Devil's Claw Harpagophytum procumbens, H. zeyheri

HerbalGram The Journal of the American Botanical Council Issue: 118 Page: 8-14 Family: Pedaliaceae by Gayle Engels, Josef Brinckmann HerbalGram. 2018; American Botanical Council INTRODUCTION A weedy, spreading perennial with gray-green, lobed leaves, devil’s claw (Harpagophytum procumbens and H. zeyheri) emerges in the rainy season from a fleshy, central tap root, which has additional lateral, tuberous roots. The trumpet-shaped flowers have been described as entirely red, purple, or pink, or any of these colors, with a yellow base and throat. The fruit, which gives the plant its common name, has numerous long arms with sharp, hooked thorns that cling to passing animals and aid in its dispersal.1-3 Harpagophytum procumbens can be distinguished from H. zeyheri to some extent by the shape of the leaves,4 but also by the length of the arms of the fruit; the arms of H. procumbens fruit are longer than the width of the fruit, and the arms of H. zeyheri fruit are shorter than the width of the fruit.1 The fleshy secondary roots of these species have been used interchangeably in South African folk medicine, as they have similar chemical constituents.1 Devil’s claw is indigenous to deciduous forests and arid savannah areas of southern Africa and occurs between 15 degrees and 30 degrees latitude in Namibia, Botswana, South Africa, and Angola, and also to a lesser extent in Zambia, Zimbabwe, and Mozambique.5 In commerce, devil’s claw root is supplied by the two main species: H. procumbens and H. zeyheri.6 Although several subspecies are described in the literature, overlaps in habitat coupled with potential introgressive hybridization complicate subspecies identification and differentiation.4 “Devil’s claw root” is defined in the European Pharmacopoeia (PhEur) as the cut and dried, tuberous secondary roots of H. procumbens and/or H. zeyheri.7 In 2009, it was estimated that 55% (208,286 kg) of Namibia’s devil’s claw root exports were H. zeyheri, while 45% (170,416 kg) were H. procumbens.8 More than 90% of the global supply of devil’s claw root comes from wild collection in Namibia, with smaller amounts from Botswana, Angola, and Zambia. Roots need to be at least four years old before they are ready to harvest. While cultivation trials began in the 1970s, the first devil’s claw farm was established in 1997 by Professor Earle Graven of Grassroots Natural Products at Groenvlei Farm in Western Cape, South Africa (N. Gericke personal communication, March 2, 2018). South Africa’s Plant Production Directorate states that commercial devil’s claw plantations were first established in South Africa and Namibia in 2002,9 and that these farms still account for a relatively small percentage of the total commercial trade. Devil’s claw root sourced from Namibia is harvested mostly by members of rural communities in communal areas, such as in the Kavango, Caprivi, Otjozondjupa, and Omaheke regions.10 HISTORY AND CULTURAL SIGNIFICANCE Devil’s claw root tuber is a traditional medicine of the San and Khoikhoi peoples of southern Africa. San names for devil's claw include //x’aatataba* and tloutaxaba. In the Afrikaans language, spoken in Namibia and South Africa, the plant is called Duiwelsklou, which phonetically is very similar to the names used in Dutch (Duivelsklauw), English (devil’s claw), and German (Teufelskralle).10 In his 1822 book Travels in the Interior of Southern Africa, English botanist and naturalist William John Burchell (ca. 1781-1863) referred to devil’s claw as “grapple plant” and initially placed it in the genus Uncaria (Rubiaceae). Burchell also assigned the species name procumbens from the Latin word meaning “prostrate” or “lying down.”11 The genus name Harpagophytum stems from the Greek words Harpagos, meaning “grappling hook,” and phyton, meaning “plant.”12 Sometime between 1824 and 1839, Swiss botanists Augustin Pyramus de Candolle (1778-1841) and son Alphonse de Candolle (1806-1893) nullified Uncaria and placed the species into the Harpagophytum genus.13 The de Candolles (DC) made their findings available to another Swiss botanist, Charles Frédéric Meissner (1800-1874), when Meissner was preparing his own work, Plantarum vascularium Genera (1836-1843).14 Thus, Meissner first published the genus name Harpagophytum DC around 1840,15 which explains why the botanical name used today (i.e., H. procumbens [Burch.] DC. ex Meissn) includes abbreviations of all three botanists involved in the nomenclature evolution from Uncaria to Harpagophytum. As for the second species of devil’s claw, Belgian botanist Joseph Decaisne (1807-1882) assigned the species name zeyheri,16 which referred to the German botanist Karl Ludwig Philipp Zeyher (1799-1858), who had worked extensively in southern Africa. The tuber has been used traditionally as a laxative and to treat arthritic and blood conditions, headache, fever, indigestion, pain after childbirth, and malaria.2,3,17 It is considered an analgesic, and a devil’s claw ointment is applied topically to boils, sprains, sores, and to ease childbirth. It has been used as a bitter tonic and for its anti-inflammatory properties, both internally and externally.3 Devil’s claw preparations also have folk uses in diabetes, gout, and tuberculosis, as a mouthwash for bleeding gums, and for hypertension, menstrual cramps, peptic ulcers, snakebites, lumbago (lower back pain), and wound and burn healing.2,18 European awareness of devil’s claw as an effective therapeutic agent reportedly traces back to observations of a German soldier-cum-farmer in Namibia, Gottreich Hubertus Mehnert (1880-1967), who was interested in devil’s claw and other local medicinal plants used by the Nama people.19 Dr. phil. nat. Otto Heinrich Volk (1903-2000) also played a central role while he was a prisoner of war from 1940 to 1944 at the Internment Camp Andalusia in Bloemfontein, South Africa.20 There, he met Mehnert, the initial marketer of a devil’s claw herbal tea called “Harpago-Tee,” and other German scientists including botanist Heinrich Johann Wilhelm (Willi) Giess (1910-2000), who made color illustrations of devil’s claw during internment in Andalusia.21 In the 1950s, the Mehnert family sent samples of devil’s claw root for analysis to Volk and Prof. Dr. Paul Tunmann, at that time both working at the University of Würzburg Institute of Pharmacy and Food Chemistry, and also to Prof. B. Zorn at the University of Jena (former East Germany). In 1957, Zorn carried out studies in rats with formaldehyde-induced arthritis and demonstrated anti-arthritic action from subcutaneous injection as well as oral ingestion of a decoction of the roots. In 1962, Tunmann co-authored a paper on the constituents of devil’s claw root, and, in 1964, Volk published information on its ecology, harvesting and yields, macroscopic description, and traditional uses.22,23 Commercial harvesting of devil’s claw began in the early 1960s in Namibia and Botswana. The formal export trade commenced in 1962 when the Namibian company Harpago Proprietor Limited began exporting dried devil’s claw root tubers to the German company Erwin Hagen Naturheilmittel GmbH, mainly for the production of herbal medicinal tea products indicated for the treatment of arthritis and rheumatism.24 Commercial harvesting in South Africa began closer to the end of the 20th century.25 In the United Kingdom, a monograph titled “Harpagophytum” was published in part three of the second edition of the British Herbal Pharmacopoeia in 1981, with therapeutic indications including rheumatism, arthritis, gout, myalgia (muscle pain), fibrositis (an outdated term for fibromyalgia), lumbago, and pleurodynia (sudden occurrence of stabbing chest pain or abdominal pain attacks).26 Therapeutic uses approved by the German Commission E authority in a 1989 monograph (revised in 1990) for devil’s claw root tuber (südafrikanische Teufelskrallenwurzel – Harpagophyti radix), prepared as an herbal tea infusion or equivalent preparations, were for loss of appetite, dyspepsia, and as supportive therapy of degenerative disorders of the locomotor system.27 Also in 1989, a quality standards monograph titled “Harpagophyton” entered the 10th edition of the French Pharmacopoeia,28 followed by the addition of a monograph for devil’s claw dry extract (Extrait d’Harpagophytum sec – Harpagophyti extractum siccum) in 1992.29 In 1990, French health authorities approved the oral and topical use of devil’s claw root tuber as a traditional herbal medicine used for symptomatic treatment of minor painful articular conditions.30 In Germany, a quality standards monograph first entered the second supplement to the 10th edition of the German Pharmacopoeia (DAB 10.2) in 1993.31 In 1994, the European Directorate for the Quality of Medicines (EDQM) published its first draft quality standards monograph for devil’s claw root (Harpagophyti radix PhEur) for public comment.32 Three years later, in 1997, an official monograph entered the third edition of the PhEur, at that time specifying H. procumbens only.33 However, in the 1970s, Prof. Dr. Franz-Christian Czygan and Almuth Krüger at the Institute of Botany and Pharmaceutical Biology, University of Würzburg, carried out studies, published in Planta Medica, which concluded that due to the lack of significant differences in anatomy, morphology, and histochemistry, the secondary root tubers of both species should be accepted as equivalent sources of the herbal drug Harpagophyti radix.34 In 2000, researchers at Finzelberg GmbH (Andernach, Germany) carried out a retrospective study of retention samples of Harpagophyti radix (from 1995 to 1999) using a new analytical method that could chemically differentiate the two species, and found that batches were composed of either H. procumbens or H. zeyheri or, in some cases, mixtures of both species.35 In recognition of these facts, and with awareness that the commercial supply of devil’s claw originated from either H. procumbens or H. zeyheri (or a combination of both), the monograph was corrected in PhEur 4 (2002) in order to formally add the second species, H. zeyheri. In 2006, the EDQM published a draft monograph for devil’s claw root dry extract, after which the final monograph was added to PhEur 6 in 2008. With the entering of these monographs into the PhEur, former monographs of the national pharmacopeias of Germany and France were retired. In 2007, a comprehensive monograph (quality and therapeutics) for “Radix Harpagophyti” entered volume three of the WHO Monographs on Selected Medicinal Plants.36 Also in the early 21st century, national labeling standards monographs of European Union (EU) member states, such as the aforementioned German Commission E monographs, became superseded by new monographs of the European Medicines Agency (EMA). The EMA initially published a labeling standards monograph for devil’s claw root in 2008 (which was superseded by a revised monograph in 2016), applicable when used as an active ingredient of registered traditional herbal medicinal products (THMPs) in the European Union.37 CURRENT AUTHORIZED USES IN COSMETICS, FOODS, AND MEDICINES In the EU, registered THMPs composed of Devil’s Claw Root PhEur prepared in the dosage forms of herbal tea infusion, tincture (1:5), liquid extract (1:1), soft extract (2.5-4.0:1), or in solid dosage forms containing Devil’s Claw Root Dry Extract PhEur, may be labeled and marketed for “relief of minor articular pain” and “relief of mild digestive disorders such as bloating and flatulence and where there is temporary loss of appetite,” at the dosages prescribed in the EMA labeling standards monograph.37 In Canada, devil’s claw root is regulated as an active ingredient of licensed natural health products (NHPs), which require pre-marketing authorization from the Natural and Non-prescription Health Products Directorate (NNHPD). Labels of licensed NHPs prepared from PhEur-quality devil’s claw may carry the following claim statements: “Traditionally used in Herbal Medicine as a bitter to help stimulate appetite;” “Traditionally used in Herbal Medicine to help relieve digestive disturbances such as dyspepsia;” and “Used in Herbal Medicine to help relieve joint pain associated with osteoarthritis.”38 Additionally, devil’s claw is listed as an active ingredient in the NNHPD’s “Multiple Ingredient Joint Health Products” monograph.39 In the United States, devil’s claw root may be used as a component of dietary supplement products, which require US Food and Drug Administration notification within 30 days of marketing if a structure-function claim is made and product manufacturing that adheres to current Good Manufacturing Practices (cGMPs).40 It should be noted that H. procumbens is considered a pre-1994 old dietary ingredient and is listed in the American Herbal Products Association’s Herbs of Commerce, 2nd ed. (although the book’s disclaimer states that listing of a species is not, in and of itself, evidence that the species was marketed in the United States before October 15, 1994).41 Due to a lack of awareness in the early 1990s that both species or mixtures of both species were being imported into the United States labeled as H. procumbens, coupled with the lack of an analytical method that could differentiate the two species at the time, H. zeyheri was inadvertently omitted from the Herbs of Commerce. MODERN RESEARCH The characteristic bitter taste of devil’s claw root is due to iridoid constituents such as harpagoside. In the late 1970s, initial studies in Germany found bitterness values between 5,000 and 12,000 using the method of the eighth edition of the German Pharmacopoeia (DAB 8, 1978). Due to a correlation between bitterness and harpagoside content, it was suggested at that time that therapeutic-quality devil’s claw root should have a minimum harpagoside content of 0.5% and a minimum bitterness value of 6,000.23 Today, for use in medicinal products, the PhEur requires devil’s claw root to contain a minimum 1.2% harpagoside content, but does not prescribe a bitterness value.7 Using a bitterness test adapted from PhEur and World Health Organization methods, Olivier and van Wyk (2013) determined bitterness values ranging from 1,440 to 14,400 in samples of H. procumbens, and suggested that the traditional uses of devil’s claw may be attributable, in part, to a bitter tonic (amarum) effect (i.e., the stimulation of gastric juices by way of the vagus nerve).42 Mncwangi et al. (2014) compared harpagoside levels of the two official species by analyzing 348 samples obtained from 10 different localities in three countries (South Africa, Namibia, and Zimbabwe). Significant variation in harpagoside content was found, ranging from 0.17% to 4.37% in H. procumbens samples, and from 0.00% to 3.07% in H. zeyheri samples. Only 41% of the H. procumbens samples and 17% of the H. zeyheri samples met the PhEur standard of a minimum 1.2% harpagoside content.43 Published in 2012, a thorough review of the ethnobotany, phytochemistry, and biological activity of H. procumbens confirmed the presence of iridoid glycosides (harpagoside, harpagide, procumbide, procumboside, 8-O-p-coumaroyl-harpagide, and 6’-O-p-coumaroylprocumbide) as well as harpagoquinones, amino acids, flavonoids, phytosterols, and carbohydrates. This review also substantiated that H. procumbens exerts anti-inflammatory, analgesic, antioxidant, anti-diabetic, antimicrobial, antimalarial, anticancer, cardiovascular, central nervous system, and uterotonic effects. The authors opine that while the phytochemistry of the species is well researched, research on the additive or synergistic effects of the major compounds is lacking.44 They state that “Harpagophytum zeyheri is a close taxonomic ally of H. procumbens but H. procumbens is the favoured species of commerce, and contains higher levels of the pharmacologically active constituents. The two are used interchangeably and H. procumbens raw material is often intentionally adulterated with H. zeyheri and this may [have an] impact on the efficacy of inadequately controlled health products.” Use of the term “adulterated,” however, is problematic in that the PhEur expressly defines devil’s claw root as the tuberous secondary roots of H. procumbens and/or H. zeyheri. The authors also discuss botanical and chemical identification of H. zeyheri and quality control methods that can be used to avoid substitution when a customer specifies one species over the other.44 Chrubasik and Wink (1998)45 reported on early clinical studies in the 20th century that investigated the efficacy of devil’s claw extracts in improving osteoarthritis (OA) of the hip, knee, fingers, and spine46,47; rheumatic joint pain48,49; and lower back pain (LBP).50-52 All of these studies showed positive outcomes in pain reduction with specific dosages of either 1.5% to 3% iridoid glycosides or 30-100 mg harpagoside. An article by Tankred Wegener in HerbalGram issue 50 (2000)53 discussed the results of six of the studies mentioned above46-50,52 and addressed four more. One randomized, controlled trial demonstrated improvements in pain and the Lequesne index (a measurement of the severity of OA) over six months of treatment with 2.6 g dried tuber per day (Harpadol; Arkopharma; Carros, France).54 A double-blind, placebo-controlled study showed reduction of pain in radiating LBP in a dose-dependent manner, with patients receiving a devil’s claw preparation that contained 100 mg harpagoside (WS 1532; Dr. Willmar Schwabe; Karlsruhe, Germany) twice daily for four weeks experiencing the greatest relief.55 In an uncontrolled study, patients with OA and rheumatoid arthritis who took a daily dose of 750 mg powdered tubers (Arkogélules Harpagophyton; Arkopharma; Carros, France) for 30 days achieved significant improvement in symptoms.56 In another uncontrolled study, 13 seropositive arthritis patients who took 1.23 g per day of devil’s claw extract (no additional information provided) attained insignificant improvements in grip strength and flexibility.57 Since 2000, at least four systematic reviews have evaluated studies from the late 20th and early 21st centuries that investigated the effects of devil’s claw on OA and LBP. In one that reviewed studies on H. procumbens as a treatment for OA,58 the authors identified eight observational studies, two comparator studies, and four randomized, double-blind, placebo-controlled studies47-49,59 that “provide some support for the potential therapeutic value” of devil’s claw in treating OA, despite “a considerable number of methodologic caveats that make further clinical investigations warranted.” In a 2007 systematic review of randomized, controlled trials of herbal medicines used for non-specific LBP, Gagnier et al. concluded that “Two high-quality trials utilizing Harpagophytum procumbens (devil’s claw) found strong evidence for short-term improvements in pain and rescue medication for daily doses standardized to 50 mg or 100 mg harpagoside with another high-quality trial demonstrating relative equivalence to 12.5 mg per day of rofecoxib” (a nonsteroidal anti-inflammatory drug [NSAID] that has since been withdrawn from the market due to adverse effects).60 However, in a 2016 follow-up review, Gagnier et al. downgraded the two studies that compared devil’s claw to placebo50,51 to “low quality” based on “imprecise data” and sample sizes of less than 400. They also downgraded the study that compared devil’s claw to rofecoxib61 to “very low quality” based on problems with allocation concealment and compliance, and its small sample size.62 Oltean et al. (2014) reviewed the same studies and stated that, while devil’s claw appeared to reduce pain more than placebo, evidence was “of moderate quality at best” and that researchers should follow the Consolidated Standards of Reporting Trials (CONSORT) statement extension when reporting studies on herbal medicine interventions.63 One randomized, double-blind, placebo-controlled study published in 2017 investigated the efficacy of a combination product in treating symptoms of gonarthritis (OA of the knee). Rosaxan (MA212; Medagil Gesundheitsgesellschaft mbH; Friedrichshafen, Germany) contains 20 g rose hip (Rosa canina, Rosaceae) ripe fruit puree, 4 g R. canina ripe fruit juice concentrate derived from fruit puree, 160 mg stinging nettle (Urtica dioica, Urticaceae) leaf dried aqueous extract (10:1), and 108 mg H. procumbens or H. zeyheri root dried aqueous extract. For 12 weeks, patients (N = 92) with clinically diagnosed unilateral or bilateral gonarthritis and moderate pain symptoms consumed either 40 mL of Rosaxan or placebo daily. At baseline, six weeks, and 12 weeks, Western Ontario and McMaster Universities Arthritis Index (WOMAC) scores, quality of life (QoL) ratings, and analgesic consumption were recorded. The test group experienced a significant improvement in WOMAC scores from baseline compared to placebo. Additionally, both physical and mental QoL ratings improved significantly with Rosaxan compared to placebo, and there was a trend toward taking less pain medication in the test group.64 FUTURE OUTLOOK From 1992 to 2013, Namibia exported more than 9,500 tons of dried devil’s claw root, with an average annual export quantity of approximately 435 tons. The main importing countries between 2009 and 2013 were France, Italy, Germany, Poland, Spain, and South Africa.65 In 2000, there was a proposal from Germany to list Harpagophytum species in Appendix II of the Convention on International Trade in Endangered Species of Wild Fauna and Flora (CITES). Ultimately, the proposal was rejected because, at the time, insufficient data were available covering the extent, distribution, age, and biology of devil’s claw populations that would confirm the need for protection under CITES.65 Furthermore, the range states (i.e., the exporting countries) rejected the proposal, in part due to concerns about potential negative impacts on the livelihoods of impoverished and marginalized communities that depend on the devil’s claw trade for income.66 In the meantime, Harpagophytum species became protected in Namibia under Schedule 9 of the Nature Conservation Ordinance, and, in 2010, the Namibian government ratified a devil’s claw resource management policy, which is enforced by the Ministry of Environment and Tourism (MET). Per this policy, permits are required for all stages of devil’s claw production, with the wild harvesting and sale of devil’s claw permitted only between March 1 and October 31. In addition, traders and exporters are required to pass a test and be registered with MET.65 In Botswana, Harpagophytum species are protected under the Agricultural Resources Conservation Act. Harvest, trade, and export of devil’s claw from South Africa also require a permit. Similar legislation for the protection of devil’s claw wild populations has been enacted in Zambia, but not in Angola. Namibia’s continual development of legislation for implementation of the Nagoya Protocol on Access to Genetic Resources and the Fair and Equitable Sharing of Benefits Arising from their Utilisation is likely to impact devil’s claw trade relationships in the future.67 An Interim Bioprospecting Committee (IBPC) was established in 2007 to focus on the issue of access and benefit sharing (ABS) in the use of genetic resources such as Namibian indigenous medicinal plants, including devil’s claw. The IBPC was established for Namibia to fulfill its obligations under the Convention on Biological Diversity (CBD) and to facilitate ABS agreements for commercial use of indigenous knowledge and associated genetic resources. The aim is for local and indigenous communities to benefit from the use of their traditional knowledge, practices, and innovations.68 Over the past 20 years, Namibia has made significant investments in implementing policies and practices necessary for sustainable resource management and trade of its indigenous plant products, most notably devil’s claw root. This includes frameworks for protecting the traditional ecological and medical knowledge of indigenous communities for commercial access and use of genetic resources like devil’s claw. Namibia also has seen an increase in devil’s claw production operations that implement international sustainability standards such as organic and fair trade. For example, several Namibian devil’s claw wild harvesting operations (Balyerwa Conservancy, Dzoti Conservancy, Kwandu Conservancy and Community Forest, Masida Community Forest, and Wuparo Conservancy) have organic wild crop certification as per the US Department of Agriculture’s National Organic Program (NOP).69 Additionally, organic farms like EcoSo Dynamics (Okahandja, Namibia) are marketing both cultivated and wild-crafted devil’s claw root with “Fair for Life – Social & Fair Trade Certification,”70 and operations in Zimbabwe like Organic Africa are implementing the Ethical BioTrade Standard for sustainable wild collection of devil’s claw.71 For a wild medicinal plant of southern Africa that has been commercialized and exported for only about 60 years, significant progress has been made in understanding the chemical composition, quality grades, and appropriate therapeutic uses of devil’s claw. The range states, Namibia in particular, with the local and indigenous communities that make their livelihoods by managing genetic plant resources, appear to be laying the groundwork necessary for equitable and sustainable trade and use of devil’s claw. —Gayle Engels and Josef Brinckmann References van Wyk B-E, van Oudtshoorn B, Gericke N. Medicinal Plants of South Africa. Arcadia, Pretoria, South Africa: Briza Publications; 1997. van Wyk B-E, Gericke N. People’s Plants: A Guide to Useful Plants of Southern Africa. Arcadia, Pretoria, South Africa: Briza Publications; 2000. Iwu M. Handbook of African Medicinal Plants. Boca Raton, FL: CRC Press; 1993. Ihlenfeldt HD, Hartmann H. Die Gattung Harpagophytum (BURCH.) DC. ex MEISSN. (Monographie der afrikanischen Pedaliaceae II). Mitt Staatsinst Allg Bot Harnburg. 1970;13:15-69. Hachfeld B, Schippmann U. Conservation data sheet 2: Exploitation, trade and population status of Harpagophytum procumbens in southern Africa. 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