garra del diablo

Devil's Claw (Harpagophytum procumbens): A Comprehensive Reference

1. Identity and Botanical Description

Botanical and Chemical Names

Harpagophytum procumbens subsp. procumbens (Burch.) DC. ex Meisn. (Sesame seed Family—Pedaliaceae) is the plant popularly known as Devil's Claw. The generic name Harpagophytum is derived from the Greek words harpago meaning "hook" and phyton meaning "plant." The specific epithet procumbens means prostrate, referring to the creeping stems of the plant.

Devil's Claw is also called grapple plant and wood spider; the common name derives from the peculiar appearance of its hooked fruit. The only other species in the genus is H. zeyheri, also found in Southern Africa on Kalahari sands, but with much shorter spiny arms on its fruits than those of H. procumbens. The closely related H. zeyheri and H. procumbens are used interchangeably in commerce, but H. zeyheri has a lower concentration of biologically active constituents and is often found as an adulterant of H. procumbens, the preferred species of commerce.

Plant Morphology and Geographical Distribution

Harpagophytum procumbens is a perennial herb with a succulent taproot. The annual, creeping stems can be up to 2 m long and grow from a primary (or "mother") tuber whose taproot can reach up to 2 m deep. Secondary tubers (called "babies") develop on fleshy roots growing from the primary tuber and can be up to 25 cm long and 6 cm thick. Leaves are large, have 3–5 lobes, and are covered in white mucilaginous cells, giving them a grayish-green appearance. Flowers are trumpet-shaped and pink, red, or purple with a yellowish center.

H. procumbens is mainly found in the eastern and south-eastern parts of Namibia, southern Botswana, and the Kalahari region of the Northern Cape, South Africa. H. zeyheri is found in the northern parts of Namibia (Ovamboland) and southern Angola. More broadly, devil's claw is found in Angola, Botswana, Zambia, Zimbabwe, Namibia, Mozambique, and South Africa.

Medicinal Part and Commercial Forms

The secondary tubers of the herb contain twice as much harpagoside as the primary tubers and are the chief source of devil's claw used medicinally. As traditional medicine, devil's claw has been long used in the forms of infusions, decoctions, tinctures, powders, and extracts. Today, the medicine is available in the form of pills, capsules, teas, tinctures, and creams.

Commercial sources of devil's claw extract contain 1.4% to 2% of harpagoside. The European Pharmacopoeia stipulates a minimum of 1.2% harpagoside in the raw material, while dry extracts are standardized to contain a minimum of 1.5% m/m of harpagoside. Once harvested, botanical differentiation between species and subspecies is virtually impossible. Accordingly, current official compendia do not distinguish between the two botanical sources of devil's claw but require compliance in terms of contents of the marker compound harpagoside, a cinnamoylated iridoid glucoside.

2. Traditional and Historical Use

Indigenous African Use

For centuries, the first inhabitants of Southern Africa, also well known as the indigenous "Khoisan" people, utilized Devil's Claw in ancient prescriptions for various health conditions. Historically, the native Khoisan people harvested and utilized devil's claw for childbirth, loss of appetite, and as a purgative, as well as for the treatment of various diseases and ailments such as menstrual problems, indigestion, bitter tonic, inflammation, febrifuge, and syphilis. The Southern African Khoisan and Bantu-speakers also used devil's claw for indigestion, blood diseases, fevers, sprains, and boils.

In traditional South African tribal medicine, devil's claw is appreciated as an effective medicinal plant capable of reducing blood pressure and of treating disturbances of organs such as the kidney, liver, and bile. Traditional methods of administration included drinking it as a tea or eating the powdered root, and it was also applied topically to the skin.

Introduction to Western Medicine

The first Westerner to learn about devil's claw was a German, G.H. Mehnert, who learned about this plant from the San and Nama people in Namibia in 1904. In North America and Europe, especially in Germany, the plant and its healing effects have been known for nearly a century and became increasingly popular during the last decade of the twentieth century. Contrary to the traditional African applications, modern Western medicine and homeopathy use the plant chiefly to treat ailments of joints such as osteoarthritis and rheumatism.

No specific monograph for devil's claw was included in the German Pharmacopoeia (DAB) until 1993, which required testing for harpagoside content. The first monograph in Europe appeared in the British Herbal Pharmacopoeia in 1981. The Commission E of the former German Bundesgesundheitsamt published a positive monograph "Radix harpagophyti" in 1989. According to this publication, preparations from devil's claw roots are employed for dyspeptic conditions (daily dose of 1.5 g of the drug) and in supportive therapy of degenerative diseases of the locomotor system (daily dose of 4.5 g of the drug).

In Europe, the current focus is more on painful arthritis, tendinitis, loss of appetite, and dyspeptic complaints, as reflected in the EMA 2021 monograph.

3. Key Constituents and Active Compounds

Primary Phytochemicals

The main compounds of devil's claw are iridoid glycosides, such as harpagoside, harpagide, and procumbide, which are present in the plant tubers. Additionally, chemical constituents such as sugars (mainly the tetrasaccharide stachyose), triterpenoids (oleanolic and ursolic acid), phytosterols (primarily β-sitosterol), aromatic acids (caffeic, cinnamic, and chlorogenic acids), and flavonoids (luteolin and kaempferol) can be found in the plant.

The first iridoid glycoside isolated from H. procumbens was harpagoside, widely regarded as the active constituent, followed by harpagide and procumbide. In 1983, three additional iridoid glycosides with similar structures but different linkages were discovered, including procumboside. Other major active components include 8-coumaroylharpagide and verbascoside, which are believed to interact either synergistically or antagonistically in modulating the enzymes responsible for inducing inflammation.

Flowers, stems, and ripe fruits are essentially devoid of harpagoside, while traces have been isolated from the leaves. Harpagoside can be progressively hydrolyzed to harpagide and harpagogenin.

The Harpagoside Controversy: Whole Extract vs. Isolates

Some ethnobotanical claims have been confirmed through in vitro studies; however, when the constituents deemed to be the biologically active compounds were isolated, the efficacy was lower than that of the whole extract. This necessitates an approach where all metabolites are considered. Harpagide was found to cause a significant increase in levels of COX-2 expression after 6 hours of topical application. The data suggest that the efficacy of H. procumbens is dependent upon the ratios of compounds present, which is inconsistent with some current official monograph specifications based solely on harpagoside content. Whether harpagoside is more than just a marker, but also the (only) active compound, remains to be demonstrated.

4. Established Mechanisms of Action

Inhibition of Pro-Inflammatory Enzymes and Mediators

Mechanisms elucidated include inhibition of COX-2 enzymes and other pro-inflammatory enzymes, antioxidant activity, reductions in expression of prostaglandin PGE2, and inhibition of cysteinyl-leukotrienes.

Harpagoside inhibited lipopolysaccharide-induced mRNA levels and protein expression of cyclooxygenase-2 (COX-2) and inducible nitric oxide in HepG2 cells; these inhibitions appeared to correlate with the suppression of NF-κB activation by harpagoside.

A standardized ethanol H. procumbens extract dose-dependently inhibited the release of TNFα as well as that of interleukin (IL)-6, IL-1β, and prostaglandin E₂ (PGE₂). The extract prevented TNFα and IL-6 mRNA expression in human monocytes and COX-2 in RAW 264.7 cells, and inhibited LPS-stimulated AP-1-mediated gene transcription activity. The data indicate that a standardized ethanol extract inhibits induction of pro-inflammatory gene expression possibly by blocking the AP-1 pathway—novel evidence of a possible mechanism of action.

COX-1, COX-2, and Nitric Oxide

In a whole-blood assay, the fraction containing the highest concentration of harpagoside inhibited COX-1 and COX-2 (37.2% and 29.5%, respectively) and greatly inhibited NO production (66%). In contrast, the iridoid-pool fraction increased COX-2, and the cinnamic acid fraction only suppressed NO production. These results demonstrated that the harpagoside fraction is primarily responsible for the effect of devil's claw on these enzyme activities; however, other components could antagonize or increase the synthesis of inflammatory mediators.

Harpagoside and harpagide, which are monoterpenoids commonly found in H. procumbens, have been shown to inhibit TNFα-secretion in PMA-differentiated THP-1 cells. Stabilization of harpagoside and harpagide occurred at the active site of COX-2 through 7 and 10 hydrogen bonds, respectively. It has been concluded that harpagoside and harpagide are promising leads for additional study as potential anti-inflammatory/analgesic compounds and highly selective COX-2 inhibitors.

Leukotriene Modulation

An ex vivo study found that devil's claw extract (9% harpagoside) reduces cysteinyl-leukotriene (Cys-LT) levels in blood samples from healthy male subjects in a biphasic pattern, with a significant correlation between serum harpagoside levels and LT inhibition demonstrated. The difference in results among studies is most likely due to variations in the constituents of devil's claw extracts. The available mechanism-of-action studies "tentatively suggest" that devil's claw extract modulates LT and/or TX synthesis, but this effect may not be through a direct effect on the COX and 5-LOX pathways.

IL-6 Suppression in Chondrocytes

The ability of harpagoside to inhibit interleukin (IL)-6 production in primary human osteoarthritis chondrocytes challenged with IL-1β was consistently observed.

5. Scientific Evidence by Area of Use

5.1 Low Back Pain

A 2014 Cochrane review of 2 clinical trials involving 315 participants found low-quality evidence that daily doses of devil's claw may be better than placebo for short-term improvements in low back pain and may reduce use of rescue medication. The 2016 Cochrane review on herbal treatment for low back pain concluded that, with caveats for methodological quality, devil's claw has an impact on arthritic pain greater than placebo. An earlier review had concluded that there was moderate evidence of benefit in osteoarthritic conditions as well as low back pain for devil's claw preparations delivering between 50–100 mg harpagoside.

A later Cochrane review retrieved three randomized clinical trials. Two compared a H. procumbens product to a placebo (a total of 315 volunteers), while a third compared its effect to that of rofecoxib. The studies using placebo employed a 50 mg dose in the first and 50 and 100 mg doses in the second study. A significant reduction in pain score was reported over placebo; however, a low score was attained for the quality of evidence when the GRADE criteria were applied. Similar pain reduction scores were obtained for devil's claw and rofecoxib in the third study, which involved 88 participants.

Indications in trials were primarily degenerative joint diseases and low back pain. Trials utilized a variety of methodological designs, with different preparations and daily doses of harpagoside varying from less than 30 to more than 100 mg. An investigation into the harpagoside content of commercially available devil's claw preparations revealed substantial variation, with contents often below the recommended daily dose of 4.5–9 g crude drug (equivalent to more than 50 mg harpagoside).

Evidence strength: Clinical trials are generally supportive of its use as an anti-inflammatory and analgesic in low back pain; however, the Cochrane review found evidence in support of short-term reduction in pain greater than placebo based on only 2 low-quality clinical trials.

5.2 Osteoarthritis

Although systematic reviews indicate that there is evidence that devil's claw preparations benefit inflammatory/painful conditions, a meta-analysis by Brien et al. (2006) encompassing 14 studies from 1966 to 2006 on H. procumbens as a treatment for osteoarthritis—including eight observational studies, two comparator trials, and four double-blinded, placebo-controlled RCTs—found that data from the better quality studies indicate that the herbal drug is effective in reducing pain associated with osteoarthritis, although several studies did not adhere to important quality criteria in methodology.

A 2008 review of dietary supplements for osteoarthritis concluded that there is insufficient reliable evidence of long-term safety or effectiveness of devil's claw for this condition.

A review of H. procumbens preparations for the treatment of joint and lower back pain found that studies utilizing extracts containing 50–60 mg harpagoside daily gave more reliable data and were more effective at alleviating pain and improving mobility than extracts with lower amounts.

Evidence strength: Few quality double-blind, placebo-controlled, or comparator randomized trials have been conducted in osteoarthritis; however, there is general support for evidence of effect in pain reduction, and other clinical studies (open-label) are also supportive. Well-designed, adequately powered studies are required before definitive statements regarding optimal dose, efficacy, and duration of therapy can be made.

5.3 Digestive Disorders and Appetite

According to the Commission E monograph, indications include loss of appetite and dyspeptic complaints, as well as supportive therapy of degenerative diseases of the musculoskeletal system. The ESCOP monograph covers pain treatment, osteoarthritis, back pain, loss of appetite, and dyspeptic complaints.

Devil's claw is traditionally used in herbal medicine as a bitter to help stimulate appetite and to help relieve digestive upset/indigestion, as recognized by the EMA (2016), ESCOP (2003), and Blumenthal et al. (2000).

For traditional use, the EMA differentiates between two indications and the corresponding reference daily doses: symptomatic relief of digestive disorders such as dyspepsia and flatulence, with a recommended daily dose of 2–3 times 100 mg; and adjuvant treatment of degenerative diseases in the locomotor system, with a recommended daily dose of 3 times 750–800 mg (i.e., 2,250–2,400 mg).

Research has investigated the effect of a plant extract derived from the dried tuberous roots of H. procumbens on GHS-R1a receptor modulation in vitro and on food intake in vivo. In traditional medicine, the plant has historically been used as an appetite modulator, among other applications. Future studies are needed to identify the specific bioactive responsible for the appetite suppressant effects of H. procumbens; nonetheless, the crude extract has demonstrated potent anorexigenic effects in preclinical research.

Evidence strength: The digestive and appetite-stimulating uses are primarily supported by traditional and ethnobotanical evidence and have been recognized in official monographs (Commission E, ESCOP, EMA). Clinical trial data specifically for the digestive indication is very limited.

5.4 Cardiovascular Effects

Older animal studies demonstrated cardiac effects of extracts of H. procumbens, including dose-dependent reduction in blood pressure, decreased heart rate, and anti-arrhythmic activity, with mixed results for inotropic and chronotropic activity. Devil's claw may affect heart rate and blood pressure and may be harmful in people with heart disease or circulatory system disorders. These effects are primarily from animal data; dedicated human cardiovascular trials are lacking.

5.5 Preclinical Evidence: Other Areas

Recent scientific studies show that extracts of the secondary tubers of H. procumbens are being explored for their potential in the treatment of degenerative rheumatoid arthritis, osteoarthritis, tendonitis, kidney inflammation, heart disease, dyspepsia, and loss of appetite. H. procumbens has also been used in the treatment of ulcerative colitis, one of the chronic disorders of the digestive tract, where the lining of the colon becomes inflamed, resulting in small open sores or ulcers. This remains largely preclinical.

Devil's claw may lower blood glucose levels; this effect has been noted in published reports. Human clinical data on diabetic outcomes are absent, and this observation originates from preliminary and pharmacovigilance reports.

6. Body Systems and Health Areas of Association

• Musculoskeletal system: The primary medicinal uses of devil's claw are the management of arthritis, pain, and dyspepsia. Osteoarthritis, rheumatoid arthritis, lower back pain, tendinitis, and muscle pain are all described in clinical and traditional literature.
• Gastrointestinal system: Devil's claw is used as a traditional herbal medicinal product for the relief of mild digestive disorders such as bloating and flatulence and where there is loss of appetite.
• Cardiovascular system: Animal data suggest effects on blood pressure, heart rate, and cardiac rhythm; human evidence is absent.
• Metabolic: Devil's claw may lower blood glucose levels, a consideration for people with diabetes.
• Immune/Inflammatory: Its traditional uses include treatment of menstrual problems, inflammation, fever, and syphilis. A number of bioactive compounds such as terpenoids, iridoid glycosides, glycosides, and acetylated phenolic compounds have been isolated and studied for anti-inflammatory and analgesic effects.

7. Dosage Forms and Reported Dosages

Devil's claw has been studied for low back pain, muscle pain, and osteoarthritis using daily doses of crude tuber up to 9 g, 1 to 3 g of extract, or harpagoside 50 to 100 mg.

The EMA, for traditional use, differentiates between two indications: for digestive disorders, the recommended daily dose (RDD) is 2–3 times 100 mg; for the adjuvant treatment of degenerative diseases of the locomotor system, the RDD is 3 times 750–800 mg (2,250–2,400 mg).

According to Commission E (1989), preparations from devil's claw roots are employed for dyspeptic conditions at a daily dose of 1.5 g of the drug, and in supportive therapy of degenerative diseases of the locomotor system at a daily dose of 4.5 g of the drug.

Previous research using dose levels in the range of 50–100 mg harpagoside daily has shown devil's claw to be at least as well tolerated as more traditional pain medications (e.g., nonsteroidal anti-inflammatory drugs), and allergic reactions have been rare.

Clinical trials have utilized a variety of methodological designs, with different preparations and daily doses of harpagoside varying from less than 30 to more than 100 mg. While harpagoside is considered to contribute to the overall activity of devil's claw preparations, it is not yet fully understood which other compounds may also be of relevance. An investigation of commercially available preparations revealed substantial variation in harpagoside content, often falling below the recommended daily dose equivalent to more than 50 mg harpagoside.

The accepted oral dosage forms recognized in official monographs include dry powder, non-standardized extracts (dry extract, tincture, fluid extract, decoction, and infusion).

8. Safety Considerations and Drug Interactions

General Tolerability

A 2008 systematic review of 28 clinical trials on the safety of devil's claw for osteoarthritis and low back pain concluded that although the incidence of adverse events during treatment with devil's claw is low, more long-term safety data are needed. There is not enough reliable evidence for experts to advise on the safety of using devil's claw for more than a year.

Potential side effects include mild gastrointestinal symptoms such as diarrhea, nausea, vomiting, and abdominal pain; headaches; ringing in the ears; loss of appetite; and loss of taste. It may also be related to allergic skin reactions, menstrual problems, and changes in blood pressure.

Rare adverse effects consist generally of headache, tinnitus, or anorexia. A case of devil's claw-induced hypertension has been documented. Clinically important toxicity has not been observed in limited, short-term use.

Gastrointestinal Contraindication

Because of the bitterness of the preparation and consequent increase in gastric secretion, devil's claw is contraindicated in patients with gastric or duodenal ulcers.

Cardiovascular Drug Interactions

Devil's claw should not be used with antiarrhythmic, chronotropic, or inotropic medicines. Devil's claw may affect heart rate and blood pressure and may be harmful in people with heart disease or circulatory system disorders.

Anticoagulant Interaction

Devil's claw (Harpagophytum procumbens) was associated with purpura (bleeding under the skin) in a patient treated with warfarin. However, key details in this case—including other medications taken and the amounts and duration of warfarin and devil's claw taken—were not reported, making it impossible to evaluate this reported interaction.

Blood Glucose

Devil's claw may lower blood glucose levels, so people with diabetes should monitor blood glucose levels closely.

Pregnancy and Lactation

Documented oxytocic adverse effects have been reported for devil's claw. Devil's claw may be unsafe for pregnant people to use and may cause harm to the fetus. There is insufficient evidence for experts to know whether devil's claw is safe for people to use while breastfeeding.

Toxicological Overview

Toxicological data have shown that H. procumbens has adverse effects at high concentrations, and various models promote low dose levels as a safety parameter. The literature shows a decline in safety investigations after 2011. Prior to 2011, there were many studies conducted on the acute and chronic toxicity of H. procumbens plant extracts and their bioactive compounds.

Quality and Adulteration Concerns

H. procumbens contains higher levels of the pharmacologically active constituents than H. zeyheri. The two are used interchangeably and H. procumbens raw material is often intentionally adulterated with H. zeyheri, which may impact the efficacy of inadequately controlled health products. The high demand for health products based on this plant has led to over-harvesting, raising concerns about sustainability.

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