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Autumn 2005
O'Shaughnessy's
Journal of the California Cannabis Research Medical Group

Listening to Marinol:
Rational Guidelines for Dosing

By Gregory T. Carter, MD; Patrick Weydt, MD; Muraco Kyashna-Tocha, PhD; and Donald I. Abrams, MD

 
DRONABINOL is synthetic THC in sesame-oil capsules. It was marketed as Marinol by Roxane Laboratories in 1987. By comparing rates at which THC from drobabinol and smoked natural cannabis are absorbed into the bloodstream, the authors calculated equivalent doses. The FDA originally approved Marinol as a treatment for nausea and subsequently approved it as an appetite stimulant. After years on Schedule II it was moved to Schedule III by the DEA in 1999.

Typically, cannabis is smoked as a cigarette weighing between 0.5 and 1.0 g. After combustion and inhalation, peak venous blood levels of 75 to 150 nanograms per milliliter of plasma appear about the time smoking is finished.

The main advantage of smoking is rapid onset of effect and easy dose titration. When cannabis is smoked, cannabinoids in the form of an aerosol in the inhaled smoke are absorbed and delivered to the brain rapidly as would be expected of a highly lipid-soluble drug.

A person’s smoking behavior during an experiment is difficult for a researcher to control and smoking behavior is not easily standardized, although some research protocols for standardization of smoking have been developed. An experienced cannabis smoker can titrate and regulate dose to obtain the desired acute effects and to minimize undesired effects.

Each puff delivers a discrete dose of cannabinoids to the body. Puff and inhalation volume changes with phase of smoking, tending to be highest at the beginning and lowest at the end of smoking a cigarette.

Heavy users could absorb as much as 27% of available THC, which may be twice as much as an infrequent user may absorb.

Some studies found frequent users to have higher puff volumes than did less frequent cannabis users. Heavy users could absorb as much as 27% of available THC, which may be twice as much as an infrequent user may absorb.

During smoking, as the cigarette length shortens, the concentration of THC in the remaining cannabis increases. Thus, each successive puff contains an increasing concentration of THC. However, up to 40% of the available THC may be completely combusted in the process of smoking and not be biologically available.

Post smoking assay of cannabinoids in blood or urine can partially quantify dose actually absorbed after smoking, but the analytic procedures are methodologically demanding.

The only form of cannabinoid that is available by a formal, dose specific, prescription is dronabinol. There are too many variables in the published clinical trials and case series with raw cannabis to use those studies as a basis for deriving dosages. Thus we will use the dronabinol prescription guidelines as published by the manufacturer and accepted by United States Food and Drug Administration (FDA) as the basis for formulating our dosing recommendations for natural cannabis.

It is critical to note that dronabinol is an oral preparation and contains only THC. Most medicinal cannabis patients use smoking as the route of delivery. As noted, there are significant differences in pharmacokinetics between oral consumption and smoking. There are varying physiological effects when other cannabiods are present, as is the case with cannabis plant material.

It is also not clear how the original dosing construct for dronabinol was arrived at, although we assume it was done through clinical testing for therapeutic benefit versus side effects. Despite these inherent limitations, these calculations do provide approximate dose equivalents by weight and are useful as long as one recognizes these limitations.

By directly applying these figures to the recommended dronabinol dosing model of 30-90 mg per day, we arrive at the dosages shown in table 2 (assuming negligible amounts of cannabidiol present in the cannabis)

Our derived figures lie very closely within the range of reported amounts. In informal surveys from patients in Washington and California, the average reported consumption of cannabis by medicinal users typically ranges between 10 - 20 g per week, or approximately 1.42 to 2.86g per day.

If the mean strength of the medical cannabis is 19% THC (negligible CBD), and the average strength is 15% THC as reported by Geiringer, then the amount of cannabis needed to absorb a 30mg THC dose is .88-1.23g, and the amount needed for 90mg of THC is 2.65-3.69g. of cannabis. These figures all share a strikingly similar range.

Our recommended dosages are reinforced by two of the only studies that utilized smoked cannabis in a dosing regime (Chang, 1975, and Vinciguerra, 1988). These dosages are also within the medical cannabis guidelines allowed in the Canadian medical system. (The Canadian medical allowance is for 1-12 g a day with less than 5 g being the mean.)

Thus, despite all of the noted variables, there is remarkable consistency among the derived and reported doses noted here. The biggest limitations of our dosing model is that it is based on THC concentrations, despite growing evidence that THC may not even be the most clinically useful cannabinoid. However, given the current state of the known, published pharmacology of cannabis, this is the best dosing model that can be derived.

Tolerance
An issue that warrants discussion is physiological tolerance, which plays a role in dosing cannabis. With regard to treating chronic, intractable pain, physicians will often prescribe increasingly larger doses of long-acting opioids as patients develop tolerance. These patients are also generally given prescriptions of fast-onset, short-acting opioids for “breakthrough pain.” This is accepted practice, despite the fact that opioids, even in an opioid-dependent patient, still have the capacity to suppress breathing to the extent of inducing respiratory arrest.

Long-term cannabis users can develop tolerance but there is essentially no risk for overdose. Thus, it is conceivable that a long-term cannabis user may require significantly larger amounts of cannabis to achieve a therapeutic effect. In addition, those who use cannabis by ingestion may also require significantly higher amounts. Until more refined and purified cannabinoid preparations are available, it will not be possible to derive a more specific or exact dosing schedule. It is therefore critical that legal authorities consult with medical experts before arriving at any conclusions at to the appropriateness of the amount of usage.

We have outlined reasonable guidelines for dosing of medical cannabis, based on the known pharmacology. However, because of the complexities of the cannabis plant, the chemistry of the various forms of cannabinoids, patient tolerance, differing routes of intake and delivery systems, there are inherent limitations to these guidelines.
Recognizing this, we recommend that an individual, patient-controlled, self-titration dosing model be used. The guidelines we have described provide a dosing construct for patients and physicians to do this. These guidelines also provide legal authorities some reference points as to what would be considered a reasonable amount of cannabis to use for medicinal purposes.

Gregory Carter is with the Department of Rehabilitation Medicine and Patrick Weydt with Department of Neurology at the University of Washington School of Medicine in Seattle. Muraco Kyashna-Tocha is with the Cyber Anthropology Institute, Seattle. Donald I. Abrams is with the Division of Hematology/Oncology, Department of Medicine, San Francisco General Hospital.

This paper, excerpted from CannabisMD.org, was supported by a grant from the National Institute on Disability and Rehabilitation Research, Washington, D.C., USA. It can be read in its entirety, with ample footnotes, at
http://cannabismd.org/foundation/mmjdosingguidelines.php

 

 

O'Shaughnessy's
O'Shaughnessy's is the journal of the CCRMG/SCC. Our primary goals are the same as the stated goals of any reputable scientific publication: to bring out findings that are accurate, duplicable, and useful to the community at large. But in order to do this, we have to pursue parallel goals such as removing the impediments to clinical research created by Prohibition, and educating our colleagues, co-workers and patients as we educate ourselves about the medical uses of cannabis.
 
SCC
The Society of Cannabis Clinicians (SCC) was formed in the Autumn of 2004 by the member physicians of CCRMG to aid in the promulgation of voluntary standards for clinicians engaged in the recommendation and approval of cannabis under California law (HSC §11362.5).

As the collaborative effort continues to move closer to issueing guidelines, this site serves as a public venue for airing and discussing these guidelines.

Visit the SCC Site for more information.