approach to cannabinoid therapeutics that takes into account the entourage effect. Meanwhile, this manual of cannabis therapeutics will facilitate the recommendation of cannabis for a range of medical conditions and symptoms

--Juan (Zeno) Sanchez-Ramos, PhD, MD