Neurology -- Correspondence for Killestein et al., 58 (9) 1404-1407

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Correspondence published:

Reply to Letter to the Editor: Joep Killestein, Bernard MJ Uitdehaag and Chris H Polman (23 October 2002)

Safety, tolerability, and efficacy of orally administered cannabinoids in MS: Ethan B Russo (23 October 2002)

Reply to Letter to the Editor 23 October 2002

Joep Killestein
VU Medical Center Amsterdam The Netherlands,
Bernard MJ Uitdehaag and Chris H Polman
Send Correspondence to journal:
Re: Reply to Letter to the Editor

j.killestein{at}vumc.nl Joep Killestein, et al.

Even though we agree with Dr. Russo that there is an urgent need for more conclusive data concerning cannabinoid therapy in MS, we would like to respond to some of the issues raised.
Dr. Russo argues that numerous methodological issues of our study require discussion, for example the dosage, which was considered inadequate, and the absence of dose titration. Russo suggests that this might account for the discrepancy between our results and those of a previously published study. [1]
Obviously, we cannot exclude that our dose regimen was inadequate to produce benefit, but we were the first to apply such a high dose for 4 weeks in a relatively large MS patient group and observed a significant increase in adverse events at this dosage. In fact, as mentioned in the methods section of our manuscript, we did pursue dose titration up to 5 mg THC twice a day. The discrepancy with the previously published study [1] may have many reasons, including the fact that it addressed the efficacy of only a single dose of THC and not of prolonged administration. In addition, this study by no means fulfilled current standards for a randomized, controlled trial (unclear randomization, no separate treating and assessing physician, no report of efficacy of masking etc.).
Dr. Russo also highlights interesting preliminary results of recent trials that, unfortunately, cannot be considered in terms of quality of design and data, since they have not been published yet. [2, 3]
We do not ignore the possibility that cannabinoids can modulate the function of immune cells. In vitro studies unequivocally demonstrated that high doses of cannabinoids suppress immune responses. [6] However, physiologically relevant concentrations of cannabinoids resulted in metabolic stimulation of lymphocytes [7] and an increase in pro- inflammatory cytokine production [8] rather than immunosuppression. Although several animal studies suggest that the immunosuppressive properties of cannabinoids can play a favorable role in the MS disease process, [9, 10] the compounds were used at concentrations that most likely will not be tolerated in humans. Given the nature of the disease, in our view the observation of an unspecified “improved MRI result” in a single MS patient treated with cannabis should not be interpreted as evidence for relevant immunosuppressive activity by cannabinoids in MS.
Researchers encounter a number of difficulties in designing studies that use cannabinoids. Whether the future of clinical cannabis indeed appears much brighter than would be evident from our study can be derived only from well designed and carefully executed clinical trials that, unlike our study, are powered for efficacy.
References
1.Petro DJ, Ellenberger C. Treatment of human spasticity with delta9- tetrahydrocannabinol. Journal of Clinical Pharmacology 1981;21:413S-416S.
2.Vaney C, Jobin P, Tschopp F, Heinzel M, Schnelle M. Efficacy, safety and tolerability of an orally administered cannabis extract in the treatment of spasticity in patients with multiple sclerosis. In: Symposium on the Cannabinoids; July 13, 2002; Asilomar Conference Center, Pacific Grove, CA: International Cannabinoid Research Society, 2002:57.
3.Robson PJ, Wade DT, Makela PM, House H. Cannabis medicinal extracts (CME), including cannabidiol, alleviated neurogenic symptoms in patients with multiple sclerosis and spinal cord injury. In: Symposium on the Cannabinoids; July 13, 2002; Asilomar Conference Center, Pacific Grove, CA: International Cannabinoid Research Society, 2002:56.
4.Baker D, Pryce G, Croxford JL, Brown P, Pertwee RG, Huffman JW, et al. Cannabinoids control spasticity and tremor in a multiple sclerosis model. Nature 2000;404:84-87.
5.Russo EB, Mathre ML, Byrne A, Velin R, Bach PJ, Sanchez-Ramos J, et al. Chronic cannabis use in the Compassionate Investigational New Drug Program: An examination of benefits and adverse effects of legal clinical cannabis. Journal of Cannabis Therapeutics 2002;2:3-57.
6.Klein TW, Newton C, Friedman H. Cannabinoid receptors and immunity. Immunol Today 1998;19:373-381.
7.Sanchez C, Velasco G, Guzman M. Metabolic stimulation of mouse spleen lymphocytes by low doses of delta 9-tetrahydrocannabinol. Life Sci 1997;60:1709-1717.
8.Berdyshev EV, Boichot E, Germain N, Allain N, Anger JP, Lagente V. Influence of fatty acid ethanolamides and delta9-tetrahydrocannabinol on cytokine and arachidonate release by mononuclear cells. Eur J Pharmacol 1997;330:231-240.
9.Lyman WD, Sonett JR, Brosnan CF, Elkin R, Bornstein MB. Delta 9- tetrahydrocannabinol: a novel treatment for experimental autoimmune encephalomyelitis. J Neuroimmunol. 1989:23:73-81.
10.Wirguin I, Mechoulam R, Breuer A, Schezen E, Weidenfeld J, Brenner T. Suppression of experimental autoimmune encephalomyelitis by cannabinoids. Immunopharmacology 1994:28:209-214.

Safety, tolerability, and efficacy of orally administered cannabinoids in MS 23 October 2002

Ethan B Russo
Montana Neurobehavioral Specialists Missoula MT
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Re: Safety, tolerability, and efficacy of orally administered cannabinoids in MS

erusso{at}blackfoot.net Ethan B Russo

Numerous methodological issues require discussion with reference to the recent article on cannabis in MS [1], in which a poorly characterized cannabis extract was studied in 16 MS patients with spasticity, few benefited and significant side effects were reported. This contrasts dramatically with a previous double-blind study in nine subjects employing THC 5-10 mg that demonstrated improvement in spasticity measures to the p<0.01 level [2]. In fact, the material employed in the current study contained daily doses of up to 5 mg tetrahydrocannabinol (THC) with 2 mg cannabidiol (CBD), and was likely inadequate to produce benefit. No dose titration was pursued.
A subsequent study in Switzerland employing a larger patient cohort with the identical extract in higher doses has provided improved results [3]: 57 patients in a prospective, randomized, double-blind, placebo- controlled crossover study used 15 mg THC with 6 mg CBD daily in three divided doses, demonstrating significant reductions in spasms (p<0.05), and improvement in mobility, with no quantitative differences in adverse events compared to placebo. Results from a much larger study in the UK employing the same extract are pending.
Available results with another cannabis-based medicine extract (CBME) trial in the UK are even more encouraging. [4] Large scale Phase III trials are underway in MS patients employing sublingual application of whole plant extracts containing equal proportions of THC and CBD. This oro -mucosal route of administration provides a more predictable onset of action and an improved ability for patients to titrate their own required dosages, which in the pilot study [4] averaged 22.5 mg THC and CBD daily in divided doses, most often within the range of 7.5-40 mg of THC daily. Results to date support significant improvements in pain, spasticity and muscular spasm attacks in MS [4], bladder-related symptoms, and sleep. Adverse events were characterized as predictable and well tolerated, and lowest in the 1:1 THC:CBD mixture, underlining the well-known tendency of CBD to counter THC-associated side effects.
These results mirror those seen in MS patients employing cannabis in medical practice. My personal experience and correspondence with approximately 100 MS patients would indicate failure of tolerability or symptomatic improvement with oral THC as Marinol®, but marked benefit with oral, smoked or vaporized cannabis on spasticity, hyper-reflexia, appetite, sleep, neuropathic pain, and mood, but not ataxia.
We should not ignore the fact that experimental data not only documents the benefit of cannabinoids in spasticity and tremor, but also immunomodulatory aspects of MS in a chronic relapsing experimental allergic encephalomyelitis (CREAE) model [5], supporting the finding of an improved MRI result in one clinical cannabis patient with chronic MS not taking interferon treatments. [6]
Overall, the future of clinical cannabis as a useful tool in the pharmacopoeia of MS treatments appears much brighter than would be evident from the preliminary results from Killestein et al.
References:
1.Killestein J, et al. Safety, tolerability, and efficacy of orally administered cannabinoids in MS. Neurology 2002;58:1404-1407.
2.Petro DJ, Ellenberger C. Treatment of human spasticity with delta9- tetrahydrocannabinol. Journal of Clinical Pharmacology 1981;21:413S-416S.
3.Vaney C, Jobin P, Tschopp F, Heinzel M, Schnelle M. Efficacy, safety and tolerability of an orally administered cannabis extract in the treatment of spasticity in patients with multiple sclerosis. In: Symposium on the Cannabinoids; July 13, 2002; Asilomar Conference Center, Pacific Grove, CA: International Cannabinoid Research Society, 2002:57.
4.Robson PJ, Wade DT, Makela PM, House H. Cannabis medicinal extracts (CME), including cannabidiol, alleviated neurogenic symptoms in patients with multiple sclerosis and spinal cord injury. In: Symposium on the Cannabinoids; July 13, 2002; Asilomar Conference Center, Pacific Grove, CA: International Cannabinoid Research Society, 2002:56.
5.Baker D, Pryce G, Croxford JL, Brown P, Pertwee RG, Huffman JW, et al. Cannabinoids control spasticity and tremor in a multiple sclerosis model. Nature 2000;404:84-87.
6.Russo EB, Mathre ML, Byrne A, Velin R, Bach PJ, Sanchez-Ramos J, et al. Chronic cannabis use in the Compassionate Investigational New Drug Program: An examination of benefits and adverse effects of legal clinical cannabis. Journal of Cannabis Therapeutics 2002;2:3-57.