From: sumbuddie@sumbuddie.net   
      
   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.   
      
      
      
   MAILING ADDRESS FOR PROOFS/REPRINTS:   
      
   Gregory T. Carter, M.D.   
      
   1809 Cooks Hill Road   
      
   Centralia, WA 98531   
      
   USA   
      
   Phone: (360) 330-8626 FAX: (360) 330-8623   
      
   e-mail: gtcarter@u.washington.edu   
      
      
      
   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   
      
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