2: Cannabis Compounds for
Arthritis

UPDATED date

THC and CBD help control arthritis symptoms, which is well known. These and 15 other cannabis compounds, mainly cannabis terpenes, may help to also deter arthritis progression. The 15 are:

α-humulene
β-caryophyllene
apigenin
β-pinene
d-limonene
geraniol
eucalyptol
β-eudesmol
α-terpineol
eucalyptol
trans-nerolidol
β-caryophyllene oxide
α-pinene
4-terpineol
α-terpinene
  

Fourteen of these are terpenes, the exception being the flavonoid apigenin. Appendix A: Common Cannabis Compounds provides a brief introduction to these compounds.

The traditional approach to consuming terpenes is through aromatherapy — the inhalation and topical absorption of essential oils. Aromatherapy is a well-known approach to the treatment of arthritis pain. The new element reported here is its potential use in retarding the progression of arthritis.

In addition to pure terpenes, there are also terpene-rich essential oils. Humulus lupulus (hops) is an excellent source of α-humulene and β-Caryophyllene. Bergamot orange is a good source of d-limonene. Pinus sylvestris (pine) is a good source of α-terpineol and α-pinene. Natural sources for the remaining 10 compounds are given in the Common Cannabis Compounds list.

This article is organized as a series of presentations. Each presentation ends with a door that opens onto an exposition of supporting research documented with in-text citations in the form of hyperlinked daggers. Mousing over a dagger brings up its corresponding reference hyperlinked to the supporting research[CiOn].

A discussion of salient characteristics of common kinds of arthritis provides the basis for identifying cannabis compounds that, based on animal studies, may slow the progression of arthritis.

2.1 Types of Arthritis 

According to the Arthritis Foundation, there are more than 100 different forms of arthritis, including osteoarthritis, rheumatoid arthritis, spinal arthritis, and psoriatic arthritis[arth-found].

Osteoarthritis, the most common form, is traditionally viewed as a degenerative disease caused by wear and tear. However, obesity leads to a higher prevalence of osteoarthritis in non-weight-bearing areas as well as weight-bearing areas. Inflammatory cytokines are found in arthritic joints, and they contribute to arthritis progression. Moreover, inflammatory cytokine levels increase with age. So, there is reason to believe that inflammation either causes or strongly contributes to osteoarthritis. ⮛ RESEARCH ⮛

Elevated levels of TNF-α, IL-1, and IL-6 occur in osteoarthritis — in the synovial fluid that lubricates the joints, in the membranes that hold the synovial fluid, and in the bone below a joint's cartilage. The link with obesity is that fat tissue is a source of inflammatory cytokines[Wang_2018][Greene_2019][Wang_2015].

Increasing age brings increasing levels of inflammatory and erosive chemicals throughout the body, some of which are secreted by aging cartilage. There is increased systemic inflammation, increased inflammation of the joints, and increased chemically induced deterioration of cartilage[Greene_2019].

Spinal arthritis is usually a form of osteoarthritis. It occurs most commonly in the lower back or neck. Again, inflammation plays a key role.  ⮛ RESEARCH ⮛

spine illustrationSpinal arthritis is associated with inflammation and degeneration of the vertebrae, facet joints, and disks, as illustrated in the image to the right[TBI_2016]. The degeneration leads to a narrowing (stenosis) of the spinal canal. The result is pressure on nerves leaving the spine that initially causes back pain and muscle spasms. The pinched nerves may include those associated with the lower extremities, causing pain to radiate downward through the pelvis, buttocks, legs, and knees[Regan_2019][TBI_2016]. The pinched nerves may also cause bladder problems, including urgency and frequency of urination[Eidelson_2019].

Ankylosing Spondylitis is an inflammatory arthritis of the spine. There is evidence that a particular bacterium can cause this form of arthritis. In this case, the cannabis compounds guaiol, BCPO (β-caryophyllene oxide), linalool, eucalyptol, and α-terpineol may help kill the bacterium. ⮛ RESEARCH ⮛

The implicated bacterium is Klebsiella pneumoniae[Rashid_2006]. The effectiveness of guaiol, caryophyllene oxide, linalool, eucalyptol, and α-terpineol was determined by studying traditional Australian herbal remedies, specifically, Tasmanian mountain pepperberry[Winnett_2017].

Rheumatoid arthritis is an autoimmune disease. The immune system attacks the synovial membranes that hold the fluid that lubricates the joints. Psoriatic arthritis is also an autoimmune disease. Its first symptom is usually psoriasis. With both conditions, pain is lessened, and disease progression is slowed by suppressing inflammation.

2.2 Fighting Arthritis  

In a survey of Canadian cannabis users, the most popular strains for arthritis were Sweet Skunk CBD, OG Shark, Cannatonic, and CBD House Blend. Sweet Skunk CBD is a high-CBD strain whose primary terpenes include α-pinene, β-myrcene, and trans-nerolidol. ⮛ RESEARCH ⮛

A 2018 paper presenting the research on Canadian cannabis preferences includes an outstanding review of previous relevant research. It concludes that their survey presents the first published research to explicitly address the fact that different strains have different medical benefits[Baron_2018]. The information on Sweet Skunk CBD comes from the Leafy website. The presence of trans-nerolidol in Sweet Skunk CBD is somewhat unusual[Leafy_2019].

CBD appears to reduce arthritis pain and deter joint damage. Moderate doses of CBD have proved more effective than large or small doses. THC also has an anti-inflammatory effect and has been shown to reduce pain and slow cartilage erosion. The terpene α-pinene has deterred the breakdown of cartilage and may also deter arthritis progression. ⮛ RESEARCH ⮛

The relevant cytokines are produced mainly in joint cartilage[Melchiorri_1998].

CBD and THC have both reduced pain and inflammation and have prevented nerve damage in animal models of osteoarthritis[Philpott_2017][Yang_2015][Gamble_2018][Morouj_2018]. A clinical trial demonstrated a significant analgesic effect of the Sativex brand of THC+CBD in rheumatoid arthritis[Blake_2006]. The use of CBD brought improvement in an animal model of arthritis used to study rheumatoid and reactive arthritis[Hammell_2015][Malfait_2000]. One motivation for using THC is that it tends to be less toxic than the commonly used low-dose methotrexate[Morouj_2018][Kivity_2014]. THC stimulates the CB2 cannabinoid receptor, which is more highly expressed in patients with rheumatoid arthritis than in patients with osteoarthritis[Dunn_2016][Yang_2015][Fukuda_2014][Gertsch_2008].

The CB2 agonist JWH-133 has reduced inflammation and bone destruction in a mouse model of arthritis, and the same may be true of the stronger CB2 agonist β-caryophyllene (BCP)[Fukuda_2014][Gertsch_2008].

The anti-inflammatory and anti-catabolic effects of d-limonene and α-pinene in human cartilage cells have been observed by Rufino and others[Rufino_2015][Rufino_2014].

Arthritic pain and inflammation appear to be primarily caused by the four inflammatory cytokines IL-1, IL-6, TNF-α, and IL-17. These cytokines promote the initiation and progression of common forms of arthritis, including osteoarthritis, rheumatoid arthritis, septic arthritis, and post-traumatic arthritis. Much of the destruction is performed through IL-1 stimulation of nitric oxide production. An additional source of inflammation and destruction occurs when new blood vessels invade cartilage — healthy cartilage does not contain blood vessels.

For each destructive mechanism, the presentation proceeds in four steps: cannabis compounds that help, the mechanism's causal role in arthritis, conventional medicines whose success may block that mechanism, and, finally, an explanation of how the identified cannabis compounds block the destructive mechanism.

In some cases, there is a lack of research on lowering cytokines that have been elevated by arthritis. In these cases, it has been necessary to substitute educated guesses based on research into lowering cytokines that have been raised in other diseases such as cancer or rat paw edema. The same problem concerns research on preventing blood vessels from invading cartilage.

The IL-1 Cytokine

CBD, THC, BCP (β-Caryophyllene), α-humulene, geraniol, trans-nerolidol, d-limonene, α-terpineol, eucalyptol, and 4-terpineol may retard the progression of arthritis and associated pain by lowering IL-1 levels. ⮛ RESEARCH ⮛

Causal Link. People living with arthritis, including those with post-traumatic arthritis, have high levels of IL-1α, IL-1β, TNF-α, and IL‐17. These cytokines contribute to bone loss by stimulating the production of osteoclasts — cells that break down cartilage[Schett_2011][Olson_2015]. IL-1α, IFN-γ, and TNF-α all induce apoptosis (programmed cell death) in bovine cartilage. This finding is relevant to most forms of arthritis, including osteoarthritis, rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis[Schuerwegh_2003].

Conventional Treatments. Multiple studies have shown that blocking IL-1 helps. The human body already has an IL-1 antagonist that lowers IL-1, and there is a synthetic analog, anakinra (brand name Kineret), that lowers IL-1 levels and slows the progression of rheumatoid arthritis[Olson_2015][Molecular_and_Cell_Biology_2013][Pharmacology_2016][Mertens_2015]. Moreover, the body has a 'decoy' receptor that binds nitric oxide nonproductively to IL-1, again blocking its inflammatory role and helping in an animal model of arthritis[Shimizu_2015]. Since blocking IL-1 helps, it may also be the case that lowering IL-1 helps.

Cannabis Compounds. THC lowerd IL-1β in a brief human trial and in an animal model of RA[Morouj_2018][Bidwell_2018]. Both CBD and THC lowerd IL-1β in chemically stressed mouse microglial cells[Kozela_2009]. CBD lowerd IL1-β and TNF-α in a mouse model of multiple sclerosis[Mecha_2013]. BCP (Beta-caryophyllene) lowerd IL-1β and TNF-α in in vitro tests[Gertsch_2008][Rufino_2015][Medeiros_2007][Guo_2014].

Nerolidol inhibited IL1-β and TNF-α in mouse peritonitis[Fonsêca_2015]. Perillyl alcohol reduced IL-1β and TNF-α in a rat model of stroke, and eucalyptol lowerd IL-1. α-Humulene lowerd IL-1β and TNF-α in rat paw edema[Medeiros_2007]. Geraniol lowerd IL-1β and TNF-α in rat tongue cancer[Madankumar_2017]. Perillyl alcohol, a metabolite of d-limonene, lowered IL-6, IL-1β, and TNF-α in a rat model of stroke[Tabassum_2014].

The IL-6 Cytokine

CBD, THC, BCP, d-limonene, α-terpineol, 4-terpineol, eucalyptol, and apigenin may retard the progression of arthritis and associated pain by lowering IL-6 levels. ⮛ RESEARCH ⮛

Causal Link. People with osteoarthritis[Wojdasiewicz_2014][Stannus_2010] or rheumatoid arthritis[Misato_2011] have elevated IL-6, which is thought to play an active role in disease progression and increased pain.

Conventional Treatments. The drug tocilizumab lowers RA disease activity by blocking the IL-6 receptor. The experimental drug sarilumab lowered RA disease activity by lowering IL-6 levels directly, but it failed to win FDA approval due to some fatalities[Avci_2018]. These results suggest that other ways of lowering IL-6 may help as well.  

Cannabis Compounds. CBD lowered IL-6 in ischemic rat hearts and in chemically stressed mouse microglial cells[Durst_2007][Kozela_2009]. THC lowered IL-6 in a brief human trial and in an animal model of rheumatoid arthritis[Bidwell_2018][Morouj_2018]. THC also reduced IL-6 in chemically stressed macrophages and in an eternalized mouse microglial cell line[Kozela_2009][Chang_2001][Puffenbarger_2000]. BCP lowerd IL-6, IL-1β, and TNF-α in a microglia cell line used to study neuroinflammation[Guo_2014]. 

Perillyl alcohol, a metabolite of d-limonene, lowered IL-6, IL-1β, and TNF-α in a rat model of stroke[Tabassum_2014]. α-Terpineol lowerd IL-6 in human cheek cells stressed with desiccated orange juice[Held_2007]. α-Terpineol and 4-terpineol (aka terpinen-4-ol) lowerd both IL-6 and IL-1β in chemically stressed human macrophages[Nogueira_2014][Trinh_2011]. Eucalyptol lowerd IL-6, IL-1β, and TNF-α in various in vitro and animal models of inflammation[Caceres_2017][Lima_2013][Yadav_2017][Li_2016][Kennedy-Feitosa_2016][Yu_2018][Khan_2013][Trinh_2011]. The flavonoid apigenin lowerd IL-6 in chemically stressed mice[Smolinski_2003].

The TNF-α Cytokine

CBD, THC, BCP, eucalyptol, geraniol, α-humulene, α-terpineol, and apigenin may retard the progression of arthritis and associated pain by lowering TNF-α levels. ⮛ RESEARCH ⮛

Causal Link. TNF-α is implicated in destroying bone and cartilage in osteoarthritis and in post-traumatic arthritis[Schett_2011][Stannus_2010].

Conventional Treatments. The commercial TNF-α inhibitors adalimumab (Humira) and infliximab (Remicade) bind directly to TNF-α, thereby disabling it. They have demonstrated effectiveness in treating rheumatoid and psoriatic arthritis as well as psoriasis itself[Adalimumab][Infliximab]. Inflammatory hand osteoarthritis has been successfully treated by blocking TNF-α with the off-label use of etanercept (Enbrel, Benepali)[Kloppenburg_2018]. The success of TNF-α blocking drugs suggests that lowering TNF-α via cannabis compounds may help in the same way.

Cannabis Compounds. As noted above, CBD, BCP, nerolidol, perillyl alcohol, α-humulene, eucalyptol, α-terpineol, and geraniol all lower TNF-α. THC also lowerd TNF-α in an animal model of rheumatoid arthritis[Morouj_2018]

The flavonoid apigenin lowerd TNF-α in an experimental model of mouse pancreatitis[Charalabopoulos_2019]. Apigenin lowerd TNF-α and upregulated the anti-inflammatory cytokine IL-10 in mouse leukemia macrophages[Palacz-Wrobel_2017].

The IL-17 Cytokine

BCP, CBD, and THC may be of benefit in rheumatoid arthritis by slowing bone loss and lowering IL-17 levels. ⮛ RESEARCH ⮛

Causal Link. The breaking down of bone tissue is a normal part of bone metabolism. This process is carried out by specialized bone cells called osteoclasts. In rheumatoid arthritis, there are too many osteoclasts. Here's what happens: IL-23 induces synovial tissue to produce IL-17, which in turn promotes the production of new osteoclasts[Paradowska-Gorycka_2010]. These cause synovial inflammation, cartilage and bone degradation, and joint destruction according to in vitro and animal experiments[Kellner_2013]. Much of this chaos is also apparent in ankylosing spondylitis[Koenders_20016].

Conventional Treatments. Secukinumab and ixekizumab (IL-17 neutralizing agents), and perhaps brodalumab (an IL-17 receptor antagonist),  have shown promise in treating psoriasis, psoriatic arthritis, and rheumatoid arthritis[Koenders_20016][Kunwar_2016].

Cannabis Compounds. CBD lowerd IL-17 in animal studies[Giacoppo_2016][Harvey_2013]. THC lowerd IL-17 in an in vitro study[Kozela_2013]. The CB2 agonist JWH-133 lowerd IL-17 in macrophages[Norooznezhad_2016][Guillot_2013], so the same is likely to be true of the stronger CB2 agonist BCP[Gertsch_2008].

Nitric Oxide

α-Humulene, α-terpinene, α-pinene, β-pinene, and d-limonene may help with arthritis by lowering nitric oxide levels. ⮛ RESEARCH ⮛

Causal Link. Nitric oxide is produced in cartilage due to stimulation by IL-1 and, for rheumatoid arthritis, TNF-α as well[Taskiran_2002][Nagy_2008]. Nitric oxide directly stimulates the destruction of cartilage in osteoarthritis[Boileau_2002][Leonidou_2018], inflammatory arthritis[McCartney-Francis_1993], and especially rheumatoid arthritis[Farrell_1992][vant_Hof_2000].

Conventional Treatments. Reducing nitric oxide has reduced inflammation and inhibited cell death in cartilage and synovial membrane[Leonidou_2018][McCartney-Francis_1993][vant_Hof_2000].

Cannabis Compounds. It may also be the case that nitric oxide-suppressing cannabis compounds impede arthritis progression. α-Humulene, α-terpinene, α-pinene, and β-pinene have lowered nitric oxide levels[Coté_2017]. d-limonene has lowered nitric oxide indirectly by inhibiting IL-1β[Rufino_2015].

Blood Vessel Invasion of Cartilage

CBD, THC, BCP, BCPO, d-Limonene, and β-eudesmol may help with arthritis by preventing inappropriate angiogenesis in which new blood vessels invade cartilage. ⮛ RESEARCH ⮛

Causal Link. The destruction of cartilage by nitric oxide and other factors is followed by new blood vessels invading cartilage. This abnormal angiogenesis takes place in several types of arthritis, including osteoarthritis, rheumatoid arthritis, and chronic septic arthritis[Walsh_2007][Bonnet_2004][Elshabrawy_2015][Pessler_2008]. It is apparently stimulated by inflammation, at least in the case of osteoarthritis[Haywood_2003]. In the case of rheumatoid arthritis, angiogenesis leads to the growth of "pannus" tissue that covers the synovial membrane and releases additional chemicals that destroy cartilage, bone, tendons, ligaments, and blood vessels[Pannus_2018].

Conventional Treatments. There have been some successes in treating arthritis by inhibiting angiogenesis. In rheumatoid arthritis, blockade of TNF-α and IL-1 significantly inhibits VEGF. This key signaling protein promotes the growth of new blood vessels[Paleolog_2002]. Szekanecz and Koch have enumerated several more angiogenesis inhibitors[Szekanecz_2008].

Cannabis Compounds. Although there has been no research on slowing angiogenesis in cartilage with cannabis compounds, there have been some results on slowing angiogenesis in cancer. CBD in colon cancer[Massi_2012] and glioblastoma[Dumitru_2018]; THC in breast cancer[Caffarel_2010] and glioblastoma[Dumitru_2018]; BCP viz JWH-133 in glioma[Blázquez_2004];  BCPO in breast and prostate cancer[Park_2011]; β-eudesmol in cervical, gastric, and liver cancers[Ma_2008]; and d-limonene
in gastric cancer [Lu_2004].

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