Pain relief (analgesia) or decreased pain sensitivity (antinociception)  are among the most commonly-cited therapeutic effects of smoking cannabis.  Although cannabis products have been used for thousands of years to treat pain and other conditions, it was not until the discovery of the ‘cannabis receptor’ in the late 1980s that modern medicine started to take cannabis seriously.

The past two decades have seen an explosion of research into cannabinoid metabolism, with at least two types of receptors (CB1 in the brain and spinal cord, and CB2 in the peripheral tissues) identified, and a number of endogenous ligands (endocannabinoids), the best known of which is anandamide. Pharmaceutical research is developing apace, with discovery of a number of substances  (synthetic cannabinoids) which both bind to the receptors producing an effect (agonists) and block receptors preventing any effect (antagonists), as well as enzymes which break down or modulate the activity of endocannabinoids.

Research has moved on from asking ‘whether’ – i.e. do cannabinoids produce analgesia – there is now overwhelming evidence of this, through the ‘how’ – via receptor-mediated regulation of pain thresholds in the peripheral and spinal tissues, towards the question of how to produce analgesia  more effectively, and the further questions arising from these discoveries.  The ‘Holy Grail’ of cannabinoid research is to develop a drug which specifically targets  the pain mechanisms, but does not produce the psychotropic effects (the ‘high’) from THC.  Discovery of the endocannabinoid system has revolutionised pain research, and led to greater understanding of brain and spinal function.

One of the first modern reviews of the use of cannabis as an analgesic (pain relief) agent was undertaken by Professor Rafael Mechoulam .  A number of researchers using ∆9 THC injections in mice, with dosages of 5-80 mg/kg, have observed significant antinociceptive (pain relieving) activity against thermal, mechanical, electrical and chemical stimuli.  In some cases the effect of cannabinoids was stronger than with opioid preparations, and other researchers noted a flat response curve (i.e. once the effective dose level is reached, further dose increases cause no additional effect).  Other researchers have found cannabis to potentiate the analgesic effects of opiates .  Significant analgesia has been produced in animals with injections into the brain stem and spinal cord.   

The dosages required to produce detectable pain relief in animal models were substantially in excess of dosages encountered in normal social use (typically 0.1-1.0 mg/kg).  The effective dose of THC in the early mouse studies (approx. 5mg/kg) would be the equivalent of an average 70kg man consuming 350mg THC, or smoking 10 grams of cannabis with a potency of 3.5%.  However in most clinical trials of cannabis-extracts, dosages have generally been much lower than would be encountered in typical social use.

The following sections provide detailed reviews and citations from original scientific papers, including anecdotal evidence, animal and receptor studies, human studies including clinical trials, and learned reviews.  Much of the language, particularly within quotations, is technical and intended for a specialist reader with a background in biological sciences.  Non-specialist readers may wish to skip to the summary (section 6.9).

Many new leads for medical research have arisen from reports of cannabis users as to how the drug has affected their condition.  Such reports must be treated with caution as the effects described might be due to placebo-effects or increased general feelings of well-being.  However the results of surveys, particularly where a number of patients report similar symptoms, provide an early warning of potential effects and side-effects of cannabis and cannabinoids.

In Judge Young’s report  numerous cases histories were described outlining the use of cannabis to reduce muscle tension (spasticity) in individuals with multiple sclerosis or spinal injury.  The potential efficacy of cannabis in treatment of MS is increasingly accepted by patients and medical practitioners alike.  Gill & Williams , in a preliminary study of attitudes to cannabis-based medicine among 67 chronic pain patients in the UK, found “Fifty-two percent of patients were doubtful about taking cannabinoids: unwillingness was strongly associated with specific concerns about side effects, addiction, tolerance, and losing control but not with general beliefs about medication or personal or medical variables other than age”  In a similar German study of 128 patients, Schnelle et al  found “The most frequently mentioned indications for medicinal cannabis use were depression (12.0%), multiple sclerosis (10.8%), HIV-infection (9.0%), migraine (6.6%), asthma (6.0%), back pain (5.4%), hepatitis C (4. 8%), sleeping disorders (4.8%), epilepsy (3.6%), spasticity (3.6%), headache (3.6%), alcoholism (3.0%), glaucoma (3.0%), nausea (3.0%), disk prolapse (2.4%), and spinal cord injury (2.4%)...  72.2% of the patients stated the symptoms of their illness to have 'much improved' after cannabis ingestion, 23.4% stated to have 'slightly improved', 4.8% experienced 'no change' and 1.6% described that their symptoms got 'worse'... 60.8% stated (themselves) to be 'very satisfied', 24.0% 'satisfied', 11.2% 'partly satisfied' and 4.0% were 'not satisfied'. 70.8% experienced no side effects, 26.4% described 'moderate' and 3.3% 'strong' side effects.”

A study of 50 medicinal- cannabis using patients in Canada by Ogborne et al  found “They reported using cannabis for a variety of conditions including HIV-AIDS-related problems, chronic pain, depression, anxiety, menstrual cramps, migraine, narcotic addiction as well as everyday aches, pains, stresses and sleeping difficulties.”  Fishbain et al  found a significant minority of chronic pain patients in the USA used cannabis but were unwilling to admit this to their doctors or researchers. Mechoulam  noted “Illegally... smoking marijuana... is used for ameliorating the symptoms of multiple sclerosis, against pain, and in a variety of other diseases.” Ware et al  studied 15 patients who claimed to use herbal cannabis for therapeutic reasons, noting “Twelve patients reported improvement in pain and mood, while 11 reported improvement in sleep. Eight patients reported a 'high'; six denied a 'high'. Tolerance to cannabis was not reported” and concluded “Small doses of smoked cannabis may improve pain, mood and sleep in some patients with chronic pain.”  Following a larger Canadian survey, Ware et al  concluded “cannabis use is prevalent among the chronic non-cancer pain population, for a wide range of symptoms, with considerable variability in the amounts used.”  Page et al  reported a survey of MS patients in Western Canada “Symptoms reported to be ameliorated included anxiety/depression, spasticity and chronic pain.”.  Clark et al  found “Medical cannabis use was associated with male gender, tobacco use, and recreational cannabis use. The symptoms reported by medical cannabis users to be most effectively relieved were stress, sleep, mood, stiffness/spasm, and pain” Swift et al , found among Australian medical users “Long term and regular medical cannabis use was frequently reported for multiple medical conditions including chronic pain (57%), depression (56%), arthritis (35%), persistent nausea (27%) and weight loss (26%). Cannabis was perceived to provide "great relief" overall (86%), and substantial relief of specific symptoms such as pain, nausea and insomnia. It was also typically perceived as superior to other medications in terms of undesirable effects, and the extent of relief provided.” In a survey of Amyotrophic Lateral Sclerosis (ALS) patients using cannabis Amtmann et al  reported “cannabis may be moderately effective at reducing symptoms of appetite loss, depression, pain, spasticity, and drooling. Cannabis was reported ineffective in reducing difficulties with speech and swallowing, and sexual dysfunction. The longest relief was reported for depression (approximately two to three hours).”

A survey of patients using smoked cannabis in the Netherlands by Gorter et al  found “A majority (64.1%) of patients reported a good or excellent effect on their symptoms. Of these patients, approximately 44% used cannabis for >/=5 months. Indications were neurologic disorders, pain, musculoskeletal disorders, and cancer anorexia/cachexia. Inhaled cannabis was perceived as more effective than oral administration. Reported side effects were generally mild.”  In a similar study, Erkens et al  noted “Of all patients, 42% suffered from multiple sclerosis, 11% suffered from rheumatic diseases, and 60% of respondents already used cannabis before the legalization. Cannabis was mainly used for chronic pain and muscle cramp/stiffness.The indication of medicinal cannabis use was in accordance with the labeled indications.”

Ware et al  conducted a survey of UK cannabis patients, reporting “Medicinal cannabis use was reported by patients with chronic pain (25%), multiple sclerosis and depression (22% each), arthritis (21%) and neuropathy (19%). Medicinal cannabis use was associated with younger age, male gender and previous recreational use (p < 0.001).”  In a survey of UK Aids patients, Woolridge et al  reported “Up to one-third (27%, 143/523) reported using cannabis for treating symptoms. Patients reported improved appetite (97%), muscle pain (94%), nausea (93%), anxiety (93%), nerve pain (90%), depression (86%), and paresthesia (85%). Many cannabis users (47%) reported associated memory deterioration. Symptom control using cannabis is widespread in HIV outpatients. A large number of patients reported that cannabis improved symptom control”  A further survey of sickle-cell disease sufferers by Howard et al  noted “The main reasons for use were to reduce pain in 52%, and to induce relaxation or relieve anxiety and depression in 39%.”

Cardenas & Jensen  studied use of alternative pain therapies in spinal-cord injury patients, finding “Seventy-three percent of the respondents had tried at least 1 of 7 alternative pain treatments, and the most frequently tried were massage, marijuana, and acupuncture. The most relief was provided by massage (mean, 6.05 +/- 2.47] on the 0-10 relief scale) and marijuana (mean, 6.62 +/- 2.54 on the 0-10 relief scale)”

In a study on the causes of migraine, Cupini et al  found sex differences in endocannabinoid responses, noting “in migraineur women an increased (anandamide) degradation by platelets, and hence a reduced concentration of (anandamide)  in blood, might reduce the pain threshold and possibly explain the prevalence of migraine in women. The involvement of the endocannabinoid system in migraine is new and broadens our knowledge of this widespread and multifactorial disease.”  Sarchielli et al  considered migraine to be caused by endocannabinoid ‘system failure’ and suggested a “potential role of the cannabinoid (CB)1 receptor as a possible therapeutic target in (chronic migraine).”

The 1994 IDMU study of cannabis users  asked respondents to report any physical or mental health problems and/or benefits which they attributed to cannabis use.  Thirty two individuals cited “pain relief” as the main benefit they received, the fourth most common benefit reported (after relaxation (n=89), stress relief (n=67) and improvements in personal development and outlook (n=36)).  Two individuals specifically mentioned use of cannabis as a muscle relaxant.  

The discovery of endocannabinoids and receptor types have opened up a field of research into potential drugs based on anandamide and other endocannabinoids .   Antagonists (blockers) of the cannabinoid receptors have been shown to increase sensitivity to pain in laboratory animals.

Meng et al  reported the analgesic activity of the cannabinoids to result from a brainstem circuit (rostral ventromedial medulla - RVM) which also contributes to the action of morphine, but in a pharmacologically different manner from morphine.  They claimed that increasing or decreasing levels endogenous cannabinoids (e.g. anandaminde) would normally regulate pain thresholds through modulation of RVM activity, and concluded: “analgesia produced by cannabinoids and opioids involves similar brainstem circuitry and that cannabinoids are indeed centrally acting analgesics with a new mechanism of action.” Meng & Johansen  noted “cannabinoids act directly within the RVM to affect off-cell activity, providing one mechanism by which cannabinoids produce antinociception”  de Novellis et al  reported “s.c. injection of formalin modifies RVM neuronal activities and this effect is prevented by PAG cannabinoid receptor stimulation. Moreover, the physiological stimulation of PAG mGlu5, but not mGlu1 glutamate receptors, seems to be required for the cannabinoid-mediated effect.”

Strangman et al  found that pre-treatment with the cannabinoid antagonist SR141716A significantly increased the response to a noxious & painful chemical stimulus in laboratory animals, and concluded: “endogenous cannabinoids serve naturally to modulate the maintenance of pain following repeated noxious stimulation” Lever et al found the cannabinoid antagonist SR 141716A increased the release of the excitatory neurotransmitted substance P in response to painful stimulation, suggesting tonic CB1 receptor  activity  inhibits the release  of excitatory neurotransmitters in response to pain.  Salio et al  reported “Several lines of evidence show that endogenous and exogenous cannabinoids modulate pain transmission at the spinal level through specific cannabinoid-1 (CB1) receptors.” Costa et al   found CB1 antagonists reversed the effects of anandamide in rats, and Martin et al   found SR141716A blocked CB1-mediated analgesia,  however Beaulieu et al  failed to replicate the pain-sensitising effects of CB1 antagonists  in the rat formalin test.  Carta et al  found dopamine antagonists blocked the analgesic effects of THC in rats.  Chapman  reported “tonic cannabinoid CB1 receptor activation, but not CB2 receptor activation, attenuates acute nociceptive transmission, at the level of the spinal cord” In mice, Guhring et al  found  the CB1 cannabinoid receptor agonist HU210  showed “higher(antinociceptive) efficacy and potency than morphine”.

In mice, Fride et al  reported “(+)-Cannabidiol-DMH inhibited the peripheral pain response and arachidonic-acid-induced inflammation of the ear.”  Than et al  reported “an alpha2-adrenoceptor agonist or micro opioid receptor agonist when combined with a cannabinoid receptor agonist showed significant synergy in antinociception in the hot plate test. However, for the tail flick nociceptive response to heat, only cannabinoid and micro opioid receptor antinociceptive synergy was demonstrated.”  Exposing mice to marijuana smoke, Varvel et al  found “the acute cannabinoid effects of marijuana smoke exposure on analgesia, hypothermia, and catalepsy in mice result from delta9-THC content acting at CB1 receptors and that the non-delta9-THC constituents of marijuana (at concentrations relevant to those typically consumed) influence these effects only minimally, if at all.”  Ulugol et al  found “WIN 55,212-2, a cannabinoid agonist, and the NSAID ketorolac, either alone or in combination, produced dose-dependent antinociception in the writhing test. Isobolographic analysis showed additive interactions between WIN 55,212-2 and ketorolac when they were coadministered systemically.” and concluded “The combination of cannabinoids and NSAIDs may have utility in the pharmacotherapy of pain.”

Studying the relationship between endocannabinoids and spinal fos proteins in rats, Nackley et al  reported “These data provide direct evidence that a peripheral cannabinoid mechanism suppresses the development of inflammation-evoked neuronal activity at the level of the spinal dorsal horn and implicate a role for CB(2) and CB(1) in peripheral cannabinoid modulation of inflammatory nociception.”  Finn et al , investigating the role of the periaqueductal grey matter in the rat, postulated “a role for the PAG in both cannabinoid-mediated anti-nociceptive and anti-aversive responses.” and noted  “These data suggest an important role for the CB(1) receptor in mediating fear-conditioned analgesia and provide evidence for differential modulation of conditioned aversive behaviour by CB(1) receptors during tonic, persistent pain.”  

Studying the interaction of cannabinoids and NSAID drugs in mice, Anikwue et al  noted “In animals given chronic Delta(9)-THC, only diclofenac and acetaminophen (paracetamol) were active”, Ates et al  observed “endocannabinoids play a major role in mediating flurbiprofen-induced antinociception at the spinal level.”  In rats, Ottani et al  found “the analgesic effect of paracetamol is prevented by two antagonists at cannabinoid CB1 receptors (AM281 and SR141716A) at doses that prevent the analgesic activity of the cannabinoid CB1 agonist HU210.”  Guindon & Beaulieu  noted “locally injected anandamide, ibuprofen, rofecoxib and their combinations decreased pain behavior in neuropathic animals. Local use of endocannabinoids to treat neuropathic pain may be an interesting way to treat this condition without having the deleterious central effects of systemic cannabinoids.”  Guindon et al  later reported “The combination of anandamide with ibuprofen produced synergistic antinociceptive effects involving both cannabinoid CB(1) and CB(2) receptors.” Investigating interactions between analgesic activities of cannabis and cocaine, Forman  reported “These findings suggest that activation of the CB1 receptor participates significantly in antinociception resulting from treatment with cocaine” Helyes et al  found cannabinoid blockers increased pain perception in rats “Both SR141716A and SR144528 increased hyperalgesia, indicating that endogenous cannabinoids acting on CB(1) and peripheral CB(2)-like receptors play substantial role in neuropathic conditions to diminish hyperalgesia.”

Maccarone et al  found anandamide to stimulate platelets, an opposite action to aspirin, suggesting cannabinoids may contribute to analgesia without the effects on blood clotting or internal bleeding associated with heavy or regular aspirin use.  Corchero et al , in a study of gene expression on receptor activity, suggested: ‘a possible interaction between the cannabinoid and opioid systems in the caudate-putamen’  However Hamann et al  found analgesia caused by the synthetic cannabinoid Nabilone not to have an opioid receptor component.  Fowler et al  found evidence that ibuprofen and similar drugs may act by reducing the rate at which a natural cannabinoid - anandamide - is broken down in the body.

Martin et al , studying the sites in the brain mediating cannabinoid analgesia, found that the cannabinoid agonist WIN55212-2 ‘significantly elevated tail-flick latencies when injected into the amygdala, the lateral posterior and submedius regions of the thalamus, the superior colliculus and the noradrenergic A5 region.’  For peripheral activity, Hohmann et al  considered their results to ‘provide anatomical evidence for presynaptic as well as postsynaptic localization of cannabinoid receptors in the spinal dorsal horn.’ In a study of spinal injury in rats, Kawasaki et al  concluded “after nerve injury, opioids lose their capability to suppress C-fiber-induced spinal neuron activation in the injured L(5) but not in the intact L(4) spinal segment, whereas cannabinoids still maintain their efficacy.”

In rats, Kelly et al  found “spinal CB1 receptors modulate the transmission of C- and A delta-fiber-evoked responses in anesthetized rats; this may reflect pre- and/or postsynaptic effects of cannabinoids on nociceptive transmission. CB1 receptors inhibit synaptic release of glutamate in rat dorsolateral striatum, a similar mechanism of action may underlie the effects of ACEA on noxious evoked responses of spinal neurons reported here.” Chapman  found HU210 reduced spinal pain transmission in healthy, but not nerve-damaged rats.  Johanek et al  concluded “cannabinoids possess antihyperalgesic properties at doses that alone do not produce antinociception, and are capable of acting at both spinal and peripheral sites”  Bridges et al  found the CB1 agonist WIN55,212-2 reduced hyperalgesia in neuropathic pain, and concluded “cannabinoids may have therapeutic potential in neuropathic pain, and that this effect is mediated through the CB(1) receptor”. Ross et al  suggested “analgesic actions of cannabinoids may be mediated by presynaptic inhibition of transmitter release in sensory neurones.” In rats, Finn et al  reported “coadministration of a low dose of morphine, but not cannabidiol, with Delta9-THC, increased antinociception and 5-hydroxytryptamine levels in the thalamus in a model of persistent nociception”. Labuda & Little  reported “The robust effects of the non-selective cannabinoid receptor agonist WIN55,212-2 and morphine support reports in the literature that systemic cannabinoid receptor agonists and opioids are active in neuropathic pain.”  Cox & Welch  found “Delta9-THC induces increased immunoreactive dynorphin A (idyn A) levels in nonarthritic rats while decreasing idyn A in arthritic rats. We hypothesize that the elevated idyn A level in arthritic rats contributes to hyperalgesia by interaction with N-methyl-D-aspartate receptors, and that Delta9-THC induces antinociception by decreasing idyn A release”

Farquhar-Smith et al , studying bladder pain models in rats found “Anandamide (via CB1 receptors) and palmitoylethanolamide (putatively via CB2 receptors) attenuated a referred hyperalgesia in a dose-dependent fashion. CB1 and CB2 receptors are strategically situated to influence the nerve growth factor-driven referred hyperalgesia associated with inflammation of the urinary bladder. These data implicate cannabinoids as a novel treatment for vesical pain.”.  Fox et al  concluded “cannabinoids are highly potent and efficacious antihyperalgesic agents in a model of neuropathic pain”.  Siegling et al  concluded “cannabinoid CB(1) receptor upregulation contributes to the increased analgesic efficacy of cannabinoids in chronic pain conditions”. Studying deep-tissue pain in mice, Kehl et al  reported “cannabinoids differentially modulated carrageenan- and tumor-evoked hyperalgesia in terms of potency and receptor subtypes involved suggesting that differences in underlying mechanisms may exist between these two models of deep tissue pain.”  In a study of nerve injury in rats, Lim et al  concluded “upregulation of spinal CB1Rs following peripheral nerve injury may contribute to the therapeutic effects of exogenous cannabinoids on neuropathic pain” Following a study of the effects of a cannabinoid agonist in a rat model of diabetic neuropathy, Dogrul et al  concluded “cannabinoids have a potential beneficial effect on experimental diabetic neuropathic pain”  Ulugol et al  found the CB1 agonist “WIN 55,212-2 has an antiallodynic effect in streptozocin-induced diabetic rats and may be a promising approach in the treatment of diabetic neuropathy.”

Studying the relationship between gamma-hydroxybutyric acid (GABA) and cannabinoids in rat spinal cord, Naderi et al  reported “Our results confirm that intrathecal administration of cannabinoid and GABA(B) receptor agonists have analgesic effects and that spinal antinociceptive effects of GABA(B) receptor agonists are likely through endocannabinoid modulation.” In a study of neuropathic pain in rats, Liu & Walker  concluded “results provide a neural basis for reports of potent suppression by cannabinoids of the abnormal sensory responses that result from nerve injury”  In a study in rats of colon distension, Sanson et al  reported “colonic inflammation enhances the antinociceptive action of CB1 and CB2 receptor agonists, and activates an endogenous, CB1 receptor mediated, antinociceptive pathway” Petrosino et al  found endocannabinoid levels in brain areas associated with pain perception to be elevated during periods of induced neuropathic pain in rats. In rats with spinal injury, Hama & Sagan concluded “a CB(1)-selective agonist may be novel therapeutic treatment for clinical SCI pain” Kukushkin et al  found “Cannabinoids suppressed allodynia and spontaneous attacks in rats with the central pain syndrome. The analgesic effect was most pronounced after intrathecal injection of cannabinoid receptor agonist”

Studying the function of the amygdala in rats, Manning et al  reported “The results constitute the first causal data demonstrating the necessity of descending pain-modulatory circuitry (of which the CeA is a component) for the full expression of cannabinoid-induced antinociception in the rat. Furthermore, the results complement previous findings suggesting an overlap in neural circuitry activated by opioids and cannabinoids.” Azad et al  concluded “The endogenous cannabinoid system is involved in the control of neuroplasticity as part of pain processing . Cannabinoids prevent the formation of (long-term potentiation) in the amygdala via activation of CB1 receptors.” Hohmann et al  noted “coordinated release of 2-AG and anandamide in the periaqueductal grey matter might mediate opioid-independent stress-induced analgesia”

Dyson et al  reported “CT-3 (ajulemic acid)  is a cannabinoid receptor agonist and is efficacious in animal models of chronic pain by activation of the CB1 receptor. Whilst it shows significant cannabinoid-like CNS activity, it exhibits a superior therapeutic index compared to other cannabinoid compounds”  Mitchell et al  reported “ajulemic acid reduces abnormal pain sensations associated with chronic pain without producing the motor side effects associated with THC and other non-selective cannabinoid receptor agonists”  Costa et al  investigating a rat model of MS, noted that the CB1 receptor agonist “SR141716 is effective not only in alleviating neuropathic pain but also in favouring the nerve myelin repair”  Combining spinal cannabinoids and yohimbine, 2-adrenoreceptor agonist, Khodayar et al  concluded “spinal cannabinoid and 2-adrenoceptor systems are able to induce antinociception in both phases of formalin test, and (2) the cannabinoid system may be involved in the antinociception induced by adrenoceptors in the early phase.” Antonoiu et al  investigated the behavioural effects of 1',1'-dithiolane delta8-THC analogue AMG-3, a cannabinomimetic molecule with high affinity for CB1/CB2 receptors in rats, finding “the administration of AMG-3 to rats elicits a specific behavioral profile, most probably associated with the activation of CB1 receptors and without effects indicating abuse potential”

6.3.14    Malan et al  investigated the  role of the CB2 cannabinoid  receptor in regulation of peripheral pain, concluding “These findings demonstrate the local, peripheral nature of CB(2) cannabinoid antinociception. .. Peripheral antinociception without CNS effects is consistent with the peripheral distribution of CB(2) receptors. CB(2) receptor agonists may have promise clinically for the treatment of pain without CNS cannabinoid side effects.”  Monhemius et al  noted  the CB1 agonist WIN 55,212-2 “markedly increased withdrawal latencies in the tail flick test and reduced responses to subcutaneous formalin. These effects were blocked by co-administration of (CB1 antagonist) SR141716A” and concluded “this system is important for the modulation of nociceptive transmission in an animal model of chronic neuropathic pain”  Similar results were reported by Drew et al , who concluded “These results strengthen the body of evidence suggesting CB agonists may be an important novel analgesic approach for the treatment of sustained pain states.” Nakamura et al  considered “peripheral endogenous cannabinoids such as anandamide are novel candidates for mediators that inhibit the excitation of nociceptors” Hanus et al  investigated the effects of a new CB2 receptor agonist (HU308), finding “HU-308 reduces blood pressure, blocks defecation, and elicits anti-inflammatory and peripheral analgesic activity. The hypotension, the inhibition of defecation, the anti-inflammatory and peripheral analgesic effects produced by HU-308 are blocked (or partially blocked) by the CB(2) antagonist SR-144528, but not by the CB(1) antagonist SR-141716A. These results demonstrate the feasibility of discovering novel nonpsychotropic cannabinoids that may lead to new therapies for hypertension, inflammation, and pain.”

Johanek & Simone  concluded “cannabinoids primarily activate peripheral CB1 receptors to attenuate hyperalgesia. Activation of this receptor in the periphery may attenuate pain without causing unwanted side effects mediated by central CB1 receptors.”  McLaughlin et al  reported the CB1 receptor agonist “AM 411 dose-dependently produced behaviors consistent with CB1 agonism, including analgesia... which were blocked by a CB1-selective antagonist.” Maione et al  concluded “endocannabinoids affect the descending pathways of pain control by acting at either CB(1) or TRPV1 receptors in healthy rats” Elmes et al  concluded “cannabinoid-based drugs have clinical potential for the treatment of established inflammatory pain responses”  

An aerosol delivery system was tested in mice by Lichtman et al , who found “The antinociceptive effects occurred within 5 min of exposure and lasted approximately 40 min in duration” and noted “inhalation exposure to Delta(9)-THC failed to produce two other indices indicative of cannabinoid activity, hypothermia and decreases in spontaneous locomotor activity” Wiley et al  found the antinociceptive effects of different cannabinoids  in rats depended upon the route of administration.  Li et al  found “low doses of cannabinoids, which do not produce analgesia or impair motor function, attenuate chemogenic pain and possess antihyperalgesic properties” Valiveti et al  investigated permeation of cannabinoids across human skin with a view to developing products for topical application, and concluded “The permeation results indicated that WIN 55,212-2 mesylate, CP 55,940, and other potent synthetic cannabinoids with these physicochemical properties could be ideal candidates for the development of a transdermal therapeutic system.”

Walker et al  concluded “cannabinoids suppress nociceptive neurotransmission at the level of the spinal cord and the thalamus. These effects are reversible, receptor mediated, selective for painful as opposed to nonpainful somatic stimuli, and track the behavioral analgesia both in time course and potency.”  Strangman et al  found “cannabinoids inhibit the activity-dependent facilitation of spinal nociceptive responses.”

Li et al  found electro-acupuncture in rats “can raise the immunoactivity of cutaneous CB2 receptor positive cells in the inflammatory tissue which maybe contribute to its effects in relieving inflammatory pain”

In monkeys, Manning et a found “systemic administration of the prototypical opioid morphine or the cannabinoid receptor agonist WIN55,212-2 produced dose-dependent antinociception on a warm-water tail-withdrawal assay. The antinociceptive effects of each drug were reversible with an appropriate antagonist”  However the effect of the drug was significantly reduced in monkeys with amydaloid lesions, concluding “the possibility should be considered that, in the primate, "antinociceptive circuitry" and "fear circuitry" overlap at the level of the amygdala.”  Ko et al  found THC reduced responses to thermal and chemical pain in monkeys when applied locally.

In Amphibians, Salio et al  noted “An endocannabinoid system is well developed... in the amphibian brain...  cannabinoids might participate in the control of pain sensitivity also in the amphibian spinal cord.”

There is increasing evidence that the pain-relieving circuits modulated by endocannabinoids and opiates are closely-linked.  Cichewicz & McCarthy  investigated synergy between THC and opiates in relieving pain, noting “The analgesic effects of opioids, such as morphine and codeine, in mice are enhanced by oral administration of the cannabinoid delta(9)-tetrahydrocannabinol (delta(9)-THC).”

Studying the interaction between cannabinoid and opioid systems in regulating pain & stress, Valverde et al  concluded “CB1 receptors are not involved in the antinociceptive responses to exogenous opioids, but that a physiological interaction between the opioid and cannabinoid systems is necessary to allow the development of opioid-mediated responses to stress.”  Also, Mao et al  found “The selective central cannabinoid receptor antagonist SR141716A, but not the generic opioid receptor antagonist naloxone, blocked the delta9-THC antinociception. Moreover, there is no cross-tolerance between the antinociceptive effects of morphine and delta9-THC in pathological pain states. ... the cannabinoid analgesic system may be superior to opioids in alleviating intractable pathological pain syndromes.”  Walkeret al  concluded “The existence of a cannabinergic pain-modulatory system may have relevance for the treatment of pain, particularly in instances where opiates are ineffective.” Salio et al  found “A strong co-localization of CB1 and mu-opioid receptors was observed”

Fuentes et al  concluded “Current evidence indicate an interaction between cannabinoid and opioid systems, the latter being of known relevance in nociception. The fact that either exogenous or endogenous opioids enhanced cannabinoid-induced antinociception suggests simultaneous activation of both opioid and cannabinoid receptors by drugs as a new analgesic strategy.”

Yesilyurt et al  suggested a combination of topical and spinal cannabinoid/opiate therapy noting “an antinociceptive interaction between topical opioids with topical, and spinal cannabinoids. These observations are significant in using of topical combination of cannabinoid and morphine in the management of pain.” Dogrul et al  reported “a reduction in the spinal CB1 receptors may enhance sensitivity to sensory stimuli and a decrease in spinal antinociceptive potency to cannabinoid agonists...   'knock-down' of spinal CB1 receptors apparently lowers the thresholds for sensory input”, Gardell et al  noted “...antinociception produced by spinal cannabinoids are likely to be mediated directly through activation of cannabinoid receptors” Yesilyurt & Dogrul  concluded “opioids and cannabinoids produce antinociception through mechanisms that are independent of each other at either the systemic or peripheral levels.”  Vigano et al  commented “This might open up new therapeutic opportunities for relief of chronic pain through cannabinoid-opioid coadministration.”  Kim et al  suggested “a direct action of anandamide on Na+ channels. The inhibition of Na+ currents in sensory neurons may contribute to the anandamide analgesia.”  Vaughan  concluded “non-opioid SIA (stress-induced analgesia) is mediated by two independent endocannabinoids within the midbrain. Furthermore, novel agents that disrupt breakdown of these endocannabinoids enhance non-opioid SIA and pave the way for novel therapies.”

Cox et al  found “a synergistic interaction between Delta(9)-THC and morphine in both the non-arthritic and the arthritic rats. Since Freund's adjuvant-induced alteration in endogenous opioid tone has been previously shown, our data indicate that such changes did not preclude the use of Delta(9)-THC and morphine in combination. As with acute preclinical pain models in which the Delta(9)-THC/morphine combination results in less tolerance development, the implication of the study for chronic pain conditions is discussed.”

Development of synthetic cannabinoids are leading to an explosion of research into new applications . Salio et al  noted the widespread distribution of CB-1 receptors and concluded “ubiquitous localization may account for the complex role played by cannabinoids in antinociception” Investigating the cannabinoid system in detail, Goutopolis et al  noted “The four cannabinoid system proteins, including the CB(1) and CB(2) receptors, fatty acid amide hydrolase, and the anandamide transporter, are excellent targets for the development of novel medications for various conditions, including pain, immunosuppression, peripheral vascular disease, appetite enhancement or suppression, and motor disorders.” Wilson & Nicoll  noted “In contrast to classical neurotransmitters, endogenous cannabinoids can function as retrograde synaptic messengers: They are released from postsynaptic neurons and travel backward across synapses, activating CB1 on presynaptic axons and suppressing neurotransmitter release. Cannabinoids may affect memory, cognition, and pain perception by means of this cellular mechanism.”  Gardell et al  reported “like opioids, repeated spinal administration of a cannabinoid CB1 agonist elicits abnormal pain, which results in increased expression of spinal dynorphin. Manipulations that block cannabinoid-induced pain also block the behavioral manifestation of cannabinoid tolerance”

Guindon et al  found a synergistic effect of both CB1 and CB2 receptor agonists and ibuprofen on antinociception in rats, noting “Anandamide, an endocannabinoid, is degraded by the enzyme fatty acid amide hydrolase which can be inhibited by nonsteroidal anti-inflammatory drugs (NSAIDs).” Bertolini et al reported “the analgesic effect of paracetamol is due to the indirect activation of cannabinoid CB(1) receptors. In brain and spinal cord, paracetamol, following deacetylation to its primary amine (p-aminophenol), is conjugated with arachidonic acid to form N-arachidonoylphenolamine, a compound already known (AM404) as an endogenous cannabinoid”  La Rana et al  postulated “a role of the endocannabinoid system in pain modulation and point to anandamide transport as a potential target for analgesic drug development” Guindon et al  reported “In a test of inflammatory pain, locally injected propofol decreased pain behavior in a dose-dependent manner. This antinociceptive effect was mediated, in part, by CB1 and CB2 receptors.”  Bingham et al  concluded “The greater antinociceptive efficacy of S-AM1241, the functional CB(2) agonist enantiomer of AM1241, is consistent with previous observations that CB(2) agonists are effective in relief of pain.”  Guindon et al  noted “pre-emptive use of cannabinoids produced greater antinociceptive effects in a model of neuropathic pain and this effect is mediated by cannabinoid CB(1) and CB(2) receptors.”

Studying the effect of cannabinoid receptor agonist CP55,940 in cancerous mice, Hamamoto et al  reported “the cataleptic effects of CP 55,940 did not fully account for its antihyperalgesic effect. The antihyperalgesic effect of CP 55,940 was mediated via the cannabinoid CB1 but not CB2 receptor. Finally, repeated administration of CP 55,940 produced a short-term and a longer-term attenuation of tumor-evoked hyperalgesia. These results suggest that cannabinoids may be a useful alternative or adjunct therapy for treating cancer pain.”  Guttierez et al  concluded “Cannabinoids act locally through distinct CB(1) and CB(2) mechanisms to suppress mechanical hypersensitivity after the establishment of chronic inflammation, at doses that produced modest changes in thermal hyperalgesia. Additive antihyperalgesic effects were observed following prophylactic co-administration of the CB(1)- and CB(2)-selective agonists. Our results suggest that peripheral cannabinoid antihyperalgesic actions may be exploited for treatment of inflammatory pain states.” Studying CB1 receptors in rats with peripheral nerve injury, Wang et al  concluded “CB1 receptors (are) a downstream target for spinal (glucocorticoid receptor) actions contributory to the mechanisms of neuropathic pain.” Lever et al  reported “data support a peripheral antihyperalgesic effect of (CB1 agonist) WIN 55,212-2 when delivered directly to the site of a nerve injury at systemically inactive doses.” Tappe-Theodor et al  suggested that analgesic tolerance to CB1 agonists is mediated by G-protein-associated sorting protein 1 “a key regulator of the fate of CB1 after agonist exposure in the nervous system and critically determines analgesic tolerance to cannabinoids” Hasanein et al  concluded “the existence of a CB1-mediated inhibitory system in the BLA that, when activated, can diminish responsivity to acute and tonic noxious stimuli, but that normally has no tonic effect on the response threshold of these stimuli.”

Agarwal et al  concluded “the contribution of CB1-type receptors expressed on the peripheral terminals of nociceptors to cannabinoid-induced analgesia is paramount, which should enable the development of peripherally acting CB1 analgesic agonists without any central side effects.” Wallace et al  concluded that the synthetic endocannabinoid “L-29 as a novel analgesic compound that may target the endogenous cannabinoid system while avoiding undesirable side effects associated with direct cannabinoid receptor activation.” Hagenacker et al  noted “the analgetic properties of endo- and exo-cannabinoids are mediated by CB1 receptors and their activation significantly modulates the calcium induced release of pain related transmitters.”

CB2-receptor studies:  Malan et al  investigated the effect of CB-2 receptors on pain perception and observed “CB(2) receptor activation is sufficient to inhibit acute nociception, inflammatory hyperalgesia, and the allodynia and hyperalgesia produced in a neuropathic pain model. Studies using site-specific administration of agonist and antagonist have suggested that CB(2) receptor agonists inhibit pain responses by acting at peripheral sites. CB(2) receptor activation also inhibits edema and plasma extravasation produced by inflammation. CB(2) receptor-selective agonists do not produce central nervous system (CNS) effects typical of cannabinoids”  They later concluded  “CB(2) receptor activation inhibits acute, inflammatory and neuropathic pain responses in animal models. In preclinical studies, CB(2) receptor agonists do not produce central nervous system effects. Therefore, they show promise for the treatment of acute and chronic pain without psychoactive effects.”  

Ibrahim et al  found “a mechanism leading to the inhibition of pain, one that targets receptors localized exclusively outside the CNS. Further, they suggest the potential use of CB2 receptor-selective agonists for treatment of human neuropathic pain, a condition currently without consistently effective therapies. CB2 receptor-selective agonist medications are predicted to be without the CNS side effects that limit the effectiveness of currently available medications.”  Yoon & Choi  noted “The antinociception of WIN 55,212-2 is mediated through the cannabinoid 1 receptor, but not the cannabinoid 2 receptor, at the spinal level.”  Dogrul et al  concluded “there is an antinociceptive synergy between peripheral and spinal sites of cannabinoid action and it also implicates that local activation of cannabinoid system may regulate pain initiation in cutaneous tissue. Our findings support that cannabinoid system participates in buffering the emerging pain signals at the peripheral sites in addition to their spinal and supraspinal sites of action. In addition, an antinociceptive synergy between topical and spinal cannabinoid actions exists. These results also indicate that topically administered cannabinoid agonists may reduce pain without the dysphoric side effects and abuse potential of centrally acting cannabimimetic drugs.”  Quartillo et al  concluded “Local, peripheral CB2 receptor activation inhibits inflammation and inflammatory hyperalgesia. These results suggest that peripheral CB2 receptors may be an appropriate target for eliciting relief of inflammatory pain without the CNS effects of nonselective cannabinoid receptor agonists.”  Hohmann et al  noted “actions at cannabinoid CB(2) receptors are sufficient to normalize nociceptive thresholds and produce antinociception in persistent pain states.” Romero-Sandoval & Eisenach  concluded “intrathecal administration of cannabinoid receptor agonists may provide postoperative analgesia while reducing spinal glial activation, and that selective cannabinoid 2 receptor agonists may do so without central side effects”

Scott et al  suggested “a role for CB-2 receptor-mediated antinociception in both acute and neuropathic pain in addition to centrally located CB-1 mechanisms.”  Nackley et al  noted “activation of cannabinoid CB2 receptors is sufficient to suppress neuronal activity at central levels of processing in the spinal dorsal horn. Our findings are consistent with the ability of AM1241 to normalize nociceptive thresholds and produce antinociception in inflammatory pain states.”  Ibrahim et al  concluded “CB(2) receptor activation stimulates release from keratinocytes of beta-endorphin, which acts at local neuronal mu-opioid receptors to inhibit nociception... This mechanism allows for the local release of beta-endorphin, where CB(2) receptors are present, leading to anatomical specificity of opioid effects.”  Valenzano et al  concluded “CB2 receptor agonists have the potential to treat pain without eliciting the centrally-mediated side effects associated with non-selective cannabinoid agonists” Sagar et al  observed “At the level of the spinal cord, CB2 receptors have inhibitory effects in neuropathic, but not sham-operated rats suggesting that spinal CB2 may be an important analgesic target”.  Fox & Bevan  advised “The design of novel compounds that either specifically target peripheral CB(1) receptors or display high selectivity for CB(2) receptors may offer avenues for harnessing the analgesic effect of CB receptor agonists while avoiding the central adverse events seen with cannabinoid structures.”  Wotherspoon et al  noted “This clear demonstration of CB(2) receptors on sensory neurons suggests an additional cellular target for CB(2) agonist induced analgesia, at least in neuropathic models.”  Whiteside et al , investigating the CB2-receptor agonist GW405833 in rats, concluded “antihyperalgesic effects of GW405833 are mediated via the cannabinoid CB2 receptor, whereas the analgesic and sedative effects are not”, Labuda et al  concluded “selective cannabinoid CB2 receptor agonists might represent a new class of postoperative analgesics”

Clayton et al  found “The CB2 agonist, 1-(2,3-Dichlorobenzoyl)-5-methoxy-2-methyl-(2-(morpholin-4-yl)ethyl)-1H-indole (GW405833) inhibited the hypersensitivity and was anti-inflammatory in vivo. These effects were blocked by SR144528. These findings suggest that CB1 receptors are involved in nociceptive pain and that both CB1 and CB2 receptors are involved in inflammatory hypersensitivity.”  Elmes et al  concluded “activation of peripheral CB2 receptors attenuates both innocuous- and noxious-evoked responses of WDR neurons in models of acute, inflammatory and neuropathic pain.”  Dajani et al  reported on CT3, a novel cannabinoid developed by Atlantic pharmaceuticals, noting  “CT-3 showed more prolonged duration of analgesic action than morphine (and)... warrants clinical development as a novel anti-inflammatory and analgesic drug.” Mason et al  postluated a “critical role for dynorphin A release in the initiation of the antinociceptive effects of the cannabinoids at the spinal level”

Beltramo et al , studying pain reactions in mice, noted “CB2 is present in the central nervous system and suggest that CB2 agonists may elicit their analgesic effect by acting not only at non-neuronal peripheral sites but also at neural level, making CB2 an attractive target for chronic pain treatment”  Ibrahim et al  noted the CB2 agonist AM1241 “produces antinociception in vivo by activating CB2 cannabinoid receptors. Further, they confirm the potential therapeutic relevance of CB2 cannabinoid receptors for the treatment of acute pain.” Guindon et al  studied the effect of the endocannabinoid CB2-receptor agonist 2-AG and the breakdown inhibitor URB602, finding “Locally injected 2-AG and URB602 decreased pain behaviour in a dose-dependent manner in an inflammatory model of pain. The antinociceptive effect of 2-AG was mediated by the CB(2) receptor.”  Whiteside et al , reviewing studies of the CB2 receptor, concluded “it is now clear that this receptor plays a critical role in nociception. To this end, CB2 receptors have been shown to modulate acute pain, chronic inflammatory pain, post-surgical pain, cancer pain and pain associated with nerve injury.” Giblin et al  noted “Selective CB2 receptor agonists are promising potential therapeutic agents for the treatment of inflammatory and neuropathic pain” Dziadulewicz et al  discovered “a novel CB1/CB2 dual agonist, naphthalen-1-yl-(4-pentyloxynaphthalen-1-yl)methanone (13), which displays good oral bioavailability, potent antihyperalgesic activity in animal models, and limited brain penetration.”

Palmitoylethanolamine (PEA) - Lambert et al  found palmitoyl-ethanolamine (PEA), a shorter and fully saturated analogue of anandamide to be “found in most mammalian tissues...  accumulated during inflammation and has been demonstrated to have a number of anti-inflammatory effects, including beneficial effects in clinically relevant animal models of inflammatory pain”  Di Marzo et al  considered cannabimimetic fatty acids to play a role in the control of tissue inflammation.  In a 2002 review, Brune  concluded “molecular biology and genomics have led to the development of new target-selective chemical entities for use in pain relief. These include .... blockers or agonists of cannabinoid and vanilloid receptors”  

Vanilloid/Capsiacin receptors - Studying capsiacin and vanilloid receptor responses to cannabinoids, Zygmunt et al  noted “The THC response depends on extracellular calcium but does not involve known voltage-operated calcium channels, glutamate receptors, or protein kinases A and C. These results may indicate the presence of a novel cannabinoid receptor/ion channel in the pain pathway.”  A similar study by Rukwied et al  described “analgesic and anti-hyperalgesic properties of a topically applied cannabinoid receptor ligand, which might have important therapeutic implications in humans”  Oshita et al  concluded “CB(1)-receptor stimulation modulates the activities of transient receptor potential vanilloid receptor 1 in cultured rat DRG cells.”  Singh Tahim et al  concluded “inflammatory mediators significantly increase the excitatory potency and efficacy of anandamide on vanilloid type 1 transient receptor potential receptor, thus, increasing the anandamide concentration in, or around the peripheral terminals of nociceptors might rather evoke than decrease inflammatory heat hyperalgesia.”  Szallasi  found “arvanil, a combined agonist of VR1 and CB1 receptors, has already proved to be a powerful analgesic drug in the mouse.” Brooks et al  reported “Activation of cannabinoid receptors causes inhibition of spasticity, in a mouse model of multiple sclerosis, and of persistent pain, in the rat formalin test. The endocannabinoid anandamide inhibits spasticity and persistent pain”, finding that anandamide is a full agonist of vanilloid receptors  which are associated with antispastic and analgesic activity.  

Enzyme Studies:  Much current research has focussed on endocannabinoid metabolism in an attempt to boost natural levels of the substances by interrupting enzymes which break down endocannabinoids.  Cravatt & Lichtmann  investigated the possibility of blocking enzymes which break down anandamide to boost endocannabinoid activity, and noted “anandamide, a natural lipid ligand for CB1, and an enzyme, fatty acid amide hydrolase (FAAH), that terminates anandamide signaling have inspired pharmacological strategies to augment endogenous cannabinoid ('endocannabinoid') activity with FAAH inhibitors”  Lichtmann et al  concluded “selective inhibitors of FAAH might represent a viable pharmacological approach for the clinical treatment of pain disorders”, and later  reported FAAH inhibitors to “raise central nervous system levels of anandamide and promote cannabinoid receptor 1-dependent analgesia in several assays of pain sensation.”  Rodella et al  considered the anadamide reuptake inhibitor “AM404 could be a useful drug to reduce neuropathic pain and that cannabinoid CB1 receptor, cannabinoid CB2 receptor and vanilloid TRPV-1 receptor are involved.”  Suplita et al  found “In all conditions, the antinociceptive effects of each FAAH inhibitor were completely blocked by coadministration of the CB(1) antagonist rimonabant. The present results provide evidence that a descending cannabinergic neural system is activated by environmental stressors to modulate pain sensitivity in a CB(1)-dependent manner.”  

In mice deficient in both fatty acid amide hydrolase (FAAH) enzyme and in CB1 receptors, anandamide failed to produce analgesia or other typical responses -  Wise et al  concluded “the cannabinoid CB(1) receptor is the predominant target mediating anandamide's behavioral effects.” Jayamane et al  concluded “FAAH inhibitor URB597 produces cannabinoid CB(1) and CB(2) receptor-mediated analgesia in inflammatory pain states, without causing the undesirable side effects associated with cannabinoid receptor activation”  La Rana et al  found “a role of the endocannabinoid system in pain modulation and point to anandamide transport as a potential target for analgesic drug development” De Lago  et al studied the effects of UCM707, an endocannabinoid reuptake inhibitor, and commented “UCM707, as suggested by its in vitro properties, seems also to behave in vivo as a selective and potent inhibitor of the endocannabinoid transporter, showing negligible direct effects on the receptors for endocannabinoids but potentiating the action of these endogenous compounds.”

Hohmann  suggested using inhibitors of endocannabinoid hydrolysis in the treatment of peripheral pain. Costa et al  studied an inhibitor of anandamide uptake, resulting in higher anandamide levels, concluding “inhibition of endocannabinoid uptake, by blocking the putative anandamide carrier, results in the relief of neuropathic pain and may represent a novel strategy for treating chronic pain” Russo et al  claimed “new evidence for a role of the endocannabinoid system in pain modulation and reinforce the proposed role of FAAH as a target for analgesic drug development.” Jhaveri et al  observed “Studies of the endogenous cannabinoids (endocannabinoids) have demonstrated that they are present in most tissues and that in some pain states, such as neuropathic pain, levels of endocannabinoids are elevated at key sites involved in pain processing. An alternative approach that can be used to harness the potential therapeutic effects of cannabinoids is to maximise the effects of the endocannabinoids, the actions of which are terminated by re-uptake and metabolism by various enzymes, including fatty acid amide hydrolase (FAAH), monoacylglycerol lipase (MAGL) and cyclooxygenase type 2 (COX2). Preventing the metabolism, or uptake, of endocannabinoids elevates levels of these lipid compounds in tissue and produces behavioural analgesia in models of acute pain.”

Mitchell et al  investigated activity of the endocannabinoid transport inhibitor AM404, concluding “acute administration of AM404 reduces allodynia in a neuropathic pain model via cannabinoid CB(1) receptor activation, without causing the undesirable motor disruption associated with cannabinoid receptor agonists.”  In a study of FAAH inhibitors, Sit et al  observed “Compound 17 (IC(50)=2 nM) dose-dependently (0.1-10mg/kg, iv) potentiates the effects of exogenous anandamide (1 mg/kg, iv) in a rat thermal escape test (Hargreaves test), and shows robust antinociceptive activity in animal models of persistent (formalin test) and neuropathic (Chung model) pain. Compound 17 (20 mg/kg, iv) demonstrates activity in the formalin test that is comparable to morphine (3mg/kg, iv), and is dose-dependently inhibited by the CB1 antagonist SR141716A”  

Substance P - Krishtal et al  found cannabinoids to modify the responses of sensory neurons to the endogenous pain-mediating agent (Substance P) released in response to trauma and other noxious stimuli. Ahn et al  found COX inhibition to modulate antinociceptive effects of CB1/2 agonists.

Cannabidiol (CBD) - In a study of the non-psychoactive CBD in chronic pain in rats, Costa et al  suggested “a potential for therapeutic use of cannabidiol in chronic painful states.” In Canada, Rajesh et al  reported “CBD… has recently been approved for the treatment of inflammation, pain, and spasticity associated with multiple sclerosis in humans” Klein & Newton  concluded “Psychoactive and nonpsychoactive cannabinoid-based drugs such as Delta9-tetrahydrocannabinol, cannabidiol, HU-211, and ajulemic acid have been tested and found moderately effective in clinical trials of multiple sclerosis, traumatic brain injury, arthritis, and neuropathic pain.”

NSAID drugs - Guindon et al  found a synergistic effect of both CB1 and CB2 receptor agonists and ibuprofen on antinociception in rats, noting “Anandamide, an endocannabinoid, is degraded by the enzyme fatty acid amide hydrolase which can be inhibited by nonsteroidal anti-inflammatory drugs (NSAIDs).” Bertolini et al reported “the analgesic effect of paracetamol is due to the indirect activation of cannabinoid CB(1) receptors. In brain and spinal cord, paracetamol, following deacetylation to its primary amine (p-aminophenol), is conjugated with arachidonic acid to form N-arachidonoylphenolamine, a compound already known (AM404) as an endogenous cannabinoid”  Dani et al  reported “Paracetamol dose-dependently decreased mechanical allodynia and lowered nociceptive scores associated with hyperalgesia testing. These effects were inhibited by the administration of cannabinoid CB(1) (AM251) and CB(2) (AM630) receptor antagonists. The participation of the peripheral cannabinoid system in paracetamol analgesia is suggested.”

Although Whiteley  noted “human studies are few and far between and have been held up by the law and the lack of standardised extracts”, in recent years, many clinical trials have been performed on cannabis-based medicines and individual cannabinoids.  

In early studies, Mechoulam found inconclusive results on pain relief from human subjects, although the dosages in most studies were lower than those found effective in animal models.  He concluded that there was “significant analgesic activity” from THC, remarking that the lack of any physical dependence was “a plus”, although he was concerned about the “psychotomimetic” effects (i.e. the high) particularly for individuals unused to the drug.  In an earlier review  Mechoulam had considered the traditional use of cannabis preparations as analgesic and anti-rheumatic agents to have “some modern substantiation”.

Noyes et al  found a clear dose-related analgesic effect from oral administration of THC.  In a second study  the analgesic effect was found to be six times as powerful as that of codeine, with 20mg THC producing significant pain relief for over 5 hours.  He considered the side effects (sedation and light-headedness) to mitigate against wider clinical use.  However, his subjects were inexperienced with marijuana use and as such may have found the psychological effects of the high more disturbing, and thus less tolerable, than experienced users.  Milstein et al  found that experienced marijuana users exposed to approximately 7.5mg THC by inhalation, achieved a greater analgesic effect than naive subjects, and were less likely to report adverse side effects.  Whether this increased response is due to more efficient inhalation techniques in the experienced group, or through a “reverse tolerance” whereby THC has a greater effect in habitués, is not clear.  

Pertwee  reports a number of patients suffering spinal injury or multiple sclerosis claiming cannabis relieves spasticity and pain associated with muscle spasms more effectively than conventional muscle relaxants and with more tolerable side effects.  Several clinical trials have supported these claims     , indicating that oral THC or inhalation of cannabis smoke can relieve muscle pain and spasticity. In a small-scale clinical trial of THC, Elsner et al  found half the patients achieved sufficient pain relief, but noted “large individual differences in the effectiveness of THC in pain management”

Burstein  finds evidence that the carboxylic acid derivatives of THC and other cannabinoids may have potent analgesic and/or anti-inflammatory activity.  Several of these derivatives are present in the body fluids of cannabis users as non-psychoactive metabolites of the drug.  These derivatives may offer a potential advantage in that they are more water-soluble than THC.  Jbilo et al , studing the effects of gene expression on human cannabinoid receptors, reported:  ‘our data highlight a possible new function of peripheral cannabinoid receptors in the modulation of immune and inflammatory responses ‘

Williamson & Evans  noted “Small clinical studies have confirmed the usefulness of THC as an analgesic; CBD and CBG also have analgesic and antiinflammatory effects” Vaughan & Christie  concluded “Cannabinoids have significant analgesic properties in animal models, particularly for chronic pain states, but there are few human studies. Well-controlled clinical trials on cannabinoids, and cannabinoid delivery systems, are now required.” Kinzbrunner  criticised the “adverse psychotropic effects” of cannabis but conceded “cannabinoids and codeine have similar effects on pain relief”  Elsner et al  reviewed 6 pain patients treated with THC (oral, 5-20mg/d) finding large individual differences in the analgesic response, 3 patients achieving satisfactory pain relief, the other three experiencing “intolerable side effects such as nausea, dizziness and sedation without a reduction of pain intensity”

Smoked Cannabis:  Haney et al  studying responses of 12 subjects  to active and placebo marijuana cigarettes, postulated a cannabis withdrawal syndrome, reporting “Abstinence from active marijuana increased ratings such as "Anxious," "Irritable," and "Stomach pain," and significantly decreased food intake compared to baseline.” Haney et al  administered the opioid antagonist naltrexone to marijuana smokers, and reported “naltrexone increases the subjective effects of oral THC. Thus, oral THC's effects are enhanced rather than antagonized by opioid receptor blockade in heavy marijuana smokers.”

In a study of smoked cannabis in the treatment of neuropathic pain associated with HIV, Abrams et al  reported “Smoked cannabis was well tolerated and effectively relieved chronic neuropathic pain from HIV-associated sensory neuropathy. The findings are comparable to oral drugs used for chronic neuropathic pain.” Following a study of allodynia and trigeminal neuralgia, Liang et al  concluded “cannabinoids may be a useful therapeutic approach for the clinical management of trigeminal neuropathic pain disorders.”

Oral THC - Clermont-Gnamien et al  treated chronic pain patients with oral THC and noted “THC did not induce significant effect on the various pain, HRQL and anxiety and depression scores. Numerous side effects (notably sedation and asthenia) were observed in 5 patients out of 7, requiring premature discontinuation of the drug in 3 patients... The present study did not reveal any significant efficacy of THC in a small cohort of patients with chronic refractory neuropathic pain, but underlined the unfavorable side effect profile of the drug. These results may partly relate to the fact that oral dronabinol exhibits a poor therapeutic ratio (efficacy at the price of side effects).”  In Denmark, a trial of Dronabinol among MS patients by Svendsen et al  found “Dronabinol reduced the spontaneous pain intensity significantly compared with placebo (4.0 (2.3-6.0) vs. 5.0 (4.0-6.4), median (25th-75th percentiles), p = 0.02). Though dronabinol's analgesic effect is modest, its use should be evaluated considering the general difficulty in treating central pain”

Naef et al  tested THC, Morphine and a combination on induced pain in healthy volunteers, and reported “THC did not significantly reduce pain. In the cold and heat tests it even produced hyperalgesia, which was completely neutralized by THC-morphine. A slight additive analgesic effect could be observed for THC-morphine in the electrical stimulation test. No analgesic effect resulted in the pressure and heat test, neither with THC nor THC-morphine. Psychotropic and somatic side-effects (sleepiness, euphoria, anxiety, confusion, nausea, dizziness, etc.) were common, but usually mild.”  Roberts et al  found “neither morphine nor Delta(9)-THC had a significant effect, there was a positive analgesic interaction between the two (p = 0.012), indicating that the combination had a synergistic affective analgesic effect” however Seeling et al  found “neither a synergistic nor even an additive antinociceptive interaction between (9)-tetrahydrocannabinol and the mu-opioid agonist piritramide in a setting of acute postoperative pain.”

A clinical trial of oral THC by Buggy et al  found “no evidence of an analgesic effect of orally administered delta-9-THC 5 mg in postoperative pain in humans.”, a similar trial by Attal et al  found “THC (mean dosage: 16.6+/-6.5 mg/day) did not induce any significant effects on ongoing and paroxysmal pain, allodynia, quality of life, anxiety/depression scores and functional impact of pain. These results do not support an overall benefit of THC in pain and quality of life in patients with refractory neuropathic pain”  In a trial of Dronabinol on MS patients, Svendsen et al  concluded “Dronabinol has a modest but clinically relevant analgesic effect on central pain in patients with multiple sclerosis. Adverse events, including dizziness, were more frequent with dronabinol than with placebo during the first week of treatment.”

In a study of THC in fibromyalgia patients, Schley et al  reported “Delta-9-THC had no effect on the axon reflex flare, whereas electrically induced pain was significantly attenuated after doses of 10-15 mg delta-9-THC (p < 0.05). Daily-recorded pain of the FM patients was significantly reduced (p < 0.01). CONCLUSIONS: This pilot study demonstrated that a generalized statement that delta-9-THC is an analgetic drug cannot be made. However, a sub-population of FM patients reported significant benefit from the delta-9-THC monotherapy. The unaffected electrically induced axon reflex flare, but decreased pain perception, suggests a central mode of action of the cannabinoid.”  

Plant Extracts - Killestein et al  conducted a clinical trial of oral THC and cannabis plant extracts on 16 MS patients, and noted “Both drugs were safe, but adverse events were more common with plant-extract treatment. Compared with placebo, neither THC nor plant-extract treatment reduced spasticity.”  Following a clinical trial of cannabis plant extracts, Wade et al  reported “Pain relief associated with both THC and CBD was significantly superior to placebo...  Cannabis medicinal extracts can improve neurogenic symptoms unresponsive to standard treatments. Unwanted effects are predictable and generally well tolerated.”  Berman et al  reported “The (mean pain severity score) failed to fall by the two points defined in our hypothesis. However, both this measure and measures of sleep showed statistically significant improvements. The study medications were generally well tolerated with the majority of adverse events, including intoxication type reactions, being mild to moderate in severity and resolving spontaneously”  

In a trial on trigeminal neuralgia Liang et al  concluded “cannabinoids may prove useful in pain modulation by inhibiting neuronal transmission in pain pathways. Considering the pronounced antinociceptive effects produced by cannabinoids, they may be a promising therapeutic approach for the clinical management of trigeminal neuralgia” In a 4-week trial of cannabis extracts on patients with allodynia and neuropathic pain, Keizer et al  found “most of the effect of the cannabis occurred in the last 2 weeks of the trial. In this phase, we observed that the pain thresholds, as measured with Von Frey monofilaments, were inversely correlated with a decrease of the perceived pain intensity”  Holdcroft et al , studying the effects of oral cannabis-plant extract on postoperative pain, found “significant dose-related improvements in rescue analgesia requirements in the 10 mg and 15 mg groups provide a number needed to treat that is equivalent to many routinely used analgesics without frequent adverse effects.”

Other Cannabinoids - After a clinical trial of 1',1'dimethylheptyl-Delta8-tetrahydrocannabinol-11-oic acid (CT-3), a potent analogue of THC-11-oic acid, Karst et al  concluded “CT-3 was effective in reducing chronic neuropathic pain compared with placebo. No major adverse effects were observed”  In a separate trial of CT3, Burstein et al  found “In preclinical studies (CT3) displayed many of the properties of non-steroidal anti-inflammatory drugs (NSAIDs); however, it seems to be free of undesirable side effects. The initial short-term trials in healthy human subjects, as well as in patients with chronic neuropathic pain, demonstrated a complete absence of psychotropic actions. Moreover, it proved to be more effective than placebo in reducing this type of pain as measured by the visual analog scale. Unlike the narcotic analgesics, signs of dependency were not observed after withdrawal of the drug at the end of the one-week treatment period.”  Salim et al  found ajulemic acid (CT3) “shows pain-reducing effects on patients with chronic neuropathic pain without clinically relevant psychotropic or physical side effects” Studying patients with pain associated with pancreatitis, Michalski et al  noted “HU210, a synthetic agonist at CB1 and CB2, abolished abdominal pain associated with pancreatitis and also reduced inflammation and decreased tissue pathology in mice without producing central, adverse effects. Antagonists at CB1- and CB2-receptors were effective in reversing HU210-induced antinociception, whereas a combination of CB1- and CB2-antagonists was required to block the anti-inflammatory effects of HU210 in pancreatitis.”

Nabilone:  A study of nabilone in 20 chronic pain patients by Berlach et al  found “Fifteen patients reported subjective overall improvement with nabilone, and nine reported reduced pain intensity. Beneficial effects on sleep and nausea were the main reasons for continuing use. Intolerable side effects were experienced in three patients (palpitations, urinary retention, dry mouth). Nabilone may be a useful addition to pain management and should be further evaluated in randomized controlled trials.” Pinsger et al  noted “a majority of patients with chronic pain classify nabilone intake in addition to the standard treatment as a measure with a positive individual benefit-risk ratio.” In a clinical trial, Wissel et al  found “Nabilone 1 mg per day proved to be a safe and easily applicable option in the care of patients with chronic UMNS and spasticity-related pain otherwise not controllable.” However, following a study of 41 patients undergoing operations, Beaulieu  concluded “Contrary to the main hypothesis, high dose nabilone in the presence of morphine patient controlled analgesia is associated with an increase in pain scores in patients undergoing major surgery.”

Sativex Clinical Trials - In 2003 GW Pharmaceuticals  announced ongoing clinical trials of cannabis extracts (Sativex) for the following conditions:
(a)    the relief of pain of neurological origin and defects of neurological function in the following indications: multiple sclerosis (MS), spinal cord injury, peripheral nerve injury, central nervous system damage, neuroinvasive cancer, dystonias, cerebral vascular accident and spina bifida, as well as for the relief of pain and inflammation in rheumatoid arthritis and also pain relief in brachial plexus injury.
(b)    spasticity and bladder dysfunction in multiple sclerosis patients
(c)    spinal cord injury
(d)    High CBD in various CNS disorders (including epilepsy, stroke and head injury).
(e)    THC:CBD (broad ratio) in patients with inflammatory bowel disease
(f)    High CBD in patients with psychotic disorders such as schizophrenia, and a preclinical trial of High CBD in various CNS disorders (including epilepsy, stroke and head injury).
(g)    THC:CBD (narrow ratio) in the following medical conditions: pain in spinal cord injury, pain and sleep in MS and spinal cord injury, neuropathic pain in MS and general neuropathic pain (presented as allodynia). Results from these trials show that THC:CBD (narrow ratio) caused statistically significant reductions in neuropathic pain in patients with MS and other conditions. In addition, improvements in other MS symptoms were observed as well.
(h)    THC:CBD (broad ratio) in a small number of patients with rheumatoid arthritis.

In September 2001, preliminary results were reported from the GW Pharmaceuticals clinical trials of a sub-lingual cannabis-extract spray on pain management:  “Only one of the 23 patients failed to benefit from the cannabis spray and two others dropped out because of side effects.  The remaining 18 experienced pain relief that varied from moderate ( "at least I can sleep at night" ) to dramatic ( "it has transformed my life" ).  Patients on morphine to control severe pain were able to cut their doses dramatically.”   In November 2002 the results of phase III trials were announced by GW Pharmaceuticals  “In a double-blind crossover study comparing the efficacy of GW’s THC:CBD product, GW’s THC alone product and placebo in the treatment of neuropathic pain in 48 patients with Brachial Plexus Injury, both the THC:CBD medicine and the THC medicine provided highly statistically significant relief of pain and statistically significant reduction in sleep disturbance. Brachial plexus injury is a rare but particularly challenging cause of intractable neuropathic pain, and to the best of our knowledge this is the first placebo-controlled trial ever conducted in this condition.  The benefits seen in all four studies are all the more notable in that they represent improvements over and above that which patients obtain with their standard prescription medicines (patients receiving both active and placebo medicines continued to take their standard prescription medicines during the trial).”  In a UK clinical trial of cannabis extracts on MS symptoms, Zajicek et al found “objective improvement in mobility and patients' opinion of an improvement in pain (which) suggest cannabinoids might be clinically useful”  In a sister trial of chronic pain Notcutt et al  noted “Extracts which contained THC proved most effective in symptom control. Regimens for the use of the sublingual spray emerged and a wide range of dosing requirements was observed. Side-effects were common, reflecting a learning curve for both patient and study team. These were generally acceptable and little different to those seen when other psycho-active agents are used for chronic pain.”  An open-label trial on MS patients by Brady et al  found “Patient self-assessment of pain, spasticity and quality of sleep improved significantly (P <0.05, Wilcoxon's signed rank test) with pain improvement continuing up to median of 35 weeks.”  Szendrei  commented on the potential of Sativex in European medicine “The new analgesic is proposed for the treatment of muscle spasticity and pains accompanying multiple sclerosis and as an efficient analgetic for neurogenic pain not responding well to opioids and to other therapies available.”  

Wade et al  investigated Sativex in MS patients, finding “Following CBME the primary symptom score reduced from mean (SE) 74.36 (11.1) to 48.89 (22.0) following CBME and from 74.31 (12.5) to 54.79 (26.3) following placebo [ns]. Spasticity VAS scores were significantly reduced by CBME (Sativex) in comparison with placebo (P =0.001). There were no significant adverse effects on cognition or mood and intoxication was generally mild.”  In a further UK trial of Sativex by Rog et al  found it “superior to placebo in reducing the mean intensity of pain… and sleep disturbance” concluding “Cannabis-based medicine is effective in reducing pain and sleep disturbance in patients with multiple sclerosis related central neuropathic pain and is mostly well tolerated.”  Blake et al  found “In comparison with placebo, (sativex) produced statistically significant improvements in pain on movement, pain at rest, quality of sleep”  Perras  reported “In some trials, THC:CBD spray significantly reduced neuropathic pain, spasticity, muscle spasms and sleep disturbances. The most common adverse events (AEs) reported in trials were dizziness, sleepiness, fatigue, feeling of intoxication and a bad taste.”

Russo & Guy , reviewing the clinical trials of sativex, noted “CBD is demonstrated to antagonise some undesirable effects of THC including intoxication, sedation and tachycardia, while contributing analgesic, anti-emetic, and anti-carcinogenic properties in its own right. In modern clinical trials, this has permitted the administration of higher doses of THC, providing evidence for clinical efficacy and safety for cannabis based extracts in treatment of spasticity, central pain and lower urinary tract symptoms in multiple sclerosis, as well as sleep disturbances, peripheral neuropathic pain, brachial plexus avulsion symptoms, rheumatoid arthritis and intractable cancer pain… The hypothesis that the combination of THC and CBD increases clinical efficacy while reducing adverse events is supported.”

Barnes  reviewed progress in clinical trials of Sativex, noting “Development has concentrated on the treatment of symptoms of multiple sclerosis, notably spasticity and neuropathic pain, as well as the treatment of neuropathic pain of other aetiologies. Positive results in placebo-controlled trials of the use of Sativex as an add-on therapy in these indications demonstrate that Sativex is efficacious and well tolerated in the treatment of these symptoms. Sativex has been approved for use in neuropathic pain due to multiple sclerosis in Canada. If ongoing studies replicate the results already observed, further approvals for the treatment of spasticity in multiple sclerosis and for neuropathic pain are likely.”  Perez  concluded “Sativex has proved to be well tolerated and successfully self-administered and self-titrated in both healthy volunteers and patient cohorts. Clinical assessment of this combined cannabinoid medicine has demonstrated efficacy in patients with intractable pain (chronic neuropathic pain, pain due to brachial plexus nerve injury, allodynic peripheral neuropathic pain and advanced cancer pain), rheumatoid arthritis and multiple sclerosis (bladder problems, spasticity and central pain), with no significant intoxication-like symptoms, tolerance or withdrawal syndrome.”  Wade et al  concluded “long-term use of an oromucosal CBM (Sativex) maintains its effect in those patients who perceive initial benefit.”

In a 2007 review of Sativex trials, Russo et al  reported “Experience to date with Sativex in numerous Phase I-III studies in 2000 subjects with 1000 patient years of exposure demonstrate marked improvement in subjective sleep parameters in patients with a wide variety of pain conditions including multiple sclerosis, peripheral neuropathic pain, intractable cancer pain, and rheumatoid arthritis, with an acceptable adverse event profile. No tolerance to the benefit of Sativex on pain or sleep, nor need for dosage increases have been noted in safety extension studies of up to four years, wherein 40-50% of subjects attained good or very good sleep quality, a key source of disability in chronic pain syndromes that may contribute to patients' quality of life.”

Assessing the oral route of administration of cannabinoid medicines, Pertwee  concluded “When taken orally, THC seems to undergo variable absorption and to have a narrow 'therapeutic window' (dose range in which it is effective without producing significant unwanted effects). This makes it difficult to predict an oral dose that will be both effective and tolerable to a patient and indicates a need for better cannabinoid formulations and modes of administration” Pertwee  summarised in a 2001 review “Mammalian tissues contain at least two types of cannabinoid receptor, CB(1) and CB(2)... CB(1) receptors are expressed mainly by neurones of the central and peripheral nervous system whereas CB(2) receptors occur centrally and peripherally in certain non-neuronal tissues, particularly in immune cells... antinociception can be mediated by cannabinoid receptors other than CB(1) and CB(2) receptors, for example CB(2)-like receptors... one endogenous cannabinoid, anandamide, produces antinociception through mechanisms that differ from those of other types of cannabinoid, for example by acting on vanilloid receptor... the endocannabinoid system has physiological and/or pathophysiological roles in the modulation of pain.” In 2006 Pertwee  concluded “CB1 and/or CB2 receptor activation appears to ameliorate inflammatory and neuropathic pain and certain multiple sclerosis symptoms. This might be exploited clinically by using CB1, CB2 or CB1/CB2 agonists, or inhibitors of the membrane transport or catabolism of endocannabinoids that are released in increased amounts, at least in animal models of pain and multiple sclerosis.”  Robson , reviewing human studies in 2005, noted “More and more scientists and clinicians are becoming interested in exploring the potential of cannabis-based medicines. Future targets will extend beyond symptom relief into disease modification, and already cannabinoids seem to offer particular promise in the treatment of certain inflammatory and neurodegenerative conditions.”

In a 2001 review, Rice  noted “Strong laboratory evidence now underwrites anecdotal claims of cannabinoid analgesia in inflammatory and neuropathic pain.”  Tsou et al  concluded “cannabinoids inhibit the spinal processing of nociceptive stimuli and ... endogenous cannabinoids may act naturally to modify pain transmission within the central nervous system.” Welch et al   reported “Delta(9)-THC and morphine can be useful in low dose combination as an analgesic. .. We hypothesize the existence of a new CB receptor differentially linked to endogenous opioid systems ... Such a receptor, due to the release of endogenous opioids, may have significant impact upon the clinical development of cannabinoid/opioid combinations for the treatment of a variety of types of pain in humans” Martin & Lichtman  concluded “The use of cannabis for the management of a wide range of painful disorders has been well documented in case reports throughout history. ... THC and its synthetic derivatives have been shown to be effective in most animal models of pain. These antinociceptive effects are mediated through cannabinoid receptors in the brain that in turn appear to interact with noradrenergic and kappa opioid systems in the spinal cord to modulate the perception of painful stimuli. The endogenous ligand, anandamide, is also an effective antinociceptive agent.” When considering options for postoperative pain,Dahl & Raeder  concluded “cannabinoids... may become important analgesic drugs.”

In a review  article for the BMJ, Campbell et al  considered “Cannabinoids are no more effective than codeine in controlling pain and have depressant effects on the central nervous system that limit their use. Their widespread introduction into clinical practice for pain management is therefore undesirable. In acute postoperative pain they should not be used. Before cannabinoids can be considered for treating spasticity and neuropathic pain, further valid randomised controlled studies are needed.”  This sparked a lively debate in the letters pages with Campbell’s review being widely-criticised.   Curatolo et al , following a general review of pain management  options, concluded  “Cannabinoid agents produce antinociception and prevent experimentally induced hyperalgesia in animals, and they may find a role in pain management” Iversen   concluded “cannabinoid agonists are antihyperalgesic and antiallodynic in models of neuropathic pain”, but also warned  “Few well controlled trials of cannabis exist for systemic review.”

Du Pont , opposing the use of medical marijuana,  warned “most supporters of smoked marijuana are hostile to the use of purified chemicals from marijuana, insisting that only smoked marijuana leaves be used as "medicine," revealing clearly that their motivation is not scientific medicine but the back door legalization of marijuana.”. In response, Rosenthal & Kleber  proposed “parallel trials on those indications under careful controls making marijuana available to appropriate patients who fail to benefit from standard existing treatments.”

Hollister  considered smoked marijuana should be investigated for efficacy in conditions including chronic pain syndrome. Clark  argued “there is a proportionate reason for allowing physicians to prescribe marijuana. Seriously ill patients have the right to effective therapies. To deny patients access to such a therapy is to deny them dignity and respect as persons.” The US Institute of Medicine  concluded “the available evidence from human and animal studies indicates that cannabinoids can have a substantial analgesic effect.”

In 2002 reviews, Pertwee & Ross  observed “Potential therapeutic uses of cannabinoid receptor agonists include the management of multiple sclerosis/spinal cord injury, pain, inflammatory disorders, glaucoma, bronchial asthma, vasodilation that accompanies advanced cirrhosis, and cancer.” Pertwee  also noted “There is a growing amount of evidence to suggest that cannabis and individual cannabinoids may be effective in suppressing certain symptoms of multiple sclerosis and spinal cord injury, including spasticity and pain... Future research should also be directed at obtaining more conclusive evidence about the efficacy of cannabis or individual cannabinoids against the signs and symptoms of these disorders, at devising better modes of administration for cannabinoids and at exploring strategies that maximize separation between the sought-after therapeutic effects and the unwanted effects of these drugs.”  Fride  noted “Endocannabinoids have been implicated in a variety of physiological functions. The areas of central activities include pain reduction, motor regulation, learning/memory, and reward.”  Walker & Huang  reported “endocannabinods function to control pain in parallel with endogenous opioids but via different mechanisms” adding  “Multiple lines of evidence indicate that endocannabinoids serve naturally to suppress pain. While it is now clear that cannabinoids suppress nociceptive neurotransmission, more work is needed to establish the clinical utility of these compounds. The few human studies conducted to date produced mixed results, with more promising findings coming from studies of clinical pain as compared with experimental pain.”  

Rice et al  stated “Whilst a proportion of the peripheral analgesic effect of endocannabinoids can be attributed to a neuronal mechanism acting through CB(1) receptors expressed by primary afferent neurones, the antiinflammatory actions of endocannabinoids, mediated through CB(2) receptors, also appears to contribute to local analgesic effects.” and Fernandez-Ruiz et al  noted “cannabinoids and related compounds (are) a promising new line of research for therapeutic treatment of a variety of conditions, such as brain injury, chronic pain, glaucoma, asthma, cancer and AIDS-associated effects and other pathologies. Motor disorders are another promising field for the therapeutic application of cannabinoid-related compounds, since the control of movement is one of the more relevant physiological roles of the endocannabinoid transmission in the brain. There are two pathologies, Parkinson's disease and Huntington's chorea, which are particularly interesting from a clinical point of view due to the direct relationship of endocannabinoids and their receptors with neurons that degenerate in those disorders.”  Beaulieu & Rice  concluded “The cannabinoid system is a major target in the treatment of pain and its therapeutic potential should be assessed in the near future by the performance of new clinical trials.”  Reviewing pain relief in MS, Smith  cautioned “In the case of pain, most of the available trials suggest that cannabinoids are not superior to existing treatments; however, few trials have examined chronic pain syndromes”  Walker et al  observed “The brain produces at least five compounds that possess sub-micromolar affinity for cannabinoid receptors: anandamide, 2-arachidonoylglycerol, noladin ether, virodhamine, and N-arachidonoyldopamine (NADA). One function of these and/or related compounds is to suppress pain sensitivity. Much evidence supports a role of endocannabinoids in pain modulation in general, and some evidence points to the role of particular endocannabinoids.”

Fowler  noted “the anaesthetic agent propofol and the non-steroidal anti-inflammatory drugs indomethacin and flurbiprofen (when given spinally), activate cannabinoid receptors as an important part of their actions”  Fowler et al  later commented “With respect to the treatment of pain, topical CB1 agonists and CB2 agonists may prove therapeutically useful, and there is evidence that the non-steroidal inflammatory agent indomethacin produces effects secondary to activation of the endocannabinoid system” and welcomed  “peripherally acting CB agonists and CB2 receptor-selective agonists for the treatment of pain,”  Hough et al  concluded “Present and previous studies suggest that Delta(9)-tetrahydrocannabinol may act at both CB(1) and other receptors to relieve pain”

Grotenhermen  commented in 2004 “Properties of cannabinoids that might be of therapeutic use include analgesia, muscle relaxation, immunosuppression, anti-inflammation, anti-allergic effects, sedation, improvement of mood, stimulation of appetite, anti-emesis, lowering of intraocular pressure, bronchodilation, neuroprotection and antineoplastic effects.” In a 2005 review Grotenhermen  noted “Properties of CB receptor agonists that are of therapeutic interest include analgesia, muscle relaxation, immunosuppression, anti-inflammation, antiallergic effects, improvement of mood, stimulation of appetite, antiemesis, lowering of intraocular pressure, bronchodilation, neuroprotection and antineoplastic effects. The current main focus of clinical research is their efficacy in chronic pain and neurological disorders. CB receptor antagonists are under investigation for medical use in obesity and nicotine addiction. Additional potential was proposed for the treatment of alcohol and heroine dependency, schizophrenia, conditions with lowered blood pressure, Parkinson's disease and memory impairment in Alzheimer's disease.” Russo concluded  “Migraine, fibromyalgia, IBS and related conditions display common clinical, biochemical and pathophysiological patterns that suggest an underlying clinical endocannabinoid deficiency that may be suitably treated with cannabinoid medicines.”  Martin & Wiley  concluded “The endocannabinoid system has been found to be a key modulator of systems involved in pain perception, emesis, and reward pathways.”  Cravatt & Lichtmann  concluded “investigations support a role for endocannabinoids in modulating behavioral responses to acute, inflammatory, and neuropathic pain stimuli.”  Rukwied et al  observed “In clinical studies oral administration of cannabinoids indicated beneficial results during the therapy of multiple sclerosis, weight loss, nausea and vomiting due to chemotherapy, and intractable pruritus. However, therapy of chronic pain conditions revealed conflicting results and unequivocal success could not have been delivered due to unwanted side effects.” Rodriguez de Fonseca et al  concluded “Recent pharmacological advances have led to the synthesis of cannabinoid receptor agonists and antagonists, anandamide uptake blockers and potent, selective inhibitors of endocannabinoid degradation. These new tools have enabled the study of the physiological roles played by the endocannabinoids and have opened up new strategies in the treatment of pain, obesity, neurological diseases including multiple sclerosis, emotional disturbances such as anxiety and other psychiatric disorders including drug addiction.”  However, Killestein et al  warned “convincing scientific evidence that cannabinoids are effective in neurological conditions is still lacking. --However, it is also not possible to conclude definitely that cannabinoids are ineffective”  

Bradshaw & Walker  noted “the growing diversity of recently discovered putative lipid mediators and their relationship to the endogenous cannabinoid system. The possibility that there remain many unidentified signalling lipids coupled with the evidence that many of these yield bioactive metabolites due to actions of known enzymes (e.g. cyclooxygenases, lipoxygenases, cytochrome P450s) suggests the existence of a large and complex family of lipid mediators about which only little is known at this time. The elucidation of the biochemistry and pharmacology of these compounds may provide therapeutic targets for a variety of conditions including sleep dysfunction, eating disorders, cardiovascular disease, as well as inflammation and pain.”  Schneider et al  concluded “cannabinoids may prove useful in... diseases, e.g. movement disorders such as Gilles de la Tourette's syndrome, multiple sclerosis, and pain.”  Corey  concluded “Cannabinoids may be useful for conditions that currently lack effective treatment, such as spasticity, tics and neuropathic pain. New delivery systems for cannabinoids and cannabis-based medicinal extracts, as well as new cannabinoid derivatives expand the options for cannabinoid therapy.”  Radbruch & Elsner  noted “Cannabinoids such as tetrahydrocannabinol offer a valuable add-on option for cancer patients with refractory pain, spasticity, nausea or appetite loss.”  In a review of MS research, Malfitano et al  concluded “increase of the circulating levels of endocannabinoids might have a therapeutic effect, and that agonists of endocannabinoids with low psychoactive effects could open new strategies for the treatment of multiple sclerosis.”

Burstein  concluded “(Ajulemic acid) AJA shows efficacy in models for pain and inflammation. Furthermore, in the rat adjuvant arthritis model, it displayed a remarkable action in preventing the destruction of inflamed joints. A phase-2 human trial with chronic, neuropathic pain patients suggested that AJA could become a useful drug for treating this condition.”

Lynch  concluded “potent antinociceptive and antihyperalgesic effects of cannabinoid agonists in animal models of acute and chronic pain; the presence of cannabinoid receptors in pain-processing areas of the brain, spinal cord and periphery; and evidence supporting endogenous modulation of pain systems by cannabinoids has provided support that cannabinoids exhibit significant potential as analgesics.”  Gourlay  concluded “There is great potential for cannabinoids in the treatment of pain”  Clark et al  recommended “off-label dosing of nabilone… and dronabinol… in the treatment of chronic pain”  Burns & Ineck  concluded “Cannabinoids provide a potential approach to pain management with a novel therapeutic target and mechanism. Chronic pain often requires a polypharmaceutical approach to management, and cannabinoids are a potential addition to the arsenal of treatment options.”  Storr et al  observed “The clinically proven effects in the treatment of pain, cachexia in conjunction with HIV, or malignant disease and treatment of nausea and vomiting in conjunction with chemotherapy now result in the prescription of cannabinoids as valuable medication.”  Azad & Rammes  concluded “the most recent preclinical and clinical data suggest that cannabinoids should be applied as low-dose co-analgesics to inhibit neuroplasticity and central sensitization rather than as analgesics in acute pain”

Investigating migraine, Cupini et al  noted “in migraineur women an increased AEA (anandamide) degradation by platelets, and hence a reduced concentration of AEA in blood, might reduce the pain threshold and possibly explain the prevalence of migraine in women. The involvement of the endocannabinoid system in migraine is new and broadens our knowledge of this widespread and multifactorial disease.”  Mbvundula et al  concluded “Endocannabinoids naturally reduce pain and are cerebroprotective. Natural and synthetic cannabinoids have the potential to reduce nociception, reverse the development of allodynia and hyperalgesia, reduce inflammation and inflammatory pain and protect from secondary tissue damage in traumatic head injury.”

Following a meta-analysis of results from clinical trials of cannabis-based medicines in neuropathic pain, Iskedjian et al  concluded “Cannabinoids including the cannabidiol/THC buccal spray are effective in treating neuropathic pain in MS” In a 2005 review, Azad & Rammes  concluded “Taken together, the most recent preclinical and clinical data suggest that cannabinoids should be applied as low-dose co-analgesics to inhibit neuroplasticity and central sensitization rather than as analgesics in acute pain.” Cox et al  concluded “the cannabinoid CB(2) receptor plays a critical role in cannabinoid-mediated antinociception, particularly in models of chronic inflammatory pain” Beaulieu & Ware  cautioned “The precise role of cannabinoids in pain treatment still needs further evaluation. Cannabinoid compounds may be more effective in the context of chronic neuropathic pain than for the management of acute pain.”

Side Effects of Cannabis & Cannabinoids

Until the last decade, the vast majority of research on cannabis was designed to find dangers and health risks associated with illicit use of cannabis, with therapeutic research developing relatively recently.  Unlike most pharmaceutical drugs, cannabis was thoroughly tested for safety long before any tests of ‘efficacy’ were carried out.  Robson , reviewing the medicinal uses over a range of conditions, reported “Cannabis is safe in overdose but often produces unwanted effects, typically sedation, intoxication, clumsiness, dizziness, dry mouth, lowered blood pressure or increased heart rate.”  The most common side-effect of therapeutic use of cannabis is the ‘drug high’

In a general 2003 review of cannabis and brain function, Iversen observed  “Central effects of cannabinoids include disruption of psychomotor behaviour, short-term memory impairment, intoxication, stimulation of appetite, antinociceptive actions (particularly against pain of neuropathic origin) and anti-emetic effects. Although there are signs of mild cognitive impairment in chronic cannabis users there is little evidence that such impairments are irreversible, or that they are accompanied by drug-induced neuropathology. A proportion of regular users of cannabis develop tolerance and dependence on the drug. Some studies have linked chronic use of cannabis with an increased risk of psychiatric illness, but there is little evidence for any causal link”.  

Although smoking cannabis, as with tobacco or other vegetable matter, can cause lung irritation and increase the risk of bronchitis or cancer, this route does provide a more rapid onset of relief, and allows greater control over dosage levels than oral preparations, where the slow onset of effects can lead to a greater risk of overdose.  The carcinogenicity of cannabis smoke is unclear, the smoke contains a number of known carcinogens, however, among others, Guzman  observes that cannabinoids “have been shown to inhibit the growth of tumour cells in culture and animal models by modulating key cell-signalling pathways.” Radbruch & Nauck  warned “Side effects on the respiratory system are induced by inhaling the smoke of cannabis cigarettes. Some reports have indicated a carcinogenic risk for the children when cannabis was used during pregnancy. In summary, a low risk profile is evident from the literature available. Life-threatening complications are very rare and were not reported after use of cannabinoids for medical indications. Cannabinoids are contraindicated during pregnancy or for patients with a history of cardiac ischemias.” Smith  warned “There is... reason to be concerned about the use of therapeutic cannabinoids by people predisposed to psychosis and by pregnant women, given the increasing evidence of their adverse effects on the fetus.”

Budney et al  identified aspects of cannabis withdrawal in a controlled human trial “A withdrawal pattern was observed for aggression, anger, anxiety, decreased appetite, decreased body weight, irritability, restlessness, shakiness, sleep problems, and stomach pain. Onset typically occurred between Days 1-3, peak effects between Days 2-6, and most effects lasted 4-14 days.”  Haney et al  compared oral THC, a mood-stabiliser (Divaloprex) and placebo in a clinical trial investigating the effects of cannabis withdrawal, and commented “Divalproex decreased marijuana craving during abstinence, yet increased ratings of 'anxious', 'irritable', 'bad effect', and 'tired.' Divalproex worsened performance on psychomotor tasks, and increased food intake regardless of marijuana condition. Thus, oral THC decreased marijuana craving and withdrawal symptoms at a dose that was subjectively indistinguishable from placebo. Divalproex worsened mood and cognitive performance during marijuana abstinence. These data suggest that oral THC, but not divalproex, may be useful in the treatment of marijuana dependence.”

Cannabis contains over 200 chemical compounds, several of which may have a beneficial, or harmful, effect either working alone, or in concert with other compounds.   There is now a scientific consensus of the efficacy of THC and other cannabinoids as analgesic (pain relieving) agents.  The volume of scientific evidence grows on a daily basis, and several credible mechanisms involved in the mediation of pain by external or endogenous cannabonids have been demonstrated, with major implications for the field of neurochemistry as a whole.  Cannabinoids appear to modulate the way pain is perceived, regulating the pain threshold, and also increasing the efficacy and duration of action of other pain-relieving drugs.  There is evidence suggestive of cannabinoid receptors playing a role in the analgesia from non-steroidal anti-inflammatory drugs such as ibuprofen and paracetamol.  The general reduction of muscle tone and specific effects on muscle spasms, indicate cannabis or cannabinoids to have a potential therapeutic role in the management of chronic musculoskeletal and/or visceral pain.

There is an overwhelming body of research, originally historical and/or anecdotal, but supported by a vast number of recent laboratory studies on animal and human models, to demonstrate increased tolerance of pain from administration of cannabis or individual, cannabinoids, including THC.  A ‘pain-threshold’ regulatory area has been found in the rostal ventromedial medulla mediated by cannabinoid receptors, and other researchers have identified roles for cannabinoid analgesia within other areas in the central nervous system and periphery. Walker et al  summarised the state of knowledge thus “Cannabinoids have been used to treat pain for many centuries. However, only during the past several decades have rigorous scientific methods been applied to understand the mechanisms of cannabinoid action. Cannabinoid receptors were discovered in the late 1980s and have been found to mediate the effects of cannabinoids on the nervous system. Several endocannabinoids were subsequently identified. Many studies of cannabinoid analgesia in animals during the past century showed that cannabinoids block all types of pain studied. These effects were found to be due to the suppression of spinal and thalamic nociceptive neurons, independent of any actions on the motor systems. Spinal, supraspinal and peripheral sites of cannabinoid analgesia have been identified. Endocannabinoids are released upon electrical stimulation of the periaqueductal gray, and in response to inflammation in the extremities. These observations and others thus suggest that a natural function of cannabinoid receptors and their endogenous ligands is to regulate pain sensitivity.”

The 1997 BMA report recommended “The prescription of Nabilone, THC and other cannabinoids should be permitted for patients with intractable pain.  Further research is needed into the potential of cannabidiol”  Clinical trials underway demonstrate cannabinoid extracts to be capable of producing pain relief ranging from moderate to ‘life changing’, and to reduce the levels of opiate painkillers used by patients.

Research has established a neurochemical mechanism for the action of cannabis (THC), based on a 'cannabis receptor' and an endogenous ligand known as 'anandamide'.  The mode of action appears to be the modulation of the responses to incoming stimuli mediated by a 'second messenger' system.  The body’s natural cannabinoids may be used to ‘turn up or down the body’s pain thresholds.  There is also increasing evidence of anti-inflammatory activity of cannabidiol (CBD).

Early Clinical trials had conflicting results, with many studies finding the drug effects not superior to placebo – later trials demonstrate sustained benefit for most, but not all, patients.  The dosages used in early studies tend to be much lower than commonly experienced by recreational drug users, in order to avoid ‘unmasking’ (subjects becoming aware of the difference between active drug and placebo), or undesirable side effects in the form of a drug ‘high’.  Studies involving oral THC have proven particularly susceptible to adverse effects, whereas sublingual THC/CBD extracts in spray form, and novel specific cannabinoids have shown more promising results.

Recent developments have found the endocannabinoid system to be integral to the control of pain whether by opiates or non-steroidal anti-inflammatory drugs or Cox-2 inhibitors.  The receptor distribution is widespread in both central nervous system and peripheral tissues.  The psychotropic effects limit the use of raw cannabis or THC in non-users of cannabis, who find such effects distressing.  Current or former recreational users of cannabis would not generally regard such effects as adverse.  The adjunctive use of cannabidiol (CBD) to minimize the psychotropic effects of THC (the high, and also risk of psychotic symptoms) may improve tolerability of treatments among the general population.  

More specific drugs acting selectively on peripheral CB-2 receptors, and enzyme inhibitors preventing the breakdown of endocannabinoids offer a potential to separate the analgesic effects from the drug high, and point to a mainstream role of cannabinoid medicines in the management of pain.  Further drug development may concentrate on inhibiting the enzymes which break down endocannabinoids in order to boost their levels in the systems concerned.