Cannabis has been utilized as a medicine and in various cultural practices for millennia with accounts of its use dating back over 5000 years.¹ There is reference to the use of cannabis for the treatment of headache from the sixth and seventh centuries.² In the mid-1800s, reports of the therapeutic potential of cannabis entered the medical literature and its use became more widespread.³ However, in the early twentieth century, cannabis was increasingly scrutinized for its psychoactive effects and recreational use, and it was removed from the US Pharmacopoeia in 1942.⁴ Nonetheless, preclinical studies continued and many neurobehavioral tests confirmed its analgesic effects.^5–8 In addition to its use for analgesia, cannabis is under investigation for use in a number of neurological disorders, glaucoma, and as an antiemetic and appetite stimulant.

In the United States, the use of medical marijuana continues to be a politically charged issue. In November 1996, voters in the states of California and Arizona passed referenda designed to permit the use of marijuana as a medicine, though Arizona’s referendum was invalidated 5 months later. Since then, several states have passed ballot initiatives in support of medical marijuana. In January 1997, the White House Office of National Drug Control asked the Institute of Medicine to conduct a review of scientific evidence to assess the health risks and benefits of marijuana. The 1999 Institute of Medicine report contained several recommendations regarding medical marijuana which stated: 1) research should continue into the physiologic effects of synthetic and plant-derived cannabinoids; 2) development of new delivery systems should be pursued;3) the psychological effects of cannabis should be evaluated; 4) studies to define health risks of smoked marijuana should be conducted, and; 5) clinical trials should involve short-term use, reasonable expectations of efficacy, and approval by an Institutional Review Board. The report stated that short-term use of smoked cannabis for patients with debilitating symptoms must meet the following conditions: (1) failure of approved medications, (2) reasonable expectation of efficacy, (3) administration under medical supervision, and (4) inclusion of an oversight strategy.⁹

1999 Institute of Medicine Recommendations for Research Focus of Medical Marijuana

1. 
   

   Physiologic effects of synthetic and plant-derived cannabinoids

   
   
2. 
   

   Development of new delivery systems

   
   
3. 
   

   Psychological effects of cannabis

   
   
4. 
   

   Health risks of smoked marijuana

The two cannabinoid receptors are CB1 and CB2.^10,11 The term cannabinoid refers to a variety of compounds which are (1) derived from cannabis plants (phytocannabinoids), (2) endogenous cannabinoids (referred to as endocannabinoids), and (3) synthetic cannabinoids.¹²

Cannabis is a genus of flowering plants that contain three species: Cannabis sativa (the largest variety), C indica, and C ruderalis. The popular name, marijuana, refers to the dried leaves and flowers of C sativa, which are most commonly smoked.⁴ Marijuana contains nearly 500 known compounds, of which more than 80 are classified as cannabinoids.¹³ The main psychoactive compound in cannabis is Δ⁹-tetrahydrocannabinol (THC).¹⁴ Additional cannabinoids in the cannabis plant are cannabidiol (CBD) and cannabinol (CBN). CBD is the second most abundant compound in cannabis following THC.¹⁵ It is less psychoactive than THC and has a low affinity for the CB1 and CB2 receptors.^16,17 CBD appears to enhance the effects of THC but it is unclear if this is due to a pharmacokinetic or pharmacodynamic interaction.¹⁸ CBN is found in trace amounts in cannabis and is a metabolite of THC.^19–22 It has weak CB receptor affinity but because of its higher affinity for the CB2 over CB1 receptor, it may have more anti-inflammatory effects.

A cannabis-based medicine extract (CBME) is derived by extraction of compounds from the marijuana plant. Two CBMEs have undergone clinical trials: Cannador and nabiximols (Sativex). Cannador is a CBME delivered in oral capsules with differing THC:CBD ratios.²³ Nabiximols is a sublingual spray that contains THC and CBD currently in phase III trials for cancer pain.^16–18,24

The two major endocannabinoids are anandamide and 2-arachidonoyl-glycerol (2-AG) and are discussed in the endocannabinoid system.

Cannabinoid Sources

Phytocannabinoids

1. 
   

   Cannabis-based plant extracts

   
   
   
   
   1. 
      

      Nabiximols

      
      
   2. 
      

      Cannador

Endocannabinoids

2. 
   

   Anandamide

   
   
3. 
   

   2-arachidonoylglycerol (2-AG)

Synthetic cannabinoids

4. 
   

   Synthetic THC (dronabinol)

   
   
5. 
   

   Synthetic analog of THC (ajulemic acid)

   
   
6. 
   

   Semisynthetic analog of THC (nabilone)

Three synthetic cannabinoids have undergone clinical trials: dronabinol (Marinol), nabilone (Cesamet), and ajulemic acid (CT3). The synthetic Δ⁹-THC analog dronabinol has been marketed in the United States since 1985 for treatment of nausea associated with chemotherapy and as an appetite stimulant in HIV/AIDS. It is currently available as generic, which eliminates some of the cost that precluded its use in the treatment of pain. Nabilone is a semisynthetic Δ⁹-THC analog approximately 10 times more potent than dronabinol with a longer duration.²⁵ In the United States, nabilone is FDA-approved for treatment of chemotherapy-induced nausea. Ajulemic acid is a synthetic Δ⁹-THC analog currently undergoing clinical trials for treatment of pain.

The endocannabinoid system refers to the ligands anandamide and 2-AG, enzymes involved in their synthesis and breakdown, and the CB1 and CB2 receptors²⁶ (Fig. 75-1). CB1 is located in the brain, spinal cord and on primary sensory nerve terminals. CB2 is found on microglia, monocytes, macrophages, B, and T lymphocytes. Both receptors belong to the G-protein coupled receptor superfamily. As such they contain seven transmembrane spanning domains. CB1 and CB2 receptors are coupled through G_i/o proteins, negatively to adenylate cyclase (inhibiting the production of cyclic AMP; cAMP) and positively to mitogen-active protein kinase (MAPK).²⁷ Additionally, CB1 has been shown to be coupled positively to inwardly rectifying and A-type outward potassium channels, and negatively to N-type and P/Q type calcium channels. The endocannabinoid, 2-AG, is synthesized in postsynaptic neuron and acts as a retrograde signaling molecule. This synthesis results from the activation of the glutamate receptor which in turns activates the phospholipase C–diacylglycerol lipase pathway to generate 2-AG from membrane phospholipid precursors. Anandamide is an amide of ethanolamine and arachidonic acid. It is generated from its membrane precursor, N-arachidonoyl phosphatidylethanolamine (NAPE) through cleavage by phospholipase D. 2-AG is degraded in the presynaptic terminal by monoacylglycerol lipase (MAG). Anandamide is degraded in the postsynaptic terminal by fatty acid amino hydrolase (FAAH) and is a low-efficacy agonist similar to Δ⁹-THC. 2-AG is far more abundant than anandamide and is considered a high-efficacy agonist.²⁸

2-AG and anandamide bind to presynaptic CB1 receptors with a resultant decrease in neurotransmitter (both excitatory and inhibitory) release. Activation of CB1 receptors on the peripheral terminal of primary sensory afferents has been shown to decrease terminal excitability and the release of proinflammatory mediators. Activation of CB2 on peripheral cells has been shown to decrease inflammatory cell mediator release, plasma extravasation, and the sensitization of afferent terminals. Additionally, activation of CB receptors by agonists leads to a reduction of elevated terminal excitability otherwise induced by local injury and inflammation.²⁸

In the rat dorsal horn, the CB1 receptor has been demonstrated to be partially co-localized with TRPV1 on the presynaptic terminals of peptidergic and nonpeptidergic primary afferents.²⁸ Activation of CB1 by agonists leads to decreased influx of calcium through N/P/Q voltage-sensitive calcium channels that results in decrease in neurotransmitter release from the primary afferent. In the postsynaptic neuron, CB1 mRNA has been demonstrated in Laminae I-V and X. CB1 agonists that bind to postsynaptic CB1 receptors lead to increase conductance through potassium channels, with a resultant membrane hyperpolarization and decreased excitability.²⁸

CB1 receptors in the brain are found in the periaqueductal gray, basolateral amygdala, and rostroventral medulla. Activation of CB receptors in these regions can have local effects on nociceptive processing and affect bulbospinal pathways which regulate dorsal horn excitability.

Concentrations of THC and other cannabinoids in marijuana vary widely depending on growing conditions, plant genetics, and processing after harvest.¹³ Naturally occurring marijuana has THC concentrations from 0.3% to 4% by weight; however, specially grown marijuana can contain 15% or more THC.^29,30

Compared with other psychoactive drugs, THC is quite potent. Despite potent psychoactivity and pharmacologic actions on multiple organ systems, cannabinoids have remarkably low lethal toxicity and lethal doses in humans are not known.^31,32 There is a significant difference in the pharmacology of THC between smoking and oral administration.

INHALED VERSUS ORAL VERSUS SUBLINGUAL DELIVERY OF CANNABINOIDS

THC is extremely lipid soluble. The bioavailability and pharmacokinetics of THC from smoked marijuana are substantially different from those of the oral form. When marijuana is smoked, aerosolized THC in the inhaled smoke is absorbed within seconds and delivered to the brain. The absorption kinetics is typical of a very lipid-soluble drug with peak venous blood levels occurring soon after initiating smoking. A serum level absorption curve of THC when marijuana is smoked is similar to IV administration. The bioavailability averages about 30%^33–35

By contrast, with oral administration, maximum THC and other cannabinoid blood levels are reached only 1 to 3 hours after an oral dose and the onset of psychoactive and other pharmacologic effects are much slower. Bioavailability is 5% to 20% due to erratic absorption from the stomach and small intestine and a large first-pass metabolism by the liver.^29,30,36

Nabiximols is a sublingual spray that contains the CBME combination of THC and CBD. It is approved in Canada to treat spasticity related to multiple sclerosis and is in phase III trials in the United States for treatment of cancer-related pain. Each spray delivers 2.7 mg of THC and 2.5 mg of CBD. As discussed, CBD appears to enhance the effects of THC; however, it is unclear if this is due to a pharmacokinetic or pharmacodynamics interaction.^37,38 Sublingual spray formulation has been developed to improve bioavailability above the oral delivery. However, the bioavailability and pharmacokinetics of both sublingual spray and oral delivery are similar.³⁶

EFFECTS OF Δ⁹-TETRAHYDROCANNABINOL: ACUTE AND CHRONIC

Cannabis induces an acute, psychoactive, mildly euphoric, relaxing intoxication or “high” that leads to slight changes in psychomotor and cognitive function. In limited cases, cannabis can also induce unpleasant effects including anxiety, panic, and paranoia. In rare cases, it may lead to acute psychosis involving delusions and hallucinations. Although CBD is not psychoactive, it has significant anticonvulsant, sedative, and other pharmacologic activities likely to interact with THC.^39,40,41

The effect of chronic use of marijuana is the subject of much investigation. Forty studies reviewed on the use of cannabis could not detect consistent evidence for persisting neuropsychological deficits in cannabis users. Twenty of the 40 studies reported at least some subtle impairment. Another study reviewed 11 articles providing data for a total of 623 cannabis users and 409 nonusers or minimal users. It concluded that there might be decrements in the ability to learn and remember new information, whereas other cognitive abilities are unaffected. There is concern that the chronic use of cannabis in adolescents may affect brain development.^42–44

There has been recent concern over the adverse effects of cannabis on adolescent brain development. Studies have suggested that long-term cannabis use is associated with harm to a person’s intelligence if started younger than 18 years of age.^45,46 However this was challenged in a subsequent analysis of the data stating that when socioeconomic status was factored, the true effect was closer to zero.⁴⁷ In addition, a study at the University of California, San Diego, failed to show any adverse effects on the adolescent brains from cannabis use. The researchers compared brain scans for subjects 16 to 20 years old that used alcohol and those that used cannabis. They observed that alcohol but not cannabis resulted in a reduction in white matter in scanned brains.⁴⁸

PRECLINICAL STUDIES

Preclinical studies have confirmed the analgesic effect of cannabis. Cannabis has been shown to have antinociceptive properties in preclinical models of acute, inflammatory, neuropathic, and visceral pain. The largest antinociceptive effect of CB1 is mediated at the spinal level. CB2 effects are more prominent in states of inflammatory and visceral pain and are mediated more in the periphery than at the spinal level.^49–51

CLINICAL STUDIES

Careful interpretation of human studies involving cannabinoids is necessary as there are a number of variables that can affect outcomes. Variables include the route of administration (oral or inhaled), the drugs studied (synthetic Δ⁹-THC, other synthetic cannabinoids, or inhaled cannabis), and the dosages of studied drugs. Other factors include the study design and if it involves experimental pain or clinical pain.³¹

Studies in Healthy Volunteers

Studies in healthy volunteers that involve experimentally induced pain have produced mixed results. Several studies demonstrated that cannabis increases the pain threshold suggesting an analgesic effect. Other studies have found either no effect on pain thresholds or even an increase in pain (a lowering of the pain threshold).^52–57 A randomized controlled trial (RCT) conducted by Wallace et al. demonstrated dose-dependent effects of smoked cannabis on capsaicin-induced pain and hyperalgesia in healthy volunteers. Compared with placebo, cannabis cigarettes with 2% THC produced no effect on pain, 4% THC significantly decreased pain, and 8% THC significantly increased pain.⁵⁸ Abrams et al. used the 4% THC dose to evaluate effects on capsaicin-induced pain in HIV patients. They showed a significant effect on both neuropathic pain and experimental pain.⁵⁹ These studies suggest that there is a therapeutic window for cannabis and emphasize that dosage and route of administration are likely to have a substantial effect on the results of a study. The therapeutic window observed in these studies is consistent with the phase II results of nabiximols in which the low dose but not the high dose met the primary endpoint.

Studies in Clinical Pain

Clinical studies that are well designed are limited. A comprehensive literature review identified only 14 studies that used a randomized, double-blind, and placebo-controlled design. They vary in the cannabinoid studied, dosages used, and routes of administration. They are discussed and grouped following according to the type of pain that was studied.

CANCER PAIN

Clinical studies with cannabinoids were first conducted in patients with cancer pain and account for the largest number of human studies. One study involved 10 patients with various cancers who were administered oral THC at 5, 10, 15, and 20 mg dosages. The results showed pain relief significantly better than placebo at dosages of 15 and 20 mg, but also noted that these dosages produced substantial confusion and sedation.⁶⁰ Another study by the same authors examined 36 patients with various cancers and compared oral THC at 10 and 20 mg dosages to codeine.⁶¹ THC at 10 and 20 mg was found to be equianalgesic to 60 and 120 mg codeine, respectively. Again, 20 mg THC produced unpleasant drowsiness and mental cloudiness, but 10 mg THC was relatively well tolerated.

Two studies investigated the effects of 4 mg of benzopyranoperidine, a synthetic analog of THC in patients with cancer pain. The first study found benzopyranoperidine superior to placebo and equivalent to 50 mg codeine; the second study found it superior to both placebo and secobarbital. Sedation was the largest adverse effect, but it occurred with similar instances for both the study drug and the comparison drugs.⁶² In contrast, a study in which benzopyranoperidine was compared to codeine and placebo in patients with cancer pain, found that at dosages of 2 and 4 mg, benzopyranoperidine was less effective than 60 and 120 mg codeine and was no more effective than placebo.⁶³ The authors reported that pain was augmented by benzopyranoperidine and found an incidence of sedation similar to codeine. It is difficult to draw conclusions from these studies as the patient population was heterogenous (i.e., suffering from different forms of cancer).