Scientific Evaluation

Cannabis is a complex alkaloid mixture of more than 400 compounds derived from the Cannabis sativa plant (1–4). Sixty different compounds have been described with activity on the cannabinergic system, and these are referred to as cannabinoids (2,3). The most abundant cannabinoids are delta-9 tetrahydrocannabinol (D9THC), cannabidiol, and cannabinol (3). D9THC is the main psychotropically active cannabinoid and was isolated in 1964 (3).

Two main cannabis receptors have been identified so far, the CB1 and the CB2 (Table 1) (3,5–10). CB1 receptors are found throughout the central nervous system, present in greatest concentration around the hippocampus, cortex, olfactory areas, basal ganglia, cerebellum, and the spinal cord (3); CB2 receptors are located peripherally and are linked closely with cells in the immune system, predominantly in the spleen and macrophages (3,9,11–13). Both receptors are members of the G protein coupled family and, like the opioid receptors, possess seven transmembrane domains and exert their action by modulating second messenger activity (3,5–7,9,10). Both CB1 and CB2 receptors modulate adenylyl cyclase activity, but in addition, CB1 is linked to Ca2+ channel function (3,5–7).

Anandamide (N-arachidonoylethanolamide) (derived from the Sanskrit word for bliss), 2-arachidonylglycerol, and palmitoylethanolamide are endogenous cannabinoid agonists, the latter thought to be the agonist for the CB2 system (1,3,10,14,15). Anandamide, first described in 1992, has been shown to produce most of the effects seen with the binding of D9THC to the cannabinoid receptors (16,17). Anandamide is a less potent agonist with a shorter half-life than that of D9THC (3,16).

A series of synthetic compounds has been developed that act on the cannabinoid system, for example, WIN 55212-2 and CP 55940. In addition, specific antagonists to both the CB1 and CB2 receptors have been developed (Table 1) (3).

The role of the endogenous cannabinoid system is not fully understood, but evidence suggests that it is involved with analgesia, cognition, memory, locomotor activity, appetite, vomiting, intestinal regulation, bronchodilation, uterine tone, intraocular pressure, inflammation, and immune control (3,7,18). Experiments in the animal model using the cannabinoid antagonist SR141716A have provided evidence that this system, or at least parts of it such as those responsible for analgesia, are tonically active, as addition of the antagonist alone produces abnormal nociceptive behavior (3,19,20).

Because of the massive first pass metabolism of cannabinoids, the oral route of administration should be avoided. After oral intake, D9THC undergoes first pass metabolism such that only 10%–20% of the ingested dose reaches the systemic circulation unchanged. This metabolism produces large amounts of active metabolite, 11 OH-delta-9-tetrahydrocannabinol, which is as active as the parent compound and has a prolonged half-life (4). The peak clinical action after oral administration occurs 1–2 h later, and the duration of action is approximately 4–6 h. In contrast, after administration via the lungs, the onset of action is within seconds, and it is, therefore, possible to titrate the levels of D9THC in the systemic circulation against the desired effect. A “high” is experienced with serum concentrations around 3 ng/mL (4), and this can be produced by as little as 2–3 mg of available D9THC (1). In social use, the average “joint” of cannabis contains 0.5–1.0 g of cannabis (1).

The use of cannabis is associated with a pattern of acute events. A feeling of euphoria and relaxation usually occurs, although in naive users, this may be replaced by an intense feeling of panic or anxiety. Acute intoxication also produces perceptual alterations, distortion of time, intensification of normal sensory experiences, forgetfulness, decreased attention span, poor motor skills, increased appetite, decreased reaction times, and impairment of skilled activities (1,3,21). Acute physiological changes after intoxication with cannabis include tachycardia and postural hypotension, but the mechanism of these changes is not clear (22,23). It has been demonstrated that anandamide causes loss of tone in resistance vessels, and several mechanisms have been proposed for this effect, including release of nitric oxide, endothelium-dependent hyperpolarization, activation of potassium channels, or negative effects on calcium flux (22). The most recent suggestion is that the relaxation is caused by the activation of perivascular vanilloid receptors which, in turn, produce a release of calcitonin gene-related peptide, which has direct vasodilator properties (24).

The overall toxicity of cannabis is relatively low probably because of its short duration of action (1). Problems associated with acute use derive from its effects on the central nervous system, particularly those related to alteration in perception, forgetfulness, impaired psychomotor skills, and decreased reaction times (1,3,21). Acute intoxication may cause severe hypotension, but the greatest concern relates to the development of long-term toxicity and creation of physical dependence. Cannabis is often mixed with tobacco to make it burn more efficiently, and there is as much tar and carcinogenic material present in cannabis smoke as there is in tobacco smoke (1,25). Thus, not surprisingly, there is evidence to suggest that smoking cannabis for many years increases the incidence of chronic obstructive lung disease and carcinoma of the lung and oropharynx (1,25). It has also been suggested that persistent use of cannabis is associated with decreased reproductive potential, and it has been shown that prolonged use causes decreased production of testosterone (1).

Cannabis has been used therapeutically for a wide range of conditions: acute and chronic pain, muscle spasticity associated with trauma and multiple sclerosis, glaucoma, asthma, migraine, inflammatory disease, and immune function (2,3,7,9,18,26). Pure D9THC and nabilone have licenses for the treatment of appetite stimulation in terminal disease and the treatment of chemotherapy-induced nausea and vomiting, respectively. Unfortunately, much of the evidence for beneficial therapeutic effects is based on anecdotal evidence (18,27,28). While there are a large number of case reports and letters testifying to the benefits of cannabis, there is scarce research-based evidence. Noyes et al. (29,30), in the mid 1970s, showed that D9THC had analgesic potency similar to that of codeine, but these studies were, however, based on small numbers of patients and did not use whole cannabis extract.

Much of the current anecdotal evidence for the therapeutic use of cannabis has been obtained from multiple sclerosis sufferers who appear to derive a great deal of benefit from smoking whole cannabis as a relief from the pain of muscle spasticity. Some patients given oral cannabinoids have reported less efficacy, possibly because of the much lower oral bioavailability and relatively delayed onset of action (18).

Cannabis has been used throughout the world for thousands of years and by all types of social classes, including Queen Victoria in the 1800s (2,3,5,6,18). It is now the most commonly used illicit drug in the world, possibly because it is so readily available and relatively inexpensive to purchase (1,2,21). Examination of trends in social use suggest that it is used predominantly by the young, and many cease regular usage in the 3rd and 4th decades (1). A recent survey in the United Kingdom (UK) revealed that approximately 30% of all students taking school-leaving examinations have tried cannabis, as had 50% of all Oxford University undergraduates (1,2). In one year, it was associated with more than 80% of all drug seizures in the UK (2). Attempts to decriminalize the use of cannabis in both the UK and the United States (US) have so far been unsuccessful because of concern that its use might lead to an increase in road traffic accidents (1) or progression to opioid addiction. There is also concern regarding long-term physical dependence, as it is thought that more than 10% of those trying cannabis progress to become users on a daily basis and another 20%–30% users on a weekly basis (1). It is likely that the power of addiction is similar to that of alcohol rather than opioid-based compounds or nicotine (1). While the degree of physical dependence on cannabis is clearly low, there is emerging human and animal evidence to suggest that behavioral changes occur on cessation of the use of cannabis, although these are mild (1,31).

For many years, in both the US and the UK, the whole extract of cannabis was classified as a Schedule I drug (Table 2). D9THC has recently been changed to a Schedule III drug in the US, with a license for use as an appetite stimulant in terminal disease. In the UK, the whole extract of cannabis has been reclassified as a Schedule II compound in response to findings of the House of Lords Select Committee on Science and Technology (18). This implies that it is now considered to have some medical indications, and it will facilitate the performance of carefully controlled clinical trials.

Cannabinoids have considerable potential in the treatment of pain. Several animal studies investigating the effect of spinally administered cannabinoids in the modulation of pain and antinociception have suggested potential clinical use (32–40). For example, Martin et al. (32) demonstrated in the rat hind paw that chemically induced allodynia could be reversed by small-dose intrathecal administration of WIN 55,212-2 10 μg without altering the withdraw threshold to von Frey filaments in the contralateral control paw.

Similar to the opioids, the potency of cannabinoid agonists is linked to lipophilicity (36). Cannabinoids are highly lipid soluble, and as we know that the CB1 receptor is found in abundance within the spinal cord (3), there are sound theoretical reasons for suggesting that the intrathecal or epidural administration of cannabinoids may produce spinal cord analgesia without effects on cerebral receptors that are associated with the psychotropic effects (3). The cannabinoid system enhances the analgesia produced by spinal opioids and may well modulate the action of endogenous opioids such a dynorphin B (33,35,36,40–42). Thus coadministration of these two compounds may produce synergistic effects (40), reducing the total amount of each that needs to be administered and thus reducing the incidence of side effects caused by systemic absorption or rostral spread within the central nervous system. It is clear, therefore, that there is sufficient anecdotal clinical data and sound experimental data to encourage proper scientific evaluation of the potential therapeutic benefit of cannabis. Although it undoubtedly possesses the potential for psychic and physical dependency, these are considerably less than the undesirable effects of opioids. The time is now appropriate, therefore, for proper evaluation of this ancient remedy.


1. Hall W, Solowij N. Adverse effects of cannabis. Lancet 1998; 352:1611–6.


2. Robson P. Cannabis. Arch Dis Child 1997; 77:164–6.


3. Hirst RA, Lambert DG, Notcutt WG. Pharmacology and potential therapeutic uses of cannabis. Br J Anaesth 1998; 81:77–84.


4. Agurell S, Halldin M, Lindgren JE, et al. Pharmacokinetics and metabolism of delta-9-tetrahydrocannabinol and other cannabinoids with emphasis on man. Pharmacol Rev 1986; 38;21–43.


5. Felder CC, Glass M. Cannabinoid receptors and their endogenous agonists. Annul Rev Pharmacol Toxicol 1998; 38:179–200.


6. Axelrod J, Felder CC. Cannabinoid receptors and their endogenous agonist, anandamide. Neurochem Res 1998; 23:575–81.


7. Petitet F, Imperato A. The therapeutic applications of cannabinoid agonists and antagonists. Emerg Drugs 1998; 3:39–53.


8. Barth F. Cannabinoid receptor agonists and antagonists. Expert Opinion Ther Patents 1998; 8:301–13.


9. Pertwee RG. Cannabis and cannabinoids: pharmacology and rationale for clinical use. Pharm Sci 1997; 3:539–45.


10. Pertwee RG. Pharmacology of cannabinoid CB1 and CB2 receptors. Pharmacol Ther 1997; 74:129–80.


11. Newton C, Klein T, Friedman H. The role of macrophages in THC-induced alteration of the cytokine network. Adv Exp Med Biol 1998; 437:207–14.


12. Cabral GA, Pettit DAD. Drugs and immunity: cannabinoids and their role in decreased resistance to infectious disease. J Neuroimmunol 1998; 83:116–23.


13. Klein TW, Newton C, Friedman H. Cannabinoid receptors and the cytokine network. Adv Exp Med Biol 1998; 437:215–22.


14. Hillard CJ, Campbell WB. Biochemistry and pharmacology of arachidonylethanolamide, a putative endogenous cannabinoid. J Lipid Res 1997; 38:2383–98.


15. Mechoulam R, Fride E, Di Marzo V. Endocannabinoids. Eur J Pharmacol 1998; 359:1–18.


16. Wiley JL, Ryan WJ, Razdan RK, Martin BR. Evaluation of cannabimimetic effects of structural analogs of anandamide in rats. Eur J Pharmacol 1998; 355:113–8.


17. McGregor IS, Arnold JC, Weber MF, et al. A comparison of delta9-THC and anandamide induced c-fos expression in the rat forebrain. Brain Res 1998; 802:19–26.


18. House of Lords Select Committee on Science and Technology. Cannabis: the scientific and medical evidence. London: The Stationery Office, 1998.


19. Meng ID, Manning BH, Martin MJ, Fields HL. An analgesia circuit activated by cannabinoids. Nature 1998; 395:381–3.


20. Gessa GL, Casu MA, Carta G, Mascia MS. Cannabinoids decrease acetylcholine release in the medial-prefrontal cortex and hippocampus, reversal by SR 141716A. Eur J Pharmacol 1998; 355:119–24.


21. Pelissier AL, Leonetti G, Villani P, et al. Cannabis: review of toxicokinetics and biomonitoring methodology. Therapie 1997; 52:213–8.


22. Randall MD, Kendall DA. Endocannabinoids: a new class of vasoactive substances. Trends Pharmacol Sci 1998; 19:55–8.


23. Lake KD, Comptom DR, Varga K, et al. Cannabinoid-induced hypotension and bradycardia in rats is mediated by CB1-like cannabinoid receptors. J Pharmacol Exp Ther 1997; 281:1030–7.


24. Zygmunt PM, Peterson J, Anderson DA, et al. Vanilloid receptors on sensory nerves mediate the vasodilator action of anandamide. Nature 1999; 400:452–7.


25. Van Hoozen BE, Cross CE. Marijuana: respiratory tract effects. Clin Rev Allergy Immunol 1997; 15:243–69.


26. Russo E. Cannabis for migraine treatment: the once and future prescription–An historical and scientific review. Pain 1998; 76:3–8.


27. Marmor JB. Medical marijuana. West J Med 1998; 168:540–3.


28. Voth EA, Schwartz RH. Medicinal applications of delta-9-tetrahydrocannabinol and marijuana. Ann Intern Med 1997; 126:791–8.


29. Noyes R Jr, Brunk SF, Avery DAH, Canter AC. The analgesic properties of delta-9-tetrahydrocannabinol and codeine. Clin Pharmacol Ther 1975; 18:84–9.


30. Noyes R Jr, Brunk SF, Baram DA, Canter A. Analgesic effect of delta-9-tetrahydrocannabinol. J Clin Pharmacol 1975; 15:139–43.


31. Lichtman AH, Wiley JL, LaVecchia KL, et al. Effects of SR 141716A after acute or chronic cannabinoid administration in dogs. Eur J Pharmacol 1998; 357:139–48.


32. Martin WJ, Loo CM, Basbaum AI. Spinal cannabinoids are anti-allodynic in rats with persistent inflammation. Pain 1999; 82:199–205.


33. Pugh G Jr, Mason DJ Jr, Combs V, Welch SP. Involvement of Dynorphin B in the antinociceptive effects of the cannabinoid CP55,940 in the spinal cord. J Pharmacol Exp Ther 1997; 281:730–7.


34. Richardson JD, Aanonsen L, Hargreaves KM. SR 141716A, a cannabinoid receptor antagonist, produces hyperalgesia in untreated mice. Eur J Pharmacol 1997; 319:R3–4.


35. Welch SP, Thomas C, Patrick GS. Modulation of cannabinoid-induced antinociception after intracerebroventricular versus intrathecal administration to mice: possible mechanisms for interaction with morphine. J Pharmacol Exp Ther 1995; 272:310–21.


36. Lichtman AH, Smith PB, Martin BR. The antinociceptive effects of intrathecally administered cannabinoids are influenced by lipophilicity. Pain 1992; 51:19–26.


37. Smith PB, Martin BR. Spinal mechanisms of delta-9-tetrahydro- cannabinol-induced analgesia. Brain Res 1992; 578:8–12.


38. Hohmann AG, Tsou K, Walker JM. Cannabinoid modulation of wide dynamic range neurons in the lumbar dorsal horn of the rat by spinally administered WIN 55,212-2. Neurosci Lett 1998; 257:119–22.


39. Richardson JD, Aanonsen L, Hargreaves KM. Antihyperalgesic effects of spinal cannabinoids. Eur J Pharmacol 1998; 345:145–53.


40. Pugh G Jr, Smith PB, Dombrowski DS, Welch SP. The role of endogenous opioids in enhancing the antinociception produced by the combination of Delta9-tetrahydrocannabinol and morphine in the spinal cord. J Pharmacol Exp Ther 1996; 279:608–16.


41. Smith FL, Fujimori K, Lowe J, Welch SP. Characterization of Delta9-tetrahydrocannabinol and anandamide antinociception in nonarthritic and arthritic rats. Pharmacol Biochem Behav 1998; 60:183–91.


42. Martin BR, Lichtman AH. Cannabinoid transmission and pain perception. Neurobiol Dis 1998; 5:447–61.


– Anesthesia & Analgesia