Rauwolfia in the Treatment of Hypertension

by Douglas Lobay, Bsc, ND

Rauwolfia serpentina is a very safe and effective natural treatment for hypertension. This paper first reviews the botany, history, and folk use of this plant. It talks about Rustom Jal Vakil and the introduction of rauwolfia in modern medicine. It then discusses the chemical composition, pharmacology, and mechanism of action of reserpine and rauwolfia. It looks at the medical use of this plant with emphasis on its role in treating hypertension. It then critically looks at adverse side effects, toxicology, and carcinogenicity. It dispels the association between this plant and breast cancer. It further discusses the importance and screening of patients that minimizes the occurrence of depression. It concludes with a discussion of my personal experience of prescribing rauwolfia in the treatment of hypertension and recommendations for dosage.

Botany

Rauwolfia serpentina is perennial shrub from the Apocynaceae, or dogbane, family. It is native to tropical and subtropical regions of Asia, including India, Burma, Bangladesh, Sri Lanka, and Malaysia. It grows in moist, warm forests to a height between 60 and 90 centimeters. It has dark, green leaves that grow up to 10 centimeters long and up to 5 centimeters wide in whorls of 3 to 5 leaves. It has numerous shiny purple or black fruit that are about 0.5 centimeters in diameter. The plant has a strong, snakelike taproot that grows up to 50 centimeters in length and 2.5 centimeters in diameter.^1,2

History and Folk Use

Rauwolfia serpentina has been used in Indian folk medicine for thousands of years to treat a wide variety of maladies, including snake and insect bites, febrile conditions, malaria, abdominal pain, and dysentery. It was also used as a uterine stimulant, febrifuge, and cure for insanity. The plant is named after the 16th-century German physician Leonard Rauwolf, who studied the plant while he was traveling in India. It is reported that Indian political leader Mahatma Gandhi drank a tea made from this plant to help him relax and sleep after a long, busy day. Rustom Jal Vakil is the British trained medical physician who first popularized the use of Rauwolfia for the treatment of hypertension.^3–5

Rustom Jal

Vakil

Rustom Jal Vakil published a watershed paper about the antihypertensive properties of Rauwolfia serpentina in the British Medical Journal in 1949. He presented detailed results of treating high blood pressure with the root of Rauwolfia serpentina in 50 patients. At this time, there was no effective pharmacological treatment of hypertension available anywhere in the world. This seminal paper stimulated widespread scientific research and pharmacologic interest in rauwolfia. By the end of 1949, 60,000 (90%) of Indian physicians were using rauwolfia in the treatment of hypertension. At its peak, India used 650 tonnes of the dried root per year, and worldwide usage was 20,000 tonnes per year to over 17 countries. One manufacturer claimed to have sold 94 million tablets of the dried root in 1954 alone.⁶

Chemical Composition

The most important group of phytochemicals found in this plant are indole alkaloids. Over 50 different indole and indoline alkaloids have been isolated in this plant. The alkaloids are derived from amino acid tryptophan into a variety of heterocyclic ring structures. The most pharmacologically active indole alkaloids are ajmaline, deserpidine, rescinnamine, reserpine, serpentine, and yohimbine. All parts of the plant contain alkaloids, but the root has the highest amount. The exact concentration of alkaloids in the root varies from 0.7% to 3.3% of the dried weight of the root. Another more conservative estimate suggests the total alkaloids varies from 0.8% to 1.3% of the dried weight of the plant. Other species in the same genus, including R. caffra, R. canescens, R. heterophylla, and R. vomitoria, have been found to be adulterants to Rauwolfia serpentina. They do contain variable amounts of indole alkaloids and may be used as a suitable alternative.^7–9

Reserpine

Reserpine is the most widely studied indole alkaloid found in this plant. In an effort by the scientific community to isolate a single constituent of rauwolfia, reserpine was believed to be the most pharmacologically active ingredient. The exact concentration of reserpine varies from 0.03 to 0.14% of the dry weight of the root of Rauwolfia serpentina. Other alkaloids believed to have medicinal action include canescine, deserpidine, recanescine, and rescinnamine. In 1952 CIBA Labs from Switzerland published the first complete report on the chemistry and pharmacology of reserpine. Also in 1952, they introduced the first isolated drug of reserpine, called Serpasil. Reserpine has a chemical formula of C33H40N209, a molecular mass of 609 grams, is odorless, insoluble in water, slightly soluble in alcohol, and freely soluble in acetic acid.^9–11

Pharmacology

Reserpine has an average absorption rate of 50% after oral ingestion. Absorption occurs usually 1 to 2 hours after oral consumption, although a slower rate between 2 to 4 hours has also been reported. Reserpine is widely distributed throughout the body to the brain, liver, spleen, kidneys and adipose tissue. It is widely distributed to red blood cells and central and peripheral neurons. It has been found in breast milk and crosses the placenta. Its initial half-life has been observed to be 4 to 5 hours. Its elimination half-life has been determined to be between 45 to 168 hours in plasma. Hepatic metabolism accounts for about 62% of the degradation of reserpine, while kidney elimination accounts for less than 8%. Up to 60% of eliminated metabolites are reserpine itself.^12,13

Mechanism of Action

The mechanism of action of reserpine is well researched. Reserpine binds to protein receptors on the membrane of specialized secretory vesicles found in the intracellular cytosol of presynaptic neurons. The membrane receptors are called vesicular monamine transporters or VMAT for short. The VMAT transporters normally bind intracellular neurotransmitters, including adrenaline, noradrenaline, dopamine, histamine, and serotonin. They facilitate the transfer of these chemicals into the vesicle. The vesicle then binds to the terminal end of the presynaptic neuron and releases these chemicals into the synapse. These chemicals pass over and bind to receptors on the postsynaptic neuron and ultimately facilitate the propagation of the nervous impulse. Reserpine binds strongly to the VMAT receptor and prevents the neurotransmitters from being incorporated into the presynaptic vesicle. It thus prevents and dampens the promulgation of the nervous signal in primarily sympathetic neurons of the brain and peripheral nervous system.^14,15

Rauwolfia and Hypertension

In a clinical trial of Rauwolfia serpentina in essential hypertension, Vakil treated 50 patients with initial blood pressures greater than 160/95 millimeters. After 4 weeks of taking the medicine, systolic blood pressure dropped between 2 and 54 millimeters in the group of patients. 22 out 47 patients showed a moderate drop in systolic blood pressure from 10 to 24 millimeters. 13 out of 47 patients showed a marked drop in systolic blood pressure greater than 25 millimeters. 38 out 47 patients showed a drop in diastolic blood pressure between 4 and 34 millimeters with an average drop of 11 millimeters. 27 patients showed a moderate drop of diastolic blood pressure between 5 and 14 millimeters, and 7 patients showed a drop greater than 15 millimeters. The hypotensive action of the drug was perceptible 2 weeks after stopping the drug in 91% of patients and in 75% of patients after 4 weeks of discontinuing the drug. No serious adverse side effects were noted. ^16,17

In 1952, a purified standardized isolated alkaloid extract called alseroxylon was introduced to the US. The active ingredients of the purified extract were a mixture of reserpine and rescinnamine. In this study 346 patients with hypertension were treated on an outpatient basis in public and private hospitals. Original blood pressure was greater than 150/100 millimeters on admission. During the control period patients received placebo. A consistent decrease in blood pressure readings of greater than 20 millimeters was observed in patients treated with the alseroxylon extract. ¹⁸

A rauwolfia product called Serpina was given to over 100 patients for periods of 1 month to 1 year. 1 to 3 Serpina tablets per daily dose were well tolerated. Its action is slow to appear from 3 to 6 days and disappears from 7 to 21 days after stopping the drug. It did not produce any serious side effects. It appears to be more effective in young, neurotic hypertensive patients with tachycardia than in those with long-established, fixed hypertension with organic, vascular disease. 39 patients with an average blood pressure reading of 192/122 millimeters and pulse of 82 were treated with Serpina alone. The average blood pressure dropped to an average of 165/95 millimeters and a pulse of 70. In 13 out of 39 patients blood pressure was controlled to normal at less than 150/90 millimeters. ¹⁹

A Cochrane Database Review was undertaken to investigate the dose-related effect of reserpine on blood pressure, heart rate, and withdrawals due to adverse effects. Medical databases included Central, Embase, and Medline. Selection criteria included only truly randomized, controlled trials comparing reserpine monotherapy with placebo or no treatment in patients with primary hypertension. Four randomized controlled trials were found to meet inclusion criteria. None of the trials reported any withdrawals due to adverse effects. The authors concluded that reserpine is effective in reducing systolic blood pressure to the same degree as other first-line antihypertensive drugs. They suggested that more randomized controlled trials are needed to assess the effects of reserpine on blood pressure and determine the dose-related safety profile before this drug could be widely recommended as a primary antihypertensive drug.²⁰ Reserpine is also one of the few antihypertensive drugs that have been shown to produce a reduction in mortality in randomized controlled trials.²¹

Adverse Side Effects and Toxicology

The most common adverse side effect of reserpine is nasal congestion that occurred in 5% to 15% patients taking rauwolfia products. Other side effects include lethargy, sedation, psychiatric depression, hypotension, nausea, vomiting, abdominal cramping, gastric ulceration, nightmares, bradycardia, anginalike symptoms, bronchospasm, skin rash, itching and withdrawal psychosis in one case, galactorrhea, breast enlargement, and sexual dysfunction.^12,22 There does not appear to be an association between reserpine and cancer. Earlier studies in the late 1960s and early 1970s suggested an association between reserpine and breast cancer. A reevaluation of three original studies showed that exclusion bias played an important role in the erroneous conclusions reached.²³ The incidence of depression in patients taking rauwolfia and reserpine products was studied between 1954 1956 in an outpatient clinic. Rauwolfia and reserpine can cause depression in susceptible patients. The authors concluded that dosage is an important factor but not the sole factor involved. They advised that before starting rauwolfia therapy, a complete medical history of mental illness and depression is recommended. They further recommended that the daily dose of reserpine is limited to less than 0.75 milligrams per day.²⁴ No increased risk of birth defects has been shown in female humans who consumed reserpine at any time during their pregnancy. No mutagenic or genotoxic effects of reserpine have been demonstrated.¹²

My Experience with Rauwolfia

I have been practicing naturopathic medicine for 21 years and have tried many different herbal and mineral supplement combinations to treat hypertension. I have used rauwolfia and reserpine products alone or in combination with herbs and minerals. I currently prefer rauwolfia combined with hawthorn and some form of magnesium. I have used capsules, tablets, and tinctures, and find that I prefer encapsulated rauwolfia root powder. I have prescribed over 80,000 capsules of rauwolfia to over 300 patients with hypertension. I do not prescribe over 500 milligrams of rauwolfia per day, and usually only prescribe the equivalent of 100 milligrams of rauwolfia twice per day. Some patients I prescribe 300 to 400 milligrams per day if needed.

I support the concept of low-dose rauwolfia; the results have been amazing. I consistently see sustained blood pressure drops in most patients with hypertension. A systolic drop of 20 to 30 millimeters and a diastolic drop of 10 to 15 millimeters are normal. I have observed rauwolfia consistently work as well as other first-line antihypertensive drugs. I have combined rauwolfia with other antihypertensive medicines. It combines well with diuretics and ACE inhibitors and ARB blockers. Caution should be exercised when the patient is on a beta blocker or calcium channel blocker. Most patients report that they feel better and less anxious and nervous. Sleep quality often improves.

I have not seen many adverse side effects. Occasional nasal congestion and loose stools have been reported. I have not seen any cases of depression. I screen all patients for history of depression and mental illness and evaluate whether they would benefit from rauwolfia therapy. I do not prescribe rauwolfia to patients who say they are depressed. Nor do I give rauwolfia to patients with congestive heart failure or cardiac decompensation, especially weak, frail elderly patients. I do not prescribe rauwolfia to patients with bradycardia or heartbeat less than 60 beats per minute. I have observed rauwolfia to lower pulse rates, usually by about 10 beats per minute in some patients. I figure that these patients may not benefit from adrenergic blockade. The potential adverse risks could potentially outweigh the benefit. I do not prescribe rauwolfia to patients who show symptoms of hypoadrenalism unless they have higher blood pressure, faster pulse, and symptoms of nervous anxiety.

As a rule, I do not prescribe rauwolfia to patients on prescription medicines for depression, including SSRIs, SNRIs, NDRIs, and tricyclic antidepressants. Logic dictates that there is conflict with giving rauwolfia to patients who are on drugs whose goal is to raise norepinephrine, serotonin, and other catecholamines. I also do not prescribe rauwolfia to patients on natural medicines whose goal is to raise these neurotransmitters. These natural medicines include 5-hydroxytryptophan; tyrosine; St. John’s wort; and other herbal medicines that might increase norepinephrine, serotonin, or other circulating catecholamines. Although these drugs and natural medicines work on different mechanisms, it is still a contraindication to give rauwolfia with other medicines whose goal is to have the opposite effect. Exercise caution and good clinical judgment when dealing with patients who might be on these drugs and natural medicines.

I am happy and confident in my use of rauwolfia in the treatment of hypertension. In my experience, I have observed rauwolfia to be the single best natural remedy for high blood pressure.

Conclusions

Based on a review of the literature, rauwolfia appears to be a safe and effective treatment for hypertension when used in appropriate low doses. An equivalent dose of pure rauwolfia alkaloids, also known as alseroxylon extract or pure reserpine, can also be used to treat hypertension. LDR (low-dose rauwolfia) can be safely recommended to patients who have been screened to benefit from this treatment. The total daily dose of rauwolfia should be less than 500 milligrams of root and in most cases can be less than 250 milligrams per day. The purified alkaloid alseroxylon extract would be less than 5 milligrams per day and in most cases less than 2.5 milligrams per day. The reserpine dose would be less than 500 micrograms per day and in most cases less than 250 micrograms per day. An equivalent tincture dose would be based on the strength of the tincture. For instance, the dose of a 1:5 tincture would be 0.5 milliliters equalling 100 milligrams of crude root. In a standard dropper, 15 drops would equal 1.0 milliliters.

Notes

1. Endress ME, Bruyns PV. A revised classification of the Apocynaceae s.l. Bot Rev. 2000;66(1):1–56.

2. Brijesh KS. Rauwolfia: cultivation and collection [online article]. Biotech Articles. http://www.biotecharticles.com/Agriculture-Article/Rauwolfia-Cultivation-and-Collection-892.html. May 23, 2011. Accessed August 2014.

3. Jerie P. Milestones of cardiovascular therapy. IV. Reserpine. [In Czech.] Cas Lek Cesk. 2007;146(7):573–577.

4. Tyler VE, Brady LR, Robbers JE. Pharmacognosy. 9th ed. Philadelphia: Lea & Febiger:222–225.

5. Weiss RF. Weiss’s Herbal Medicine. Thieme Publisher;2001:153–158.

6. Isharwal S, Gupta S. Rustom Jal Vakil: His contributions to cardiology. Tex Heart Inst J. 2006;33(2):161–170.

7. Woodson RE, Youngken HW, Schiffler E, Scheider JE. Rauwolfia. In: Botany, Pharmacognosy, Chemistry & Pharmacology. Toronto: Little, Brown and Company;1957:32–33.

8. Verma KC, Verma SK. Alkaloids analysis in root and leaf fractions of sarpagandha (Rauwolfia serpentina). Agric Sci Dig. 2010;30(2):133.

9. Ruyter CM, Akram M, Illahi I, Stockigt J. Investigation of the alkaloid content of Rauwolfia serpentina root from regenerated plants. Planta Medica. August 1991;57(4):328–330.

10. Jerie. Op cit.

11. Friedli GL. Indole alkaloids [Web page]. Friedli’s Enterprises. www.friedli.com/herbs/phytochem/alkaloid/alkaloid1/alkaloid 5.html. September 1996. Accessed August 2014.

12. Reserpine [Web page]. INCHEM: Chemical Safety Information from Intergovernmental Organization. http://www.inchem.org/documents/pims/pharm/reserpn.htm. Accessed August 2014.

13. Types of chemical compounds in plants & animals part II: phenolic glycosides & alkaloids [Web page]. Wayne’s World: An On-Line Textbook of Natural History. Indole Alkaloids – Major. 2005.

14. Schuldiner S, Liu Y, Edwards RH. Reserpine binding to a vesicular amine transporter expressed in Chinese ovary fibroblasts. J Biol Chem. 1993;Jan 5;268(1):29–34.

15. Qu K, Akbergenova Y, Hu Y, Schikorski T. Synapse-to-synapse variation in mean synaptic vesicle size and its relationship with synaptic morphology and function. J Comp Neurol. March 2009;514(4):343–352.

16. Vakil RJ. A clinical trial of Rauwolfia serpentina in essential hypertension. Br Heart J

    .

    January 1949;11(4):350–355.

17. Vakil RJ. Rauwolfia serpentina in the treatment of high blood pressure: a review of the literature. Circulation. 1955;12:220–229.

18. Moyer JH, Dennis E, Ford R. Drug therapy (rauwolfia) of hypertension ii. a comparative study of different extracts of rauwolfia when each is used alone (orally) for therapy of ambulatory patients with hypertension. AMA Arch Intern Med. 1955;96(4):530–543.

19. Wilkins RW, Judson WE. The use of Rauwolfia serpentina in hypertensive patients. N Engl J Med. 1953;248(8):48.

20. Shamon SD, Perez MI. Blood pressure lowering efficacy of reserpine for primary hypertension. Cochrane Database Syst Rev. 2009;(4):CD007655 (issn. 1469–493x).

21. Aromao D, Hakama M, et al. Breast cancer and use of rauwolfia and other hypertensive agents in hypertensive patients. A nationwide case-control study in Finland. International Journal of Cancer. December 1976; 18(6): 727–738.

22. Natural Medicines Comprehensive Database [website]. www.naturaldatabase.com. Accessed August 2014.

23. Horwitz RI, Feinstein AR. Exclusion bias and false relationship and breast cancer. Arch Intern Med. October 1985;145(10):1873–1875.

24. Lemieux G, Davignon A, Genest J. Depressive states during rauwolfia therapy for arterial hypertension: a report of 30 cases. Can Med Assoc J. April 1956;74(7):522–526.

Douglas Lobay, Bsc, ND

103B-1980 Cooper Road,

Kelowna, BC, Canada, V1Y 8K5

dglslby@shaw.ca