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Cannabinoids in rheumatology: Friend, foe or a bystander?

Abstract Objectives Cannabinoids have gained popularity recently with special emphasis on their use for chronic pain. Although NICE guidelines advise against their usage for management of chronic pain, almost all rheumatologists encounter a few patients in their daily practice who either use them or are curious about them. We reviewed the mechanism of action of cannabinoids, current knowledge about their role in rheumatology and potential drug interactions with common drugs used in Rheumatology. We attempted to answer the question “If cannabinoids are friend, foe or just a mere bystander?” Methods We adhered to a search strategy for writing narrative reviews as per available guidelines. We searched PubMed with the search terms “Cannabinoids”, “Rheumatology” and “Chronic pain” for published articles and retrieved 613 articles. The abstracts and titles of these articles were screened to identify relevant studies focusing on mechanism of actions, adverse effects and drug interactions. We also availed the services of a musculoskeletal librarian. Results Despite the NHS guidelines against the usage of cannabinoids and associated significant stigma, cannabinoids are increasingly used for the management of pain in rheumatology without prescription. Cannabinoids act through two major receptors CB1 and CB2, which are important modulators of the stress response with potential analgesic effects. Their role in various rheumatological diseases including Rheumatoid arthritis, Osteoarthritis and Fibromyalgia have been explored with some benefits. However, in addition to the adverse effects, cannabinoids also have some potential interactions with common drugs used in rheumatology, which many users are unaware of. Conclusion While the current studies and patient reported outcomes suggest cannabinoids to be a “friend” of rheumatology, their adverse events and drug interactions prove to be a “Foe”. We were unable to arrive at a definite answer for our question posed, however on the balance of probabilities we can conclude cannabinoids to be a “foe”. Under these circumstances, a disease and drug focussed research is need of the hour to answer the unresolved question.

NICE (NG144) does not recommend cannabis-derived products for the management of chronic pain in adults with the conclusion that the available evidence is modest in comparison to the high cost (NICE, 2019).
In the absence of any consistent guidelines and recommendations for cannabinoid usage in rheumatology, we performed a comprehensive literature search for evidence of the efficacy, tolerability and safety of cannabinoids, including mechanism of action and drug interactions with commonly used medications in rheumatology.

| METHODS
We undertook a detailed review of the use of cannabinoids in rheumatology including their mechanism of action, adverse effects and drug interactions.
We adhered to a search strategy for writing narrative review.
We searched PubMed with the search terms 'Cannabinoids', 'Rheumatology' and 'Chronic pain' in articles published and retrieved 613 results. The abstracts and titles of these articles were screened to identify relevant studies and articles. Besides, we also took help from the musculoskeletal librarian of our department.
This review focuses on the mechanism of action of cannabinoids, current knowledge about their role in rheumatology, adverse effects and potential drug interactions. Licences for CBD oils as medicine have not been granted; however, these products can still be sold as long as no claims about their medical benefits are made.

| The legal status of cannabinoids in the United Kingdom
Sativex, which is a 50-50 mix of THC and CBD, has been approved for use in the United Kingdom as a treatment for spasticity associated with multiple sclerosis (CPFG Drugs and Alcohol Unit, 2018; NICE, 2019).

| Perception towards complimentary medicine
Complimentary medicine including cannabinoids are widely used across various specialities. In our cross-sectional survey on the use of complimentary medicine in rheumatology, 31.8% patients reported using alternative therapies for pain management (Tharakan et al., 2019).
One self-reported study on the prevalence of cannabinoid use in fibromyalgia patients reported 13% of all patients use cannabinoids, with 80% using herbal cannabis (marijuana), 24% using prescription cannabinoids, and three percent using both herbal cannabis and prescription cannabinoids (Ste-Marie et al., 2012).

| The stigma attached in the general population
There is a significant stigma attached to the use of cannabinoids.
Most of it stems from negative addictive and psychological impact due to the THC component of cannabis. In a study exploring the experiences of therapeutic cannabinoid users, it was found that stigma arose significantly in interactions with family members and close friends, as well as from others in society (Bottorff et al., 2013).
These findings suggested complex and overlapping factors that result in stigmatisation experienced by cannabinoid users due to the ambiguous status of cannabis, lack of acknowledgement about medical cannabis and stigma associated with health disorders. While there is a gradual public acceptance, there continues to be a stigma at interpersonal and institutional levels (Bottorff et al., 2013).
Stigma stems from external and internal sources. External sources include friends, family, healthcare providers and law enforcement, while the internal sources are that of guilt and discomfort related to using a medication that is often used illegally and for recreational purposes. Thus, there is an overt need for further research and education regarding the potential use of cannabinoids as therapeutic targets.

| Forms of cannabinoids currently available
Cannabis plants (Cannabis sativa) are made up of more than 100 different cannabinoids, having different effects on the body with variable concentrations present in different parts of the plant. Their cultivation and utilisation can be traced back to 10,000 BC with the first evidence of their medicinal use as an analgesic in 4000 BC (Warf, 2014). Most common forms known are CBD and THC. THC is the component responsible for psychoactive effects. CBD does not have any psychoactive effect.

| Pharmacokinetics
Knowledge of the pharmacokinetics of any drug is essential to understand the onset, magnitude and duration of their pharmacodynamic effects, to maximise therapeutic and minimise negative side effects.
Oral bioavailability of CBD are around 6% while smoking provides around 2%-56% (Huestis, 2007). Inhalation through a vapouriser has a rapid therapeutic effect, whereas oral ingestion has a slower but more sustained effect (Huestis, 2007).
When used topically, the permeability of CBD were found to be 10-fold higher than for THC. Similarly, Sativex (CBD: THC) when administered through oro-mucosally route, resulted in lower plasma levels of THC compared to inhalation at similar doses (Huestis, 2007).
Transdermal delivery of cannabinoids bypasses the first-pass metabolism and have delayed onset with lower peak concentrations. The drug-abuse potential of cannabinoid transdermal patches are expected to be lower due to slow delivery of THC to the brain (Huestis, 2007). CBD and THC metabolism are similar, with primary oxidation of C(9) to alcohol and carboxylic acid as well as side-chain oxidation in liver. They are subjected to first-pass metabolism. Unlike THC, a large proportion of CBD dose are excreted unchanged in the faeces (Huestis, 2007).

| Endocannabinoid system
The endocannabinoid system is an important modulator of the stress response with potential analgesic effects. This plays an important role in re-establishing equilibrium after stress or 'fight or flight' event. The reversal in equilibrium is the potential target for reducing pain and inflammation and hence a prospective therapeutic target in rheumatology.
The signalling system encompasses cannabinoid receptors, endocannabinoids (endogenous ligands of cannabinoid receptors) and enzymes regulating the biosynthesis and inactivation of endocannabinoids.
The molecules that affect cannabinoid or related receptors can be found in the following settings: endogenous ligands also known as endocannabinoids that are lipid mediators termed as eicosanoids (arachidonic acid derivatives); exogenous plant-derived phytocannabinoids and synthetic tricyclic terpenes (Table 1).
Cannabinoid receptors (CB) function through G proteins having an effect on the mitogen-activated protein (MAP) kinase pathway and inhibition of adenylyl cyclase activity. They activate potassium channels and inhibit voltage-gated sodium channels thereby inhibiting the neurotransmitter release at the synapse.
There are two primary receptors CB1 and CB2 with heterogeneous and sometimes opposite actions ( Figure 1).

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2.6.1 | Cannabinoid receptor 1 CB1 is primarily present in the frontal cortex, basal ganglia and cerebellum. It is responsible for the psychotropic effects of cannabis.
Other areas involved in motor control, memory and cognition express CB1 receptors (Guindon & Hohmann, 2009;Pagotto et al., 2006;Sido et al., 2015). CB1 receptors are also found in chondrocytes and osteocytes derived from human joints. There are evidence that suggest CB1 facilitates the adhesion of fibroblast-like synoviocytes (FLSs) to fibronectin and reduce the migratory capacity of these cells. This may possibly decrease the cartilage destruction (Sido et al., 2015).
The effects of the CB1 receptor on the brain are mostly facilitated by retrograde signalling (also known as retrograde neurotransmission). Retrograde signalling is induced by the depolarisation of the postsynaptic cell, resulting in the postsynaptic production and release of endocannabinoids, which in turn activate presynaptic CB1 receptors (Castillo et al., 2012). Overall, CB1 activation exerts an inhibitory effect on the presynaptic cell ( Figure 1).

| Other cannabinoid receptors
Transient receptor potential cation channel subfamily V member 1 (TRPV1) is a ligand-activated cation channel, regarded mainly as a pain receptor. It is expressed on the C-fibre and Aδ sensory neurons.
Cannabinoids, including AEA, CBD and cannabigerol, have agonistic effects on TRPV1 (Pertwee et al., 2010). CB1 activation can cause reduction in TRPV1 activity leading to reduction in IL-6 secretion from sensitised FLSs, highlighting the potential connection between TRPV1, the endocannabinoid system and rheumatic diseases (Pertwee et al., 2010).
G protein-coupled receptor 55 (GPR55) is referred by some researchers as a 'CB3 0 receptor. GPR55 was first discovered as an orphan G protein-coupled receptor, with evidence of its expression in the central nervous, immune and gastrointestinal systems as well as on articular surface tissues (Dunn et al., 2016).
Peroxisome proliferator-activated receptor-α (PPARα) is a fattyacid-activated transcription factor. It is predominately expressed on skeletal muscles with some degree of hepatic expression, PPARα is also designated site of action for fibrates (fibric acid derivatives used in the treatment of hypercholesterolaemia; Pertwee et al., 2010).
Apart from muscular and hepatic expression, PPARα is expressed on human chondrocytes and osteocytes (Dunn et al., 2016). An association between PPARα and the endocannabinoid system is verified by evidence that PPARα is stimulated by AEA, THC and WIN 55,212-2 mesylate (Pertwee et al., 2010).
To summarise, a fine balance exists between the effects of cannabis substances on CB1 and CB2 receptors, resulting either in psychoactive or immunomodulatory effects, respectively ( Figure 2).

| Musculoskeletal pain
In a critical review of cannabinoids in the management of musculoskeletal pain (Maccarrone et al., 2015), 118 studies were included.
Out of the studies included, 56% were observational with evidence of

| Cannabinoids in rheumatology
Evidence-based medicine regarding the use of cannabinoids in rheumatology is still sparse. The systemic review of four trials including two RCTs with nabilone in 71 fibromyalgia patients, one 4- week study of 30 spinal pain patients and a 5-week study with THC/ CBD in 58 rheumatoid arthritis (RA) patients concluded the superiority of cannabinoids over controls (Fitzcharles et al., 2016). However, this conclusion was found to be inconsistent. It also highlighted cannabinoids are superior to placebo in neuropathic pain but not in   (Lowin et al., 2015). In a study by Selvi et al., while IL-1b-induced IL-6 and IL-8 production were inhibited by CBagonist CP-55940, cytokine levels were unchanged when using CB1 and CB2 antagonists, suggesting the presence of alternative anti-inflammatory receptor (Selvi et al., 2008).
The only available clinical study on the use of cannabinoids in RA was done in 58 patients who were treated with the oro-F I G U R E 2 Difference in properties of cannabinoid receptors and fine balance between them JAIN AND MOORTHY -421 mucosal spray Sativex and compared to placebo over a 5-week period (Blake et al., 2006). This parallel RCT compared active RA patients on a stable dose of DMARDs. Thirty-one of the eligible patients were randomised to Sativex and 27 to placebo. This study revealed significant improvement in pain assessed using VAS (p = 0.018), DAS28 score (p = 0.02) and sleep in the active drug group. Limitation of the study included a short follow-up (<6 months) and no clear information on the blinding method.
The study was included in the NICE appraisal on the use of cannabinoids in the management of chronic pain.
In clinical practice, there is a lack of robust clinical RCT on the use of cannabinoids. Recently, a double-blinded, randomised, placebo-controlled study of CBD, followed by an open-label add-on of THC has been proposed in RA and spondyloarthritis patients.
The oral treatment with CBD in the experimental group will be compared with placebo in a control group for 12 weeks, followed by

| Osteoarthritis
Currently, no formal RCT study about the use of cannabinoids as a disease-modifying anti-osteoarthritis drug exists. As analgesia, a potent FAAH inhibitor, PF-04457845 indicated no significant difference observed in pain control compared to placebo. While PF-04457845 was found to increase AEA in these patients, however, it did not produce any significant analgesic effect (Huggins et al., 2012). Table 2 innumerates pre-clinical studies of cannabinoids in OA for reducing joint pain. In a recent animal study on Freund's adjuvantinduced monoarthritis knee joint model of rats (Hammell et al., 2016), the efficacy and adverse effects of transdermal CBD were evaluated.
They reported significant reduction in joint swelling and pain with decreased immune cell infiltration and thickening of the synovial membrane in a dose-dependent manner. No evident side effects were reported. They concluded therapeutic potential of CBDs for pain relief and inflammation in OA.

| Fibromyalgia
In one of the first studies involving 40 patients with FM with a study period of 6 weeks, it was found that nabilone was associated with statistically significant improvements in pain and function with a 2point reduction in pain score and 12-point reduction in Fibromyalgia Impact Questionnaire score (Skrabek et al., 2008).

| Psoriasis
Endocannabinoids have been implicated in the pathogenesis of psoriasis. They (AEA, 2-AG) have been found to be expressed in the skin (Wilkinson & Williamson, 2007). AEA inhibits keratinocytes proliferation and promotes cell death through CB1 and TRPV1 activation and Ca influx (Toth et al., 2011). AEA has also shown to downregulate the expression of keratins K6 and K16, which are over-expressed in psoriasis (Ramot et al., 2013). THC and cannabinoids have been shown to reduce the proliferation of keratinocytes (Wilkinson & Williamson, 2007).
There are ongoing research into the possible efficacy of cannabinoids in reducing inflammation in psoriasis (Milando & Friedman, 2019). It could potentially be an innovative topical/oral treatment option for psoriasis.

| Adverse effects of medicinal Cannabinoids
In a systemic review of medical cannabinoids, it was found that the most consistent effects of medical cannabinoids are its AEs (Allan et al., 2018).
It is imperative to make a distinction between recreational and medicinal cannabinoid compounds. While most cannabis products share similarities, those abused for recreational purposes tend to be highly potent thus having more AEs. However, this distinction was not made when the adverse effects of cannabis were studied.
A detailed review of systemic effects is shown in Table 3. Common adverse effects of cannabinoids include dizziness, nausea, dry mouth, tachycardia and agitation. They are associated with dependence and addiction, mediated via the rewarding effects of CB1 receptors. Research is still in its infancy with regards to adverse effects of selective cannabinoids having predilection towards CB2 receptors.
In a systemic review on the use of cannabinoids for pain, spasticity and vomiting, it was shown that the adverse effects caused more patients to stop treatment (number needed to harm [NNH] was 8-22). AEs included dizziness, confusion, sedation and dissociation.
Reduced joint inflammation.
The prophylactic treatment prevented nerve damage. National Academies of Science, Engineering, and Medicine (2017) In a study published in 2017 of 5115 volunteers followed over 25 years, deficit in memory was exhibited, which also demonstrated a relationship between lifelong cannabis consumption and poor performance in cognitive tests examining verbal memory, processing speed and executive function. Auer et al. (2016) Two systematic reviews published in 2013 concluded that chronic cannabis consumption can result in anatomical changes in the brain. In one of these systematic reviews, an examination of 43 imaging studies led to the conclusion that chronic cannabis use can alter the structure of the cerebellum, medial temporal cortex and frontal cortex. Batalla et al. (2013) Following these findings, the second systematic review concluded that chronic cannabis consumption might lead to a reduction in hippocampal size. Rocchetti et al. (2013) Mental health Paranoia or psychosis is especially related to the higher concentration of THC in some strains of herbal cannabis. Immediate psychiatric effects include agitation, suicidal thoughts, acute psychosis and anxiety. Moreira et al. (2009) Zhang and Ho (2015) Indeed, a substantial body of evidence supports the association between cannabinoids and the development of psychosis and schizophrenia.
Other mental health disorders are less strongly associated with the use of cannabinoids. Moderate-quality evidence suggests that cannabinoid use slightly increases the risk of depressive disorders. A moderate level of evidence also suggests an increased incidence of suicidal ideation, suicide attempts, suicide completion and social anxiety among cannabinoid users. Contrary to these findings, cannabinoid use is only weakly associated with the development of bipolar disorder, anxiety disorders (apart from social anxiety) and increased symptoms of anxiety.
National Academies of Science, Engineering, and Medicine (2017) Addiction Although cannabinoids are commonly considered to be non-addictive, epidemiological studies indicate that 9% of adult users will develop cannabinoid dependence. Anthony et al. (1994) Cardiovascular system Tachycardia and hypotension. Tait et al. (2015) Temporal relationship to an increased risk of myocardial infarction and reduced exercise capacity of those with angina pectoris. Thomas et al. (2014) Respiratory system High doses of THC-containing products are associated with an increased risk of developing respiratory irritation, wheezing and morning phlegm as well as frequent episodes of chronic bronchitis. Ware et al. (2015) There

| Drug interactions
There are concerns regarding drug interactions of commonly used medications with cannabinoids. Currently, the data on cannabinoids and CYP450 are through in vitro studies and human data are still insufficient. However, pending further data, cannabis are presumed to act as substrate of CYP3A4, CYP2C9 and CYP2C19 (Hryhorowicz et al., 2018;Stout & Cimino, 2014;Yamaori et al., 2011). Therefore, they have potential interactions with many commonly used drugs.

Children and adolescents
Risk of cannabis poisoning due to an accidental overdose in children leading to respiratory distress is of special concern.
National Academies of Science, Engineering, and Medicine (2017) Compared with adult cannabis users, individuals who start to use cannabis during adolescence perform poorly in cognitive tests, exhibiting deficiencies in memory, attention, inhibition and verbal fluency. Furthermore, cannabis consumption during adolescence has been associated with a decline in IQ score, possibly accounting for a drop of as many as 8 points. We attempted to answer the question posed but struggled. On the balance of probabilities, with clear lack of tangible data and evidence, we concluded cannabinoids as 'foe' in rheumatology. We do believe a robust structured research is need of the hour to answer the unanswered questions in this interesting and ever-expanding area.

AUTHOR CONTRIBUTION
Authors equally contributed in the concept and writing up this article.

DATA AVAILABILITY STATEMENT
Data sharing not applicable to this article as no datasets were generated or analysed during the current study.