Jacob Bell
New Member
Sumner H. Burstein
Department of Biochemistry & Molecular Pharmacology, University of Massachusetts Medical School, Worcester, MA 01655, USA
Abstract
This is a comment on a report by Vann et al. (2006) on the pharmacological effects of ajulemic acid compared to CB1 receptor agonists. Their data, which were obtained using animal models, suggested an unfavorable therapeutic index as an analgesic. However, the available clinical data do not support such conclusions and indicate a deficiency in some of their models.
Literally hundreds of cannabinoid analogs have been synthesized over the years with the goal of separating psychotropic activity from therapeutic properties. Only a handful have advanced beyond the preclinical stage of which ajulemic acid (AJA) is one example [1]. AJA is currently undergoing development as a possible treatment for interstitial cystitis, a chronic bladder inflammatory condition for which no effective treat¬ment is known. A recurring question concerning AJA is whether its preclinical literature can predict its pos¬sible psychotropic activity in humans. The numerous reports from a number of independent laboratories have yielded occasionally conflicting conclusions [11]. The modest affinity of AJA for the CB 1 receptor appears to be the inspiration for conclusions predicting can-nabimimetic actions in humans. However, the available clinical data thus far does not support such conclusions [6,9].
Vann et al. (2006) in a recent paper, have attempted to shed light on this long-standing debate concerning the therapeutic index of AJA [10]. In their report they refer to the ratio of an analgesic effect to the response in a drug discrimination assay where they found no separa¬tion of activities. The authors claim that their findings predict certain adverse effects for AJA when given to human subjects. Thus far, in both Phase 1 and Phase 2 trials [6], these effects have not been seen suggesting limitations for the models used by Vann et al. While the authors acknowledge this problem for the tetrad assay, they feel that the drug discrimination test is highly accurate.
An example of a divergent finding is evidenced in a recent study by Dyson et al. (2005) [5]. Using a differ¬ent set of models, they obtained a therapeutic index of 5-10 in comparing psychotropic action with analgesia in contrast to the conclusion reached by Vann et al. In a recent review, Pacher et al. (2006) stated that "Pre-clinical studies (Burstein et al., 1998; Burstein, 2000; Burstein and Zurier, 2004; Dyson et al., 2005; Mitchell et al., 2005) and a recent clinical trial of 24 patients with neuropathic pain of varying etiologies demon¬strated, that ajulemic acid, a major metabolite of THC with CB 1 agonist activity, was effective in reducing pain without causing cannabinoid-like CNS side ef¬fects, the first evidence for the separability of the psy¬chotropic and analgesic effects of a THC analog in humans (Karst et al., 2003)" [8].
Moreover, it should be noted that several other thera-peutic targets for AJA have been suggested, namely, cancer, cystitis, inflammation, multiple sclerosis and disorders of lipid metabolism that have been described in a recent review on AJA by one of the authors of the Vann et al. paper [11]. It is very likely that the thera¬peutic indices for each of these targets may be different from that reported by Vann et al. in their models. Thus, caution is advised in generalizing the drug discrimina¬tion vs. analgesia data to other therapeutic targets.
In conclusion, while this comprehensive study by Vann et al. will certainly add fuel to the debate, it should not be taken as the final word. Only further studies in hu¬mans at therapeutic doses will provide some answers.
References
1. Burstein S. Ajulemic acid (IP-751): synthesis, proof of principle, toxicity studies, and clinical trials. Aaps J 2005;7:E143-148.
2. Burstein S, Zurier RB. Pain reduction and lack of psychotropic effects with ajulemic acid: comment on the article by Sumariwalla et al. Arthritis Rheum 2004;50:4078-4079; author reply 4079-4080.
3. Burstein SH. Ajulemic acid (CT3): a potent ana-log of the acid metabolites of THC. Curr Pharm Des 2000;6:1339-1345.
4. Burstein SH, Friderichs E, Kogel B, Schneider J, Selve N. Analgesic effects of 1',1' dimethylhep-tyl-delta8-THC-1 1-oic acid (CT3) in mice. Life Sci 1998;63:161-168.
5. Dyson A, Peacock M, Chen A, Courade JP, Ya-qoob M, Groarke A, Brain C, Loong Y, Fox A. Antihyperalgesic properties of the cannabinoid CT-3 in chronic neuropathic and inflammatory pain states in the rat. Pain 2005;1 16:129-137.
6. Karst M, Salim K, Burstein S, Conrad I, Hoy L, Schneider U. Analgesic effect of the synthetic cannabinoid CT-3 on chronic neuropathic pain: a randomized controlled trial. Jama 2003;290: 1757-1762.
7. Mitchell VA, Aslan S, Safaei R, Vaughan CW. Effect of the cannabinoid ajulemic acid on rat models of neuropathic and inflammatory pain. Neurosci Lett 2005;382:231-235.
8. Pacher P, Batkai S, Kunos G. The endocannabi-noid system as an emerging target of pharma-cotherapy. Pharmacol Rev 2006;58:389-462.
9. Salim K, Schneider U, Burstein S, Hoy L, Karst M. Pain measurements and side effect profile of the novel cannabinoid ajulemic acid. Neurophar-macology 2005;48: 1164-1171.
10. Vann RE, Cook CD, Martin BR, Wiley JL. Can-nabimimetic Properties of Ajulemic Acid. J Pharmacol Exp Ther 2006 Nov 14; [Epub ahead of print]
11. Wiley JL. Ajulemic acid. IDrugs 2005;8:1002-1011.
Source: In humans, ajulemic acid has a more favorable
side-effect profile than THC for the treatment of
chronic neuropathic pain
Department of Biochemistry & Molecular Pharmacology, University of Massachusetts Medical School, Worcester, MA 01655, USA
Abstract
This is a comment on a report by Vann et al. (2006) on the pharmacological effects of ajulemic acid compared to CB1 receptor agonists. Their data, which were obtained using animal models, suggested an unfavorable therapeutic index as an analgesic. However, the available clinical data do not support such conclusions and indicate a deficiency in some of their models.
Literally hundreds of cannabinoid analogs have been synthesized over the years with the goal of separating psychotropic activity from therapeutic properties. Only a handful have advanced beyond the preclinical stage of which ajulemic acid (AJA) is one example [1]. AJA is currently undergoing development as a possible treatment for interstitial cystitis, a chronic bladder inflammatory condition for which no effective treat¬ment is known. A recurring question concerning AJA is whether its preclinical literature can predict its pos¬sible psychotropic activity in humans. The numerous reports from a number of independent laboratories have yielded occasionally conflicting conclusions [11]. The modest affinity of AJA for the CB 1 receptor appears to be the inspiration for conclusions predicting can-nabimimetic actions in humans. However, the available clinical data thus far does not support such conclusions [6,9].
Vann et al. (2006) in a recent paper, have attempted to shed light on this long-standing debate concerning the therapeutic index of AJA [10]. In their report they refer to the ratio of an analgesic effect to the response in a drug discrimination assay where they found no separa¬tion of activities. The authors claim that their findings predict certain adverse effects for AJA when given to human subjects. Thus far, in both Phase 1 and Phase 2 trials [6], these effects have not been seen suggesting limitations for the models used by Vann et al. While the authors acknowledge this problem for the tetrad assay, they feel that the drug discrimination test is highly accurate.
An example of a divergent finding is evidenced in a recent study by Dyson et al. (2005) [5]. Using a differ¬ent set of models, they obtained a therapeutic index of 5-10 in comparing psychotropic action with analgesia in contrast to the conclusion reached by Vann et al. In a recent review, Pacher et al. (2006) stated that "Pre-clinical studies (Burstein et al., 1998; Burstein, 2000; Burstein and Zurier, 2004; Dyson et al., 2005; Mitchell et al., 2005) and a recent clinical trial of 24 patients with neuropathic pain of varying etiologies demon¬strated, that ajulemic acid, a major metabolite of THC with CB 1 agonist activity, was effective in reducing pain without causing cannabinoid-like CNS side ef¬fects, the first evidence for the separability of the psy¬chotropic and analgesic effects of a THC analog in humans (Karst et al., 2003)" [8].
Moreover, it should be noted that several other thera-peutic targets for AJA have been suggested, namely, cancer, cystitis, inflammation, multiple sclerosis and disorders of lipid metabolism that have been described in a recent review on AJA by one of the authors of the Vann et al. paper [11]. It is very likely that the thera¬peutic indices for each of these targets may be different from that reported by Vann et al. in their models. Thus, caution is advised in generalizing the drug discrimina¬tion vs. analgesia data to other therapeutic targets.
In conclusion, while this comprehensive study by Vann et al. will certainly add fuel to the debate, it should not be taken as the final word. Only further studies in hu¬mans at therapeutic doses will provide some answers.
References
1. Burstein S. Ajulemic acid (IP-751): synthesis, proof of principle, toxicity studies, and clinical trials. Aaps J 2005;7:E143-148.
2. Burstein S, Zurier RB. Pain reduction and lack of psychotropic effects with ajulemic acid: comment on the article by Sumariwalla et al. Arthritis Rheum 2004;50:4078-4079; author reply 4079-4080.
3. Burstein SH. Ajulemic acid (CT3): a potent ana-log of the acid metabolites of THC. Curr Pharm Des 2000;6:1339-1345.
4. Burstein SH, Friderichs E, Kogel B, Schneider J, Selve N. Analgesic effects of 1',1' dimethylhep-tyl-delta8-THC-1 1-oic acid (CT3) in mice. Life Sci 1998;63:161-168.
5. Dyson A, Peacock M, Chen A, Courade JP, Ya-qoob M, Groarke A, Brain C, Loong Y, Fox A. Antihyperalgesic properties of the cannabinoid CT-3 in chronic neuropathic and inflammatory pain states in the rat. Pain 2005;1 16:129-137.
6. Karst M, Salim K, Burstein S, Conrad I, Hoy L, Schneider U. Analgesic effect of the synthetic cannabinoid CT-3 on chronic neuropathic pain: a randomized controlled trial. Jama 2003;290: 1757-1762.
7. Mitchell VA, Aslan S, Safaei R, Vaughan CW. Effect of the cannabinoid ajulemic acid on rat models of neuropathic and inflammatory pain. Neurosci Lett 2005;382:231-235.
8. Pacher P, Batkai S, Kunos G. The endocannabi-noid system as an emerging target of pharma-cotherapy. Pharmacol Rev 2006;58:389-462.
9. Salim K, Schneider U, Burstein S, Hoy L, Karst M. Pain measurements and side effect profile of the novel cannabinoid ajulemic acid. Neurophar-macology 2005;48: 1164-1171.
10. Vann RE, Cook CD, Martin BR, Wiley JL. Can-nabimimetic Properties of Ajulemic Acid. J Pharmacol Exp Ther 2006 Nov 14; [Epub ahead of print]
11. Wiley JL. Ajulemic acid. IDrugs 2005;8:1002-1011.
Source: In humans, ajulemic acid has a more favorable
side-effect profile than THC for the treatment of
chronic neuropathic pain
