University of Oxford, Department of Pharmacology, Mansfield Road, Oxford OX1 3QT, United Kingdom
*To whom reprint requests should be addressed. e-mail:
[email protected].
See the article "Increased mortality, hypoactivity, and hypoalgesia in cannabinoid CB1 receptor knockout mice" on page 5780.
See the article "Altered gene expression in striatal projection neurons in CB1 cannabinoid receptor knockout mice" on page 5786.
Top
References
Marijuana is by far the most widely used illicit drug in the Western world, with an estimated 20 million regular users in North America and Europe. Many thousands of patients with AIDS, multiple sclerosis, and other illnesses are also illegally self-medicating with cannabis in the belief that it provides them with a therapeutic benefit. The medical use of cannabis has been highlighted recently by the publication of the Institute of Medicine report Marijuana and Medicine (1).
The history of scientific research on cannabis in the 1990s is reminiscent of the development of research on morphine and related opiate drugs during the 1970s. In each case, what began as the study of a plant-derived psychoactive drug resulted in the discovery of a naturally occurring physiological control system in the mammalian brain. Thus, research on morphine led to the discovery of opiate receptors and the naturally occurring family of morphine-like peptides the endorphins. Research on the active principal of cannabis, 9-tetrahydrocannabinol (THC) has lead to the discovery of cannabinoid receptors and more recently, the lipid derivatives anandamide and 2-arachidonyl glycerol, which are thought to represent the naturally occurring ligands for these receptors (for review, see ref. 2).
Two cannabinoid receptors have been described: the CB1 receptor, present both in the brain and in some peripheral organs, and the CB2 receptor, present only in the periphery on cells of the immune system (2). An obvious question is whether all of the effects of THC and other cannabinoids on the central nervous system are mediated by the CB1 receptor. It might be that some of the central effects of THC are mediated by actions at some other cannabinoid receptor whose identity has not yet been revealed. There have been two experimental approaches used to address this question: use of the powerful new drugs that act selectively as CB1 receptor antagonists and development of genetically modified strains of mice in which the expression of the CB1 receptor has been eliminated. The CB1 receptor knockout approach is the subject of reports by Zimmer et al. (3) and Steiner et al. (4) in this issue of the Proceedings, both emanating from the same laboratory at the National Institute of Mental Health (NIMH). Their findings need to be compared with those reported by Ledent et al. (5), who independently developed a CB1 knockout strain of mice. The CB1 receptor antagonists, epitomized by the compound SR1417161A (developed by the French company Sanofi), first became available in 1995 (6) and have been widely used in academic research studies in the past few years (2).
In an ideal world, all of these approaches would lead to the same conclusions, but as so often happens in research that addresses complex biological questions, this has not proved to be the case. As one of the most important potential indications for cannabis-based medicines is the control of pain, it is not surprising that this has been an important focus for many of the animal studies. A number of studies have used the CB1 antagonist drug SR141716A and reported that it completely blocked all of the pain-relieving effects of THC and related cannabinoids in various animal models of pain (2, 7–9). The CB1 antagonist drug given on its own, however, had no effect on the baseline sensitivity to pain stimuli in these animal studies. In agreement with these findings, Ledent et al. (5) found no change in pain thresholds in their CB1−/− mice using heat, mechanical pressure, or chemical irritants as pain stimuli. These animals also showed no analgesic response at all to THC in the one of the heat tests (hotplate) but retained a small but significant response to THC in the other heat test (tail immersion). The NIMH group (3) also found that the analgesic responses to THC in the hotplate test were abolished in the CB1−/− mice but, surprisingly, found that THC still gave a more or less normal analgesic response in the other heat test, the tail flick. On the other hand, they found that analgesic responses to a synthetic cannabinoid compound, HU210, were completely absent in the tail-flick test in the CB1−/− animals. Furthermore, Zimmer et al. (3) reported significant changes in baseline pain sensitivity in the CB1−/− mice when tested in the hotplate or formalin paw (chemical irritant) models but no changes in tail flick latency. It is possible that some of these differences among tests reflect the level in the central nervous system that is involved. The tail-flick and tail-immersion tests measure a spinal reflex, whereas both the hotplate and formalin tests measure behavioral responses that involve higher brain centers.
The European and NIMH groups (3, 5) were in agreement in finding that CB1−/− mice no longer exhibited some of the other characteristic responses to THC that are thought to be centrally mediated. These included THC-induced reduction in body temperature and spontaneous activity and THC-induced increases in immobility (catalepsy). Ledent et al. (5) also report an absence of the normal cardiovascular responses to THC (reduced blood pressure and heart rate) in CB−/− mice, although their resting heart rate and blood pressure remained normal.
The groups differed, however, in their findings on the effects of the CB−/− knockout on baseline motility. Ledent et al. (5) found that the knockout mice exhibited higher levels of spontaneous running activity, even when placed in fear-inducing novel environments (open field, elevated plus maze). This finding is consistent with the observation that THC and other cannabinoids cause reductions in spontaneous activity and at least one report that the CB1 antagonist SR141716 caused an increase in spontaneous activity in mice (7). Zimmer et al. (3), paradoxically, found that their CB1−/− mice displayed reduced activity in the open-field test and an increased tendency to immobility in a test of catalepsy. The accompanying paper by Steiner et al. (4) provides a rationale to explain this apparent anomaly, by providing evidence of alterations in the expression of neurotransmitter and neuropeptide genes in neurons in the motor control centers of the mouse brain, the basal ganglia. They found increased levels of mRNA for the γ-aminobutyric acid biosynthetic enzyme, glutamate decarboxylase, and the neuropeptides substance P, dynorphin and enkephalin, in output neurons of the mouse striatum, especially in those regions that were normally enriched in CB1 receptors. The authors point out that such alterations in the basal ganglia might account for the alterations in spontaneous activity observed in the CB1−/− animals; their results, however, remain at variance with those of the apparently similar strain of animals tested by Ledent et al. (5). A summary of the findings with CB1−/− mice and the CB1 antagonist drug SR141716A is given in Table 1.
Zimmer et al. (3) also describe some unusual effects of high doses of THC (50–100 mg/kg) in the CB1−/− mice. These effects, including strong diarrhea and abnormal posture, head movements, and grooming, are not seen in normal wild-type mice in response to THC. The doses of THC needed to elicit these effects, however, were very high, and it is hard to know how to interpret these observations. A dose of THC of 0.2 mg/kg is strongly intoxicant in man.
There is increasing evidence that the cannabinoid and opiate systems represent parallel but overlapping physiological control mechanisms, particularly in their involvement in the control of pain sensitivity (10). Ledent et al. (5) pursued this relationship in their studies of the CB1−/− mice. They found that the knockout mice showed normal analgesic responses to morphine (tail-flick and hotplate tests). However, the CB1−/− mice seemed to find morphine less rewarding; they proved less likely to self-administer morphine by intravenous injection. When morphine-dependent animals were challenged with the opiate antagonist drug naloxone, the behavioral signs of opiate withdrawal were less severe in the CB1−/− animals, suggesting again a possible involvement of cannabinoid mechanisms in the euphoriant effects of opiates and in the development of opiate dependence. The CB1−/− mice did not show any tendency to self-administer the synthetic cannabinoid WIN55,212-2 and displayed no withdrawal signs when, after repeated treatment with THC, they were challenged with the antagonist SR141716A, suggesting that the CB1 receptor does mediate the rewarding properties of cannabis and is involved in the development of dependence.
Overall, these new findings provide many valuable new insights into cannabinoid mechanisms in the brain, despite some disagreement between the NIMH and European reports. There is general agreement that the CB1 receptor plays a key role in mediating many, if not all, of the important central nervous system effects of THC and related cannabinoids. It seems likely also that the endogenous cannabinoid system may play a role in the modulation of pain sensitivity and the control of tonic activity in the output motor systems of the brain, although it remains unclear to what extent the cannabinoid mechanisms are activated under normal resting conditions. Like the opiate mechanisms in brain, it is possible that they are only called into play in response to some perturbation in the animal’s environment or circumstances. No doubt further research in this now active area will provide answers to some of the
Medical Cannabis: Rational Guidelines for Dosing
Gregory T. Carter, M.D.*
Patrick Weydt, M.D.**
Muraco Kyashna-Tocha, Ph.D.+
Donald I. Abrams, M.D.++
*Department of Rehabilitation Medicine
**Department of Neurology
University of Washington School of Medicine, Seattle, WA, USA
+The Cyber Anthropology Institute, Seattle, WA, USA
++Division of Hematology/Oncology, Department of Medicine, San Francisco General Hospital, University of California, San Francisco, CA, USA
Supported by Research and Training Center Grant HB133B980008 from the National Institute on Disability and Rehabilitation Research, Washington, D.C., USA.
The authors would like to acknowledge the following persons for their help in preparing this manuscript: Martin Martinez, Jeffrey Steinborn, and Ethan Russo
Abstract
The medicinal value of cannabis (marijuana) is well documented in the medical literature. Cannabinoids, the active ingredients in cannabis, have many distinct pharmacological properties. These include analgesic, anti-emetic, anti-oxidative, neuroprotective, and anti-inflammatory actions, as well as modulation of glial cells and tumor growth regulation. Concurrent with all these advances in the understanding of physiological and pharmacological mechanisms of cannabis, there is a strong need for developing rational guidelines for dosing. This paper will review the known chemistry and pharmacology of cannabis and then, on that basis, discuss rational guidelines for dosing.
Key words: marijuana, cannabinoids, cannabis, pharmacology, dosing
1. Introduction and Brief Historical Background
Possibly the first references to the medicinal use of cannabis are found in the Chinese pharmacopoeia of Emperor Shen-Nung, written in 2737 BC. That document recommended cannabis for analgesia, rheumatism, beriberi, malaria, gout and poor memory.[1] Eastern Indian documents in the Atharvaveda, dating to about 2000 BC, also refer to the medicinal use of cannabis.[2] Archeological evidence has been found in Israel indicating that cannabis was used therapeutically during childbirth as an analgesic.[3] This use of cannabis continued in the West until the mid-1880s and continues today in parts of Asia. In ancient Greece and Rome, both the Herbal of Dioscorides and the writings of Galen refer to the use of medicinal cannabis.[4]
The medicinal use of cannabis arrived in western medicine much later. There is mention of it in a treatise by Culpepper written in medieval times. British East India Company surgeon William O'Shaughnessy introduced cannabis for medicinal purposes into the United Kingdom following his observations while working in India in the 1840s. He used it in a tincture for a wide range of uses, including analgesia.[5] Queen Victoria used cannabis for relief of dysmenorrhoea in the same era.[6] In 1937, against the advice of most of the medical community and much of the American Medical Society, the Federal Government criminalized non-medical cannabis. Cannabis was removed from the United States Pharmacopoeia in 1942 but up until that time physicians could still write a prescription for cannabis.[7] The physiological mechanisms and therapeutic value of cannabinoids continue to be well documented in the medical literature.[6-36] However, there has been very little written on appropriate dosing regimens for the medicinal use of cannabis. With current and emerging laws allowing physicians in many areas of the world to recommend the use of cannabis to treat symptoms of certain diseases and medical conditions, there is need for medical literature describing rational dosing guidelines. This paper will review the known chemistry and pharmacology of cannabis and then, on that basis, discuss rational guidelines for dosing.
2. Chemistry and Pharmacology of cannabis
Cannabis is a complex plant, with several existing phenotypes, each containing over 400 chemicals.[14,15] Approximately 70 are chemically unique and classified as plant cannabinoids.[11,15] There are also naturally occurring cannabinoids produced in the human body.[8] The cannabinoids are 21 carbon terpenes, biosynthesized predominantly via a recently discovered deoxyxylulose phosphate pathway.[16] The cannabinoids are lipophilic. Delta-9 tetrahydrocannabinol (THC) and delta-8 THC appear to produce the majority of the psychoactive effects of cannabis. Delta-9 THC, the active ingredient in dronabinol (Marinol) is the most abundant cannabinoid in the plant and this has led researchers to hypothesize that it is the main source of the drug's impact.[15] Dronabinol is available by prescription as a schedule III drug.
Other major plant cannabinoids include cannabidiol and cannabinol, both of which may modify the pharmacology of THC and have distinct effects of their own. Cannabidiol is the second most prevalent of cannabis's active ingredients and may produce most of its effects at moderate, mid range doses. Cannabidiol becomes THC as the plant matures and this THC over time breaks down into cannabinol. Up to 40% of the cannabis resin in some strains is cannabidiol.[15] The amount varies according to plant. Some varieties of Cannabis sativa have been found to have no cannabidiol.[6] Since cannabidiol may help reduce anxiety symptoms, cannabis strains without cannabidiol may produce more panic or anxiety side effects. Cannabidiol may exaggerate some of the THC's effects, including increasing THC-induced euphoria, while attenuating others. Cannabidiol slows THC metabolism in the liver. Consequently, a dose of THC combined with cannabidiol will create more psychoactive metabolites than the same dose of THC alone.[14,15] In mice, pretreatment with cannabidiol increased brain levels of THC nearly 3-fold and there is strong evidence that cannabinoids can increase the brain concentration and pharmacological actions of other drugs.[16,17] Some researchers have proposed that many of the negative side effects of dronabinol could be reduced by combining it with cannabidiol or possibly other non-psychoactive cannabinoids.[8]
Cannabidiol breaks down to cannabinol as the plant matures.[15] Much less is known about cannabinol, although it appears to have distinct pharmacological properties that are quite different from cannabidiol. Cannabinol has significant anticonvulsant, sedative, and other pharmacological activities likely to interact with the effects of THC.[14] Cannabinol may induce sleep and may provide some protection against seizures for epileptics.[15,16,17]
Two physiologically occurring lipids, anandamide (AEA) and 2-arachidonylglycerol (2-AG), have been identified as endogenous cannabinoids (endocannabinoids), although there are likely more.[18] The physiological roles of these endocannabinoids have been only partially clarified but available evidence suggests they function as diffusible and short-lived intercellular messengers that modulate synaptic transmission. Recent studies have provided strong experimental evidence that endogenous cannabinoids mediate signals retrogradely from depolarized postsynaptic neurons to presynaptic terminals to suppress subsequent neurotransmitter release, driving the synapse into an altered state.[18,19,20] Signaling by the endocannabinoid system appears to represent a mechanism by which neurons can communicate backwards across synapses to modulate their inputs.
There are two known cannabinoid receptor subtypes. Subtype 1 (CB1) is expressed primarily in the brain whereas subtype 2 (CB2) is expressed primarily in the immune system.[10,20] Cannabinoid receptors constitute a major family of G protein-coupled, 7-helix transmembrane nucleotides, similar to the receptors of other neurotransmitters such as dopamine, serotonin, and norepinephrine.[10,11] Activation of protein kinases may be responsible for some of the cellular responses elicited by the CB1 cannabinoid receptor.[21]
Because of this biochemical complexity, characterizing the clinical pharmacology of cannabis is challenging. Further complicating the evaluation of cannabis is the variable potency of the plant material used in research studies. The concentration of THC and other cannabinoids in cannabis varies greatly depending on growing conditions, plant genetics, and processing after harvest.[19] The highest concentrations of bioactive compounds are found in the resin exuded by the flowering female plants.[18,19] Leaf mixtures of cannabis have concentrations of THC ranging from 0.3 percent to 4 percent by weight.[18-20] However, cannabis today is typically distributed as flowers and can contain anywhere from 8 to 25 percent or more THC. Thus, one gram of cannabis flowers would typically contain 80 to 250 mg of THC.[19]
The clinical pharmacology of cannabis containing high concentrations of THC may well differ from plant material containing small amounts of THC and higher amounts of the other cannabinoids. Moreover, the bioavailability and pharmacokinetics of inhaled cannabis are substantially different than those taken by ingestion.[17,18]
3. Clinical Pharmacology
Although it is a potent drug that may produce psychoactive effects, THC (and the other cannabinoids) have relatively low toxicity and lethal doses in humans have not been described.[23,24] The theoretical lethal dose in 50 percent (LD50) is estimated to be 1 to 20,000 or 1 to 40,000. Thus, it would require 1500 pounds of cannabis smoked in fifteen minutes to induce a lethal effect.[25]
Central effects of cannabinoids include disruption of psychomotor behavior, short-term memory impairment, intoxication, stimulation of appetite, antinociceptive actions (particularly against pain of neuropathic origin) and anti-emetic effects. Although there are signs of mild cognitive impairment in chronic cannabis users there is little evidence that such impairments are irreversible, or that they are accompanied by drug-induced neuropathology. A proportion of regular users of cannabis will develop some tolerance. A study by Hart and colleagues demonstrated that acute cannabis smoking produced minimal effects on complex cognitive task performance in experienced cannabis users, while still subjectively providing a euphoric "high".[38] The potential medical applications of both natural and synthetic cannabinoids are currently being tested in a number of clinical trials.
4. Delivery System and Pharmacokinetics
Route of administration is an important determinant of the pharmacokinetics of the cannabinoids in cannabis, particularly absorption and metabolism.[39-42] 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 (ng/mL) of plasma appear about the time smoking is finished.[39,43,44] 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.[45,46]
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.[44] An experienced cannabis smoker can titrate and regulate dose to obtain the desired acute effects and to minimize undesired effects.[47,48] 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. 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.[48] 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.[48] 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.[48,49]
Table 1: Maximum absorption of THC by patient per gram of cannabis
For 1g of cannabis containing: (assuming neglible cannabidiol) Maximum delivery to patient is :
10% THC 16.2 mg THC
15% THC 24.3 mg THC
20% THC 32.4 mg THC
25% THC 40.5 mg THC
30% THC 48.6 mg THC
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 we have previously noted there are significant differences in pharmacokinetics between oral consumption and smoking. Further, there are varying physiological effects when the other cannabiod forms are present, as is the case with natural 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 following dosages for cannabis containing these percentages of THC, again assuming negligible amounts of cannabidiol present in the cannabis. This is shown in table 2.
Table 2: Amount of Cannabis Equivalent to 30-90 mg dronabinol
% THC in cannabis Cannabis needed ot obtain 30mg THC For 60mg THC For 90mg THC
10% THC 1.85g 3.70g 5.55g
15% THC 1.23g 2.46g 3.69g
20% THC 0.93g 1.86g 2.79g
25% THC 0.75g 1.50g 2.25g
30% THC 0.62g 1.24g 1.86g
Interestingly, 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. Furthermore, if the mean strength of the medical cannabis is 19% THC (negligible CBD), and the average strength is 15% THC as reported by Geiringer, than 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.[74]
Our recommended dosages are also reinforced by two of the only studies that utilized smoked cannabis in a dosing regime. The 1975 Chang study dosed smoked cannabis at 5mg/meter squared, thus 35-40mg of THC a day for an average person. This translates into 1.4g of cannabis containing 15% THC.[75] The 1988 Vinciguerra study dosed smoked cannabis at 10mg/meter squared, thus 70-80mg of THC a day. This translates into about 2.8g of cannabis containing 15% THC.[76] Furthermore, 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.[77] However, given the current state of the known, published pharmacology of cannabis, this is the best dosing model that can be derived.
Therefore, table 3 shows our final derived dosing recommendations.
Table 3: Final Dosing Recommendations
Strength of Cannabis (assuming neglible canabidiol) Daily dosage of cannabis corresponding to 2.5 - 90 mg of THC
10% THC .15 g - 5.55g
15% THC .12 g - 3.69g
20% THC .08 g - 2.79g
25% THC .04 g - 2.25g
30% THC .01 g - 1.86g
A final 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, as previously discussed, 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.
9. Conclusions
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.
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