3: Cannabis Compounds for
Physical Pain

 UPDATED year month day

Research has shown that cannabis compounds can help with physical pain and chemotherapy-induced nausea. A report from the National Academies of Sciences, Engineering, and Medicine has provided carefully worded support[NASEM_2017].

This chapter explores the kinds of physical pain that cannabis compounds help alleviate. Altogether, 16 cannabis compounds are relevant. Appendix A: Common Cannabis Compounds introduces these compounds.

Typical physical pain is triggered by pain receptors in the skin, muscles, joints, and elsewhere. Neuropathic pain originates within the nervous system. Psychological pain comes from painful thoughts, feelings, and emotions. Both psychological pain and neuropathic pain can masquerade as typical physical pain.

This chapter discusses typical physical pain, neuropathic pain, cancer pain, and dysfunctional mystery pain. Mystery pain includes fibromyalgia, migraines, and adverse reactions to HPV vaccinations.

The exposition is organized as a series of explanations. Each explanation ends with a door that opens onto a summary of supporting research. The supporting research contains "dagger citations." Mousing over a dagger brings up its corresponding reference hyperlinked to the supporting research[CiOn].

3.1 Typical Physical Pain

Typical pain is a response to damaging or potentially damaging physical stimulation. It is triggered by pain receptors in the skin, joints, bone, etc. Technically, typical pain is called nociceptive pain, and pain receptors are called nociceptors. 

Typical pain often causes inflammation, which can greatly increase the magnitude of the pain. In this case, the first line of defense is usually to use  is usually to use anti-inflammatory compounds. An alternative to anti-inflammatories is to block the perception of pain. Other options include yoga, stretching exercises, and meditation.

Inflammation

Inflammation-fighting medications include NSAIDs such as aspirin and ibuprofen, the COX-2 inhibitor celecoxib (Celebrex), steroids such as hydrocortisone and prednisone, and cannabis compounds.

CBD, CBDA, THCA, CBC, and THCV are anti-inflammatory and may reduce sensitivity to pain. THC is anti-inflammatory at moderate doses but may be inflammatory at high doses. THC together with CBD or CBDA may work better than either one alone because THC works differently.

BCPO (β-Caryophyllene oxide) is comparable to aspirin in strength. It acts both locally as an anti-inflammatory and centrally as a pain-perception blocker. Unlike commercially produced NSAIDS, BCPO actively protects rather than erodes stomach linings.

α-Humulene, eucalyptol, linalool, and ɑ-bisabolol are anti-inflammatory and pain-relieving. α-Bisabolol is known to act synergistically with the commercial NSAID diclofenac. These conclusions are based on animal studies. ⮛ RESEARCH ⮛

Experiments with rats suggest that oral CBD is anti-inflammatory and pain-reducing[Costa_2004]. Chemical analyses indicate that CBDA is also anti-inflammatory; in fact, it is a COX-2 inhibitor[Takeda_2008]. In rodent experiments, CBDA out-performed CBD in reducing pain and inflammation. Moreover, CBDA and THC were found to be synergistic[Rock_2018].

In primate studies, CBC and THC reduced pain and inflammation and acted synergistically[DeLong_2010]. In vitro laboratory studies suggest that THCA is anti-inflammatory and pain-relieving, while THC at high levels may be pro-inflammatory[Verhoeckx_2005]. THCV is anti-inflammatory in mice[Bolognini_2010].

Multiple in vitro and animal studies show that BCP (β-caryophyllene) is anti-inflammatory[Klaukea_2013][Klaudyna_2016][Oliveira-Tintino_2018]. Moreover, BCPO (β-caryophyllene oxide) is anti-inflammatory and comparable to aspirin and pentazocine in strength. Apparently, it acts both locally as an anti-inflammatory and centrally as a pain-perception blocker[Klaudyna_2016][Tambe_1996][Chavan_2010][Singh_2014].

Both in vitro and animal studies show that α-Humulene is strongly anti-inflammatory[Fernandes_2007][Medeiros_2007][Coté_2017].

Rat studies have found α-Bisabolol to be anti-inflammatory and pain-relieving. Moreover, it acts synergistically with diclofenac, a commercial NSAID[Ortiz_2015]. Eucalyptol (aka 1,8‐cineole) and linalool have also been anti-inflammatory in animal studies[Santos_2000][Peana_2004].

Pain Perception

Pain perception blocking can occur in several ways:

The best-known pain blocker, acetaminophen, appears to block pain in the brain and the spinal cord. Opioids and NSAIDs can block pain as it moves up the spinal cord. CBD and THC can also work this way.

THC and morphine are synergistic in mice, which may be why marijuana legalization reduces opioid overdoses. BCP attenuates acute pain and acts as a local anesthetic, blocking pain perception at its source.

Linalool blocks pain at the top of the spinal cord.  ⮛ RESEARCH ⮛

Acetaminophen is thought to block pain in the brain and spinal cord[Drahl_2014]. Opioids, NSAIDs, and cannabinoids including CBD and CBC are can block pain by activating the brain's descending pain pathway[Maione_2010].

THC and morphine are synergistic in mice[Welch_1992], corroborating statistical data that marijuana legalization reduces opioid use and overdoses[Bradford_2016][Bachhuber_2014]. BCP attenuated acute pain and acted as a local anesthetic in animal studies[Paula-Freire_2013][Ghelardini_2001].

Linalool has been shown to be anti-nociceptive in animal studies. It blocks pain at the top of the spinal cord[Peana_2003].

3.2 Neuropathic Pain

Unlike typical nociceptive pain, neuropathic pain originates within the pain-sensing and reporting nerves themselves. Such pain may be constant or sporadic. It may seem either localized or diffuse. Two notable causes are damaged nerves and severed nerves.

Damaged Nerves

Inhalation of marijuana is effective for neuropathic pain in HIV as well as central and peripheral neuropathic pain. Raw hemp oil is helpful for treating chronic nerve irritation. A combination of equal parts THC and CBD dulls painful neuropathic responses to normal stimulation. However, THC may not be effective for neuropathic pain that has not responded to other medications.

BCP (β-caryophyllene) is effective against neuropathic pain. Moreover, unlike opioids, it does not lead to tolerance. BCP is helpful for both recurrent and chronic pain. The addition of the omega-3 fatty acid DHA improves BCP's effectiveness. Eucalyptol also decreases neuropathic pain. ⮛ RESEARCH ⮛

Smoked marijuana with known THC content has been effective for neuropathic pain in HIV[Ellis_2008][Abrams_2007] and for central and peripheral neuropathic pain[Wilsey_2008]. Sativex, which contains equal amounts of THC and CBD, has successfully treated neuropathic pain presenting as a painful response to normal stimulation[Nurmikko_2007]. But in several cases, THC was ineffective on refractory neuropathic pain[Attal_2012]. One interesting experiment tested raw hemp oil high in CBDA on chronic nerve irritation in mice with positive results[vigil_2020].

In animal studies, BCP (β-caryophyllene) was effective against neuropathic pain. Moreover, unlike opioids, it did not lead to tolerance[Klaukea_2013][Oliveira-Tintino_2018][Kuwahata_2012][Klauke_2013]. In an animal study, BCP was helpful for both acute and chronic pain[Paula-Freire_2013]. In vivo and animal studies showed that the addition of the omega-3 fatty acid DHA improves BCP's effectiveness[Fiorenzani_2014]. Eucalyptol also decreased neuropathic pain in an animal study[Zhang_2018].

Severed Nerves

Marijuana is helpful for some forms of post-operative pain. THC has reduced spasticity in patients with spinal cord injuries but was of only minor benefit for well-established trauma-induced pain. Neither marijuana nor THC alone or in combination with CBD was helpful for dental extractions, hysterectomies, and tears in the brachial plexus. ⮛ RESEARCH ⮛

THC has helped with spasticity following spinal cord injuries[Hagenbach_2006].

A study testing marijuana on post-traumatic and postsurgical neuropathic pain got positive results[Ware_2010], as did another study on postoperative pain that used a 2-to-1 preparation of THC and CBD[Holdcroft_2006].

However, even a high THC level was of only minor benefit for well-established trauma-induced neuropathic pain[Ware_2010]. Two studies that tested THC for postoperative and post-injury pain got negative results. Both found THC no better than a  placebo. One study looked at dental extractions, and the other at hysterectomies[Buggy_2003][Raft_1877]. In another study, neither THC nor THC+CBD brought much relief from the pain of brachial plexus tears[Berman_2004].

3.3 Cancer Pain

Established cancer treatments have many unfortunate, life-threatening side effects, including severe pain, nausea, vomiting, and dangerous, potentially irreversible weight loss. As explained below, several cannabis compounds can help. However, THC by itself may not be the most effective treatment. ⮛ RESEARCH ⮛

A multifaceted cannabis study from 2013 provides an intriguing look into the use of medical cannabis for cancer pain[Bar-Sela_2016]. THC, even in conjunction with codeine, is only mildly effective at stopping cancer-related pain[Noyes_1975][Noyes_1975b].

Chemotherapy Pain

CBD and BCP may be helpful in preventing peripheral neuropathy and resultant neuropathic pain caused by chemotherapy. Cannabis can be highly effective in treating pain in advanced cancer patients who are receiving chemotherapy. In combination with THC, CBD can help with intractable pain not adequately treated with opioids.  ⮛ RESEARCH ⮛

Cannabis can be highly effective in treating pain in advanced cancer patients[Bar-Sela_2016]. But some studies have found that THC was only effective at doses high enough to produce major side effects and is not associated with increases in lean body mass[Noyes_1975][Noyes_1975b].

CBD with THC (Sativex, Nabiximols) reduces intractable cancer-related pain, including pain not adequately relieved by strong opioids[Portenoy_2012][Russo_2007] and it continues to be effective in long-term use[Johnson_2012]. Animal studies suggest that CBD may be effective at preventing chemotherapy‐induced peripheral neuropathy. Co‐administration of low doses of THC enhances its effectiveness[King_2017]. Animal studies also showed that BCP prevented peripheral neuropathy and resultant neuropathic pain caused by the chemotherapy drug paclitaxel[Segat_2017][Ward_2014].

Nausea and Vomiting

The compounds CBDA and THCA contained in raw marijuana flowers control nausea more effectively than CBD and THC, respectively. Δ8-THC has been highly effective in controlling vomiting associated with conventional chemotherapy in children. Δ8-THC is well suited to this use, as it is less intoxicating than Δ9-THC

THC itself appears to work differently from conventional therapies and is often helpful for vomiting in cases where conventional drugs fail. It can be used alone but may be more effective when combined with conventional drugs. The addition of CBD also makes THC more effective.

Comparing THC with conventional drugs, the following appears to be the case:

⮛ RESEARCH ⮛

Δ8-THC has been effective in controlling vomiting in children[Abrahamov_1995]. Δ9-THC was better in children than metoclopramide syrup and prochlorperazine tablets[Ekert_1979].

CBDA displays significantly higher potency at inhibiting nausea and vomiting than CBD[Bolognini_2013b]. THCA appears to be more potent than THC[Rock_2013]. THC itself seems to work differently and is often helpful for vomiting in cases where conventional drugs fail[McCabe_1998].

Comparing THC with other therapies, the following appears to be the case:

THC is less effective than levonantradol, a synthetic cannabinoid, in terms of nausea reduction and unwanted side effects[Citron_1985].

THC is comparable to prochlorperazine, thiethylperazine, and metoclopramide in reducing nausea and vomiting[Frytak_1979][Thomaqs_1982][Ungerleider_1985][Colls_1980].

THC appears to be more effective than cyclophosphamide, fluorouracil, and doxorubicin hydrochloride[Orr_1980].

THC improves the performance of methotrexate[Chang_1979], but not Adriamycin or Cytoxan[Shiling_1981].

THC, combined with CBD given as an adjunct to standard therapies, is better for nausea and vomiting than standard therapies alone[Duran_2010].

Cachexia/Anorexia

About half of all patients with advanced cancer experience involuntary severe weight loss, usually accompanied by muscle wasting. It seriously lessens the quality of life. It is associated with poorer outcomes. It is generally not reversible by increasing caloric intake. Treatment is challenging.

Low-dose THC may bring modest weight gain for several reasons. THC improves appetite. It also enhances the senses of smell and taste that cancer can destroy. Patients have also reported improved mood and reduction of pain. However, despite these perceived benefits, taking THC for nausea has not inspired significant enthusiasm.

Megestrol acetate appears to be superior to THC both in terms of increased appetite and increased weight gain. Moreover, adding THC to megestrol acetate provides no additional benefit.

Ghrelin and THC do some of the same things, but ghrelin has some additional properties that may be helpful for treating cachexia. It inhibits protein breakdown in patients with cancer cachexia, and it has anti-inflammatory, anti-apoptotic, and anxiolytic effects.

In an animal study, CBG and CBN stimulated weight gain, whereas CBD was associated with weight loss. CBG and CBN are known to have few side effects. But so far, they have been tested only on animals. ⮛ RESEARCH ⮛

The many clinical practice articles and systematic reviews — and systematic reviews of systematic reviews — illustrate the challenging nature of treating cancer-related cachexia[Childs_2018][Dev_2017][Häuser_2017].

The evidence for THC's ability to promote weight gain is modest at best. In a small-scale study, low-dose THC brought minor weight gain[Bar-Sela_2019]. However, a phase III clinical trial failed to show that THC increases weight[Strasser_2006]. The evidence for increased appetite is more robust. Patients have reported improved appetite[Nelson_1994] and a heightened sense of smell and taste[Bar-Sela_2019][Nelson_1994]. As an aside, marijuana and obesity are also inversely correlated in the general population despite the fact that marijuana gives people the munchies[Strat_2011].

In small-scale studies, cachexia patients taking THC have reported improved mood, better sleep, and more relaxation as well as a reduction in pain and fatigue[Bar-Sela_2019][Brisbois_2011]. These results are consistent with a study of anorexic women without cancer[Avraham_2017]. However, a clinical trial failed to observe these benefits[Strasser_2006].

In one study, cachexia patients received low-dose orally administered THC augmented with a small amount of CBD. Most patients dropped out[Bar-Sela_2019]. A well-designed clinical trial also failed to generate enthusiasm[Strasser_2006].

In a small-scale study, dronabinol, which is a form of THC, proved to be inferior to megestrol acetate. Not only that, but adding it to Megestrol acetate provided no additional benefit[Jatoi_2002].

THC shares some significant properties with ghrelin, another compound being investigated for treatment of cachexia. They are both agonists for not only the CB1 receptor but the ghrelin receptor as well[Tucci_2004][Lim_2013]. However, ghrelin has some additional attractive properties. It inhibits protein breakdown in catabolic conditions such as cancer cachexia. It has anti-inflammatory, anti-apoptotic and anxiolytic effects as well[Khatib_2018]

Rats given CBG (cannabigerol) or CBN (cannabinol) ate more food and ate more frequently[Brierley_2016][Farrimond_2012]. CBD is generally thought to promote weight loss[Farrimond_2012].

3.4 Dysfunctional Mystery Pain

Researchers often refer to pain that they cannot explain in terms of an apparent stimulus or causal damage to the nervous system as "dysfunctional pain." Current examples of dysfunctional pain include fibromyalgia, irritable bowel syndrome, interstitial cystitis, migraines, and intractable pain following HPV vaccinations.

Fibromyalgia

Patients who smoke marijuana have seen significant improvement, especially in reducing pain and stiffness. Two consumer-oriented articles speak highly of high-CBD strains for fibromyalgia. ⮛ RESEARCH ⮛

Patients who smoke marijuana have seen a reduction of pain and stiffness, enhancement of relaxation, drowsiness, and a feeling of wellbeing[Fiz_2011][Habib_2018]. Marijuana is one of many therapies that people have tried for fibromyalgia[Gur_2009].

Harlequin is a high-CBD strain mentioned in a Leafy article[Rahn_2016]; ACDC is mentioned in a Marijuana Doctors article[Rosado_2021].

Migraines

Researchers know a lot about migraines — the various kinds of migraines, how the primary triggers work, and many of the genes involved. Yet the exact cause remains a mystery, and commercially recommended treatments are not always effective.

A survey of two thousand Canadian medical marijuana users found common traits among the most popular strains for taming migraine headaches. They were strains whose chemical makeup was very high in THC/THCA, but low in CBD/CBDA. They were also low in β-caryophyllene and the sedative β-myrcene. Research suggests that marijuana decreases the frequency of migraine headaches and lessens dependence on opioids. ⮛ RESEARCH ⮛

England's National healthcare service[Causes_2019], the American Migraine Foundation[What_causes_Migraine], and Wikipedia[WikiProjects_migraine] all support the view that the causes of migraines remain unknown.

The Canadian results about migraines are from a 2018 survey that established that different strains of marijuana have different medical benefits[Baron_2018]. Observational studies confirm the benefits of using marijuana for decreased frequency of migraines[Rhyne_2016].

HPV Vaccinations

Intractable pain following HPV vaccinations is thought to be caused by a malfunction of the autonomic nervous system. Treatment with CBD-enriched hemp oil has resulted in significantly reduced body pain. ⮛ RESEARCH ⮛

An observational study found that treatment with CBD-enriched hemp oil reduced pain from dysautonomia (malfunctioning of the autonomic nervous system) and somatic symptom disorder (characterized by untraceable pain) that had resulted from HPV vaccination[Palmieri_2017].

3.5 Concluding Thoughts

Studies in which patients play a significant role in managing pain tend to have better outcomes than in studies where all choices are in the hands of those performing the study. ⮛ RESEARCH ⮛

A survey of 2,897 patient self-reports from an online cannabis community indicated that 97% were able to reduce opioid use while taking cannabis, and 81% felt that cannabis by itself was more effective than taking cannabis with opioids[Reiman_2017].

A prospective study of 2,736 elderly patients carried out at a specialized medical cannabis clinic where patients received customized treatments provides further evidence. Almost all patients reported improvement, with an average drop in pain score from 8 to 4 on a scale of 0 to 10[Abuhasira_2018][Borreli_2018].

In addition to comparing the relative amount of pain relief obtained from various cannabis compounds, it may be helpful to consider the relative risks involved. More than 47,000 people died from opioid overdoses in 2018[CDC_2018]. A few thousand died from adverse NSAID side effects the same year[Tarone_2004]. There has been no reported overdose death from smoked marijuana[Wing_2017]. Moreover, very few deaths have resulted from marijuana-induced complications to other illnesses[Drummer_2019].

Given these statistics, we should ask whether patients in pain prefer risking death from conventional pain medications to risking pain from potentially ineffective cannabis compounds. But patients are often not allowed to choose between cannabis and prescription pain killers. Why? Financial incentives are likely involved. In 2015, Americans consumed 80% of the world's opioids at a cost of $19 billion[Gusovsky_2016]. The tobacco and alcohol industries have also lobbied against marijuana legalization.

As of this writing, cannabis is still a Schedule 1 drug, meaning that it has no established medical benefit. This perspective has strongly influenced coverage of cannabis in the popular press.

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