Is Cannabis an Effective Treatment for Joint Pain? R.J
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Is cannabis an effective treatment for joint pain? R.J. Miller1, R.E. Miller2 1Department of Pharmacology, ABSTRACT Introduction Northwestern University, Chicago; Cannabis has been used to treat pain Pain is one of the primary symptoms 2 Department of Internal Medicine, for thousands of years. However, since of joint disease and the major reason Division of Rheumatology, Rush University the early part of the 20th century, laws why patients seek medical advice. Un- Medical Center, Chicago, IL, USA. restricting cannabis use have limited fortunately, at this point in time, we Richard J. Miller, PhD its evaluation using modern scientific do not have a detailed understanding Rachel E. Miller, PhD criteria. Over the last decade, the situa- of how joint pain is generated under Please address correspondence to: tion has started to change because of the Dr Richard J. Miller, pathological conditions. When treating Department of Pharmacology, increased availability of cannabis in the osteoarthritis (OA) pain, non-steroidal Northwestern University, United States for either medical or recre- anti-inflammatory drugs (NSAIDs) are Chicago, IL, USA. ational purposes, making it important to usually the initial drugs of choice in pa- E-mail: [email protected] provide the public with accurate informa- tients with mild to moderate pain (1, 2). Received and accepted on September 9, tion as to the effectiveness of the drug for However, the chronic use of NSAIDS 2017. joint pain among other indications. The is often problematic, particularly with Clin Exp Rheumatol 2017; 35 (Suppl. 107): major psychotropic component of can- elder patients owing to gastrointestinal S59-S67. nabis is ∆9-tetrahydrocannabinol (THC), and renal side effects. Opiates may be © Copyright CLINICAL AND one of some 120 naturally occurring considered for patients who continue EXPERIMENTAL RHEUMATOLOGY 2017. phytocannabinoids. Cannabidiol (CBD) to have severe pain and who do not re- is another molecule found in herbal can- spond or cannot tolerate NSAIDs, and Key words: cannabis, nabis in large amounts. Although CBD can provide relief in a subset of patients phytocannabinoid, endocannabinoid, does not produce psychotropic effects, (1, 2), but tolerance, dependence and joint pain it has been shown to produce a variety other adverse effects such as consti- of pharmacological effects. Hence, the pation often occur during continuous overall effects of herbal cannabis repre- opioid use. Another serious problem is sent the collective activity of THC, CBD their abuse potential. Thus, even though and a number of minor components. The long term use of opiates may sometimes action of THC is mediated by two major produce pain relief, the current epi- G-protein coupled receptors, cannabi- demic of opiate addiction in the United noid receptor type 1 (CB1) and CB2, States clearly demonstrates the down- and recent work has suggested that other side of using opiates as anodynes over targets may also exist. Arachidonic acid extended periods of time. Although it derived endocannabinoids are the nor- is unlikely that the use of NSAIDS for mal physiological activators of the two the treatment of joint pain will be com- cannabinoid receptors. Natural phyto- pletely replaced in the near future, alter- cannabinoids and synthetic derivatives native treatments that are both effective have produced clear activity in a variety and safe would be extremely welcome. of models of joint pain in animals. These One way these may be developed is effects are the result of both inhibition of through a better understanding of the pain pathway signalling (mostly CB1) physiology and pharmacology of the and anti-inflammatory effects (mostly nerves that produce joint pain allow- CB2). There are also numerous anecdo- ing the rational development of novel tal reports of the effectiveness of smok- agents that selectively regulate their ac- ing cannabis for joint pain. Indeed, it is tivity. However, there are also currently the largest medical request for the use of several possible avenues available that the drug. However, these reports gener- might produce new agents for the treat- Funding: Richard Miller was supported ally do not extend to regulated clinical by the US National Institutes of Health/ ment of joint pain. One of the most ob- National Institute of Arthritis and Musculo- trials for rheumatic diseases. Neverthe- vious of these is cannabis. skeletal and Skin Diseases (NIH/NIAMS) less, the preclinical and human data that Cannabis is anything but a new drug, (R01AR064251). Rachel Miller was do exist indicate that the use of cannabis having been used by humans for medi- supported by NIAMS (K01AR070328). should be taken seriously as a potential cal purposes for thousands of years. Competing interests: none declared. treatment of joint pain. Some of the earliest evidence for Clinical and Experimental Rheumatology 2017 S-59 Cannabis for joint pain / R.J. Miller & R.E. Miller knowledge of the psychoactive prop- valuable source of tough fibrous mate- to the use of cannabis beside its psy- erties of cannabis can be found in the rial, which is the basis of hemp cloth. chotropic actions, including effects on Shen-nung pen-ts’ao ching, the world’s Indeed, another term for cannabis is appetite, pain, metabolism and inflam- oldest pharmacopeia, which describes “hemp” or “Indian hemp.” However, mation, Alzheimer’s disease, multi- Chinese practices from the time of Em- as discussed above, the plant has also ple sclerosis, stroke, traumatic brain peror Shen Nung (c. 2700 B.C.) (3). always been used for its beneficial me- injury, Parkinson’s disease, epilepsy, Later editions clearly describe the use dicinal effects. Pharmacologically ac- and various aspects of cancer (pain, of cannabis for a variety of conditions, tive parts of the plant include the leaves nausea, etc.). The list is endless. This including treating pain and inflamma- and flowering tops and particularly the raises an interesting question. Which tion (3). Indeed, cannabis has been con- resin (hashish, charas) that is secreted phytocannabinoids are responsible for tinuously used for the treatment of pain by glands (trichomes) in the stems, all of these therapeutic effects? Is THC in Asian countries from prehistory up flowers and leaves of the plant (5). The responsible for all of them or are there until the present day (3). The drug was drug can be smoked, eaten or extracted contributions of the other molecules as subsequently introduced into Europe using alcohol to produce a tincture. well? Smoking or eating cannabis will and the United States in the 19th century As organic chemistry developed in the obviously involve ingesting a large and soon became widely used for its an- early part of the 19th century, progress number of different phytocannabinoids. algesic and other properties (4, 5). began to be made in isolating the mole- Moreover, the exact combination of So what happened? As the reader may cules responsible for the pharmacologi- molecules ingested will depend on the be well aware, the highly restrictive cal effects of natural products. Starting strain of cannabis used, growth condi- legal status of cannabis in the United with morphine in 1805, numerous alka- tions and numerous other factors. It is States and Europe beginning in the ear- loids were isolated from different natu- therefore essential to deconvolute the ly part of the 20th century has made rig- ral sources, which helped to “explain” effects of all of the major phytocan- orous clinical evaluation of its effects pharmacological activities associated nabinoids on a particular endpoint such using modern criteria virtually impossi- with these materials. However, the iden- as pain if we wish to understand the po- ble. This situation has recently started to tity of the substances responsible for the tential effects of the drug. In particular, change. In spite of the fact that Federal pharmacological effects of herbal can- when considering the potential effects laws still list cannabis as a Schedule I nabis remained elusive until well into of cannabis, we should be interested in drug “having no medical utility”, many the 20th century, and it was not until 1964 the actions of both THC and CBD, the individual states have moved to make that ∆9-tetrahydrocannabinol (THC) two major phytocannabinoids, as well the drug legal for “medical” purposes, was shown to be the component of herb- as any beneficial interactions between or even for recreational use in some al cannabis responsible for producing its them, and whether cannabis is superior instances. It is therefore time to assess psychotropic effects (5). Interestingly, to either pure substance used by itself. whether we might expect cannabis to THC does not contain a nitrogen atom be effective for joint pain and, ancient and so is not an alkaloid, distinguish- The endocannabinoid system texts aside, what clear indications there ing it from many of the natural prod- What is the signal transduction mecha- are from the scientific point of view for ucts isolated from other plant sources. nism through which cannabinoids act? believing that it might be useful. It also explains its lipid like properties Two major observations “explain” the This raises several questions. First of that make it chemically difficult to work effects of THC. Two G-protein cou- all, what is cannabis and what active with. THC is the archetypal member of pled receptors have been identified that molecules does it contain? Second, the family of cannabis derived mole- mediate its cellular effects. These two what is the evidence that any of these cules which are known as cannabinoids receptors, known as cannabinoid recep- components might have beneficial ef- or, considering subsequent develop- tor type 1 (CB1) (8) and CB2 (9), have fects on joint pain? Third, is there any ments in the field of cannabis medicinal closely related amino acid sequences. evidence that these substances do ac- chemistry, phytocannabinoids, indicat- Their transmembrane regions are ap- tually ameliorate joint pain in animals ing that they are natural plant products proximately 70% similar (9), and they and humans? (6).