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EDITORIALS: Eija Kalso Cannabinoids for pain and nausea BMJ 2001; 323: 2-3 [Full text]

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Cannabinoid therapy:seeing through the haze

Gareth Pryce   (6 July 2001)

Ignorance is not bliss

Ned Hoke   (8 July 2001)

Cannabis analgesia

Bryan A Krumm   (9 July 2001)

Besmirch Research

Chris Wright   (11 July 2001)

Pooled data of elder studies miss relevant information

Franjo Grotenhermen   (20 July 2001)

Cannabinoid therapy:seeing through the haze 6 July 2001
Gareth Pryce, Research Scientist Institute of Neurology, London Send response to journal: Re: Cannabinoid therapy:seeing through the haze	What becomes clear on reading the papers on cannabinoid therapy in emesis and pain management is that in many cases the studies were doomed from the start in light of the huge advances in cannabinoid biology over the past few years. In particular the identification of an endogenous cannabinoid signalling system makes it possible to predict that in instances where this system is perturbed (such as spasticity associated with neronal degeneration in MS) then cannabinoid therapy is highly likely to be effective. Many scientists in light of the current biological evidence would not now sanction the use of cannabinoids in many of the areas previously investigated where clinical outcome was disappointing such as acute post- operative pain, wheras chronic neropathic pain is likely to respond well to cannabinoid therapy. In the future further understanding of this exciting area of neurobiology will enable us to develop vastly improved therapeutic agents to not only treat symptoms effectively but also greatly reduce contraindications such as central psychoactive effects. Yours faithfully Gareth Pryce
Ignorance is not bliss 8 July 2001
Ned Hoke, private practice Western US Send response to journal: Re: Ignorance is not bliss	This interesting review of literature and opinion remains squarely in the vanity of it's rut. For the genuine medicinal herbalist cannabis lives purposefully as a functional anodyne, nervine, sudorific, anti-spasmodic. The patentable fractions for the profit-driven perspectives sway with commercial and political winds and proport to report and respect fact. While it is quite interesting yes, important even, for these voices of pharmaceutical exploitation, to examine this issue it is laughable and regretable they are heard as prime or sole experts of the subject.
Cannabis analgesia 9 July 2001
Bryan A Krumm, Director New Mexicans for Compassionate Use Send response to journal: Re: Cannabis analgesia	The conclusion reached by Fiona A. Campbell et.al, that "the best that can be achieved with single dose cannabis in nociceptive pain is analgesia equivalent to single dose codeine 60 mg, which rates poorly on relative efficacy compared with nonsteroidal antiinflammatory drugs or simple analgesics" (1) is premature. The authors acknowledged that all of the studies reviewed involved single cannabinoids. Findings from single cannabinoid studies do not demonstrate the therapeutic potential of whole cannabis. Cannabis contains over 60 cannabinoids which may have therapeutic potential either by themselves or in some combination. Cannabinoids have been shown to act synergistically to provide increased therapeutic value. For instance, when the CB1 receptor agonist, anadamide, and CB2 receptor agonist, palmitoylethanolamide, are administered together, the two compounds reduce pain responses 100-fold more potently than either compound alone (2). A study conducted by the New Mexico Department of Health found that smoked cannabis was more effective at alleviating vomiting than THC (3) The authors also claim that "adverse effects associated with the cannabinoids were common and sometimes severe." However, synthetic cannabinoids were associated with the most problematic side effects in the studies they reviewed. Cannabidiol, which is found in whole cannabis, has been shown to alleviate many of the problematic side effects associated with THC (4). The New Mexico study found that THC was far more likely to cause problematic side effects than smoked cannabis (3). Cannabis is an incredibly safe drug. In over 5,000 years of use, there has never been a recorded fatal overdose. The low density of receptors in medullary nuclei is consistent with the lack of lethal effects in humans (5). The studies on chronic marijuana use that have been conducted suggest that tolerance rapidly develops to many of the effects of cannabis use and field studies have failed to find any major consequences from chronic heavy use of cannabis (6). No clinical evidence has been discovered suggesting increased prevalence of opportunistic infection or malignancy among cannabis users (7). Marijuana use appears to have little effect on human mortality (8). The authors were correct in pointing out the serious lack of human studies into the therapeutic potential of whole cannabis as an analgesic. However, there are thousands of anecdotal reports from humans and hundreds of animal studies demonstrating the potential for cannabis to alleviate many types of pain. Given the safety of cannabis, those who are suffering should be allowed access to this medication, while studies are conducted to determine what types of cannabinoids are most effective as analgesics. References: 1. Campbell FA, Tramr MR, Carroll D, Reynolds DJM, Moore RA, McQuay HJ. BMJ 2001;323:13-16 2. Calignano A, La Rana G, Giuffrida A and Piomelli D. Control of pain initiation by endogenous cannabinoids. Nature 1998;394:277-281. 3. State of New Mexico, Health and Environment Dept. Report of the Lynn Pierson Therapeutic Research Program : oral vs. inhaled cannabinoids for nausea/vomiting from cancer chemotherapy. Santa Fe: N.M. Health and Environment Dept., Behavioral Health Services Division, 1984 4. Zuardi AW, Shirakawa I, Finkelfarb E, Karniol IG. Action of cannabidiol on the anxiety and other effects produced by delta 9-THC in normal subjects. Psychopharmacology 1982;76:245-250,. 5. Mechoulam R, Hanus L, Martin BR. Search for endogenous ligands of the cannabinoid receptor. Biochemical Pharmacology 1994;48:1537-1544. 6. Hollister LE. Health aspects of cannabis. Pharmacological Reviews 1986;38:1-20. 7. Hollister LE. Cannabis-1988. Acta Psychiatr Scand Suppl 1988;345:108-118. 8. Sidney S, Beck JE, Tekawa IS, Quesenberry CP Jr, Friedman GD. Marijuana use and mortality. Am J Pub Health 1997;87:585-590.
Besmirch Research 11 July 2001
Chris Wright Genesis Computers, Inc. Send response to journal: Re: Besmirch Research	Never once did your research mention the testing of the potent cannabinoid painkiller known as WIN55212. WIN55212 has far greater painkilling capability than codeine. Back to the drawing board mates, you didn't do your homework.
Pooled data of elder studies miss relevant information 20 July 2001
Franjo Grotenhermen, Chairman International Association for Cannabis as Medicine, Cologne, Germany Send response to journal: Re: Pooled data of elder studies miss relevant information	Dear Sirs: The articles by Campbell et al. (2001) and by Tramer et al. (2001) are indeed high quality reviews, but I am less sure whether the methods applied are able to answer the questions of today's interest. If you pool the data on elder pain studies you will miss most of the interesting information, particularly differences in efficacy for different painful conditions and differences between the cannabinoids and interindividual differences with regard to side effects. It is well-known that cannabinoids are weak analgesics compared to the opiates (Grotenhermen 1999). The question of interest is not so much whether cannabinoids are potent analgesics compared to codeine but in which painful conditions cannabinoids are effective. By stating that cannabinoids may have potential in neuropathic pains particularly with spastic components even Kalso (2001) hints to a need for such a differentiated assessment. The same is true for side effects. Levonantradol has not been brought on the market because of a higher rate of side effects compared to THC. Today an interesting question might be by which strategies psychotropic side effects could be reduced (Pertwee 2001). There is a high interindividual variation with regard to side effects and the ratio of side effects and benefits. Some patients may profit more since they tolerate relative high doses without perceiving unpleasant effects (Brenneisen 1996). Will we learn to find out which patients have a favourable ratio of risks and benefits? With regard to the antiemetic efficacy I agree that modern serotonin receptor antagonists are very effective to treat nausea and vomiting in cancer chemotherapy, but sometimes they fail and sometimes cannabinoids seem to be superior (Gonzalez-Rosales and Walsh 1997). The study by Maurer et al. (1990) cited by Campbell and colleagues refers to another important aspect, the synergistic use of several pharmacological effects of cannabinoids, in this case the analgesic and antispastic effects in a patient with a spinal cord injury. Research that cannabinoids reduce opioid-induced emesis (Simoneau et al. 2001) and act synergistically with opioids against pain point to a possible combination of analgesic and antiemetic effects of cannabinoids. In my opinion cannabinoid receptor agonists will find their place in modern medicine within the next few years. It will be interesting to see for which indications they will be approved and used and whether they will be limited to synthetic derivatives from Bayer (Siegling et al. 2001), Novartis (Fox et al. 2001) and other companies engaged in cannabinoid research. Sincerely, Franjo Grotenhermen, M.D. References 1. Campbell FA, Tramčr MR, Carroll D, Reynolds DJM, Moore RA, McQuay HJ. Are cannabinoids an effective and safe treatment option in the management of pain? A qualitative systematic review. BMJ 2001;323:13. 2. Tramčr MR, Carroll D, Campbell FA, Reynolds DJM, Moore RA, McQuay HJ. Cannabinoids for control of chemotherapy induced nausea and vomiting: quantitative systematic review. BMJ 2001;323:16. 3. Brenneisen R, Egli A, Elsohly MA, Henn V, Spiess Y. The effect of orally and rectally administered delta 9-tetrahydrocannabinol on spasticity: a pilot study with 2 patients. Int J Clin Pharmacol Ther 1996;34(10):446-452. 4. Fox A, Kesingland A, Gentry C, McNair K, Patel S, Urban L, James I. The role of central and peripheral Cannabinoid(1) receptors in the antihyperalgesic activity of cannabinoids in a model of neuropathic pain. Pain 2001;92(1-2):91-100. 5. Gonzalez-Rosales F, Walsh D. Intractable nausea and vomiting due to gastrointestinal mucosal metastases relieved by tetrahydrocannabinol (dronabinol). J Pain Symptom Manage 1997;14(5):311-314. 6. Grotenhermen F. Cannabis in der Schmerztherapie - ein neues Adjuvans [Cannabis in pain therapy – a new adjuvans]? Forschung und Praxis, Wissenschaftsjournal der Ärztezeitung 1999;276:22-26. Kalso E. Cannabinoids for pain and nausea. Some evidence but is there any need? [Editorial] BMJ 2001;323:2-3. 7. Maurer M, Henn V, Dittrich A, Hofmann A. Delta-9-tetrahydrocannabinol shows antispastic and analgesic effects in a single case double-blind trial. Eur Arch Psychiatry Neurol Sci 1990;240(1):1-4. 8. Pertwee R. Sites and Mechanisms of Action. In: Grotenhermen F, Russo E, eds. Cannabis and cannabinoids. Pharmacology, toxicology, and therapeutic potential. Haworth Press, Binghamton/New York 2001, in press. 9. Siegling A, Hofmann HA, Denzer D, Mauler F, De Vry J. Cannabinoid CB(1) receptor upregulation in a rat model of chronic neuropathic pain. Eur J Pharmacol. 2001 Mar 9;415(1):R5-R7. 10. Simoneau II, Hamza MS, Mata HP, Siegel EM, Vanderah TW, Porreca F, Makriyannis A, Malan TP Jr. The cannabinoid agonist WIN55,212-2 suppresses opioid-induced emesis in ferrets. Anesthesiology 2001 May;94(5):882-887.