Chemistry:Yohimbine

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Short description: Chemical compound
Yohimbine
Yohimbine structure.svg
Yohimbine-3D-balls-Trans.png
Clinical data
Routes of
administration		By mouth
ATC code
Legal status
Legal status
Pharmacokinetic data
Bioavailability7-86% (mean 33%)
Elimination half-life0.25-2.5 hours[1]
ExcretionUrine (as metabolites)
Identifiers
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
ChEBI
ChEMBL
Chemical and physical data
FormulaC21H26N2O3
Molar mass354.450 g·mol−1
3D model (JSmol)
  (verify)

Yohimbine (/joʊˈhɪmbiːn/),[2] also known as quebrachine, is an indole alkaloid derived from the bark of the African tree Pausinystalia johimbe; also from the bark of the unrelated South American tree Aspidosperma quebracho-blanco. Yohimbine is an α2-adrenergic receptor antagonist, and has been used in a variety of research projects. It is a veterinary drug used to reverse sedation in dogs and deer.

While yohimbine behaves as an aphrodisiac in some mammals, it does not do so in humans. It has been prescribed as a treatment for erectile dysfunction, but its reported clinical benefits were modest and it has largely been superseded by the PDE5 inhibitor class of drugs. Substances that have purported to be extracts from the yohimbe tree have been marketed as dietary supplements for various purposes, but they contain highly variable amounts of yohimbine, if any; no published scientific evidence supports their efficacy.

Uses

Yohimbine is a drug used in veterinary medicine to reverse the effects of xylazine in dogs and deer.[3] It is used as a research reagent. In the US, it is prescribed, but now rarely, for erectile dysfunction in men.

Yohimbine and yohimbe

Confusion

Yohimbine should not be confused with yohimbe[4] but often is.[5]

Yohimbe is the common English name for the tree species P. johimbe and, by extension, the name of a medicinal preparation made from its bark, sold as an aphrodisiac.[6] In contrast, yohimbine is a pure alkaloid that can be isolated from yohimbe bark.

Yohimbine is just one of at least 55 indole alkaloids that have been isolated from the bark;[7] and, while it has been described as the most active of these,[8] it constitutes only 15% of the total alkaloid content.[9] Others include rauwolscine, corynanthine and ajmalicine;[9] the bark also contains non-alkaloids about which virtually nothing is known.[9]

Yohimbe, thus a complex mixture, has been studied far less thoroughly than yohimbine, the pure compound.[9] Pharmaceutical grade yohimbine is usually presented as the hydrochloride,[10]:3,14,34[9] which is more soluble.

Effect on sexual function

History, research and literature

Yohimbe is used in folk medicine as an aphrodisiac. In 1900, it attracted scientific interest in Germany, where an initial report claimed that yohimbe exerted a strong aphrodisiacal effect in animals and humans.[9] Attention soon shifted from the plant to its active constituents, particularly yohimbine.[9] According to a 2010 encyclopedia article by Joseph M. Betz[11] of the National Institutes of Health:

Probably as a result of this trend, no reports of human studies on the effects of crude yohimbe bark or its extracts on sexual performance can be found in the [scientific] literature... Any discussion of the use of the bark for sexual enhancement thus begins and ends with folklore.

In contrast, there is a "fairly rich literature on yohimbine".[9]

Subsequent work on yohimbine, while confirming that it behaves as an aphrodisiac in animals, including rats, dogs and golden hamsters,[9] has failed to do so in humans. According to Betz:

experiments show that the alkaloid increases sexual motivation even in sexually exhausted rats due to its action on the central α2-adrenoreceptors found in the locus coeruleus in the brain. Blockage of these brain adrenoreceptors appears to reverse a central negative feedback mechanism that regulates penile erection and maintains detumescence... [But] the compound does not increase sexual desire and thoughts in human clinical trials. The combined evidence from human and animal clinical studies indicates that yohimbine is far less potent in stimulating sexual behavior in humans than in rats. One possible explanation for this finding is the existence of powerful and multiple inhibitory controls on sexual behavior in humans that are not present in rats i.e. the cognitive aspects of sex are far more important in humans than the basic instinctive functions observed in animals.[9]

Clinical efficacy

Yohimbine has been used to treat female sexual dysfunction, but there are few reported clinical trials and these do not show it to be better than placebo.[12] On treatment for male erectile dysfunction (ED), a review article by Tam et al. (2001) concluded:

Although well-tolerated and safe, even when greatly exceeding the likely therapeutic range, it is obvious that the efficacy of [yohimbine] as monotherapy in the general ED population is likely to be modest.[13]

Again according to Betz (2010),

The modern consensus appears to be that the pure compound yohimbine is effective for treating certain mild types of erectile dysfunction in some men, but does not act as an aphrodisiac".[9]

A 2011 review by Andersson said:

The effects of yohimbine have been investigated in several controlled trials on patients with different types of ED, but the effect has been modest... It cannot be excluded that orally administered yohimbine may have a beneficial effect in some patients with ED. However, as a consequence of the conflicting results, it is not currently recommended in most guidelines for management of ED.[14]

It has been largely superseded by the PDE5 inhibitor drugs such as sildenafil (Viagra). Prescription are now rare, and most US pharmaceutical manufacturers have discontinued production of prescription capsules and tablets.[8]:357–8

Yohimbine has been found to be effective in treating delayed ejaculation in men [15]

Yohimbine and dietary supplements

In the US, "yohimbe" preparations are sold as a dietary supplements for enhancing libido, for weight loss and as aids for bodybuilding; but "There is virtually no published research on yohimbe which supports these or any other claims".[9]:861 Often, these products explicitly claim to contain yohimbine.[8]

Cohen et al. found that samples of brands sold in American brick-and-mortar stores contained highly variable amounts of yohimbine, and sometimes none at all.[8]:368 Labelling claims were often misleading.[8]:368 Similar results have been reported by other laboratories for products sold in the U.S., in other countries and on the internet.[16][17][18][19][20] One study found that many brands of "yohimbe" might not derive from the P. johimbe tree in the first place.[21] According to yet another source the yohimbe sold in markets in West Africa, where the tree grows, is frequently adulterated with other species of the genus Pausinystalia; these contain little yohimbine.[22] The amounts of alkaloid found even in genuine P. johimbe bark vary considerably, depending on the source of the bark (roots, stem, branches, height, etc.).[23]

Some brands sold over-the-counter were found to contain more yohimbine per serving than a standard pharmaceutical dose;[8]:368 yet, in the US, pharmaceuticals are subject to the strict regulatory regime pertaining to medicines. It is illegal to introduce or deliver "drugs" into interstate commerce without the permission of the FDA. The FDA has asserted that some yohimbine-containing products are "drugs" because they are so promoted as to show "they are intended for use in the cure, mitigation, treatment or prevention of disease": 21 U.S.C. § 321(g)(1)(B).[24] However the legal position is not entirely straightforward,[25] and as of 1 February 2019 there does not appear to be any record of a successful prosecution.

Because of the lack of reliable scientific data on yohimbe, the European Food Safety Authority Panel on Food Additives determined that it was not possible to conclude on its safety or to establish a health-based guidance value.[10]:38 They wrote:

Overall the missing information include[s] quantitative data on the composition and specifications of yohimbe bark and its preparations used in food and food supplements covering other alkaloids besides yohimbine, data on the bioavailability of active ingredients from the yohimbe bark extract and data on the toxicity of well specified individual preparations of yohimbe bark and the major yohimbe bark alkaloids, especially regarding subchronic toxicity, genotoxicity and reproductive toxicity.

Extracts and chemistry

Yohimbe (Pausinystalia johimbe) is a tree that grows in western and central Africa;[26] yohimbine was named as originally extracted from the bark of yohimbe in 1896 by Adolph Spiegel.[27] (In fact, it had been isolated earlier from the bark of the South American tree A. quebracho-blanco and named as quebrachine, but this was overlooked). In 1943 the correct constitution of yohimbine was proposed by Witkop.[28] Fifteen years later, a team led by Eugene van Tamelen used a 23-step synthesis to become the first persons to achieve the synthesis of yohimbine.[29][30][31]

Pharmacology

Yohimbine has high affinity for the α2-adrenergic receptor, moderate affinity for the α1 receptor, 5-HT1A, 5-HT1B, 5-HT1D, 5-HT1F, 5-HT2B, and dopamine D2 receptors, and weak affinity for the 5-HT1E, 5-HT2A, 5-HT5A, 5-HT7, and dopamine D3 receptors.[32][33] It behaves as an antagonist at α1-adrenergic, α2-adrenergic, 5-HT1B, 5-HT1D, 5-HT2A, 5-HT2B, and dopamine D2, and as a partial agonist at 5-HT1A.[32][34][35][36] Yohimbine interacts with serotonin and dopamine receptors in high concentrations.[37]

Pharmacologic profile
Molecular target Binding affinity
(Ki in nanomolar)[33]		 Pharmacologic action
[32][34][35][36][38]		 Species Source
SERT 1,000 Inhibitor Human Frontal cortex
5-HT1A 346 Partial agonist Human Cloned
5-HT1B 19.9 Antagonist Human Cloned
5-HT1D 44.3 Antagonist Human Cloned
5-HT1E 1,264 Unknown Human Cloned
5-HT1F 91.6 Unknown Human Cloned
5-HT2A 1,822 Antagonist Human Cloned
5-HT2B 143.7 Antagonist Human Cloned
5-HT7 2,850 Unknown Human Cloned
α1A 1,680 Antagonist Human Cloned
α1B 1,280 Antagonist Human Cloned
α1C 770 Antagonist Human Cloned
α1D 557 Antagonist Human Cloned
α2A 1.05 Antagonist Human Cloned
α2B 1.19 Antagonist Human Cloned
α2C 1.19 Antagonist Human Cloned
D2 339 Antagonist Human Cloned
D3 3,235 Antagonist Human Cloned

Research

Yohimbine has been studied as a way to improve the effects of exposure therapy in people with post traumatic stress disorder (PTSD).[39][40][41]

It has also been studied as a potential treatment for erectile dysfunction but there is insufficient evidence to rate its effectiveness.[42][43][44] It is illegal in the United States to market an over the counter product containing yohimbine as a treatment for erectile dysfunction without getting FDA approval to do so.[45] Nevertheless, the quantity of yohimbine in dietary supplements, often advertised as promoting sexual function, has been found to overlap with prescription doses of yohimbine.[46]

Yohimbine blocks the pre- and post-synaptic α2 receptors. Blockade of post-synaptic α2 receptors causes only minor corpus cavernosum smooth muscle relaxation, due to the fact that the majority of adrenoceptors in the corpus cavernosum are of the α1 type. Blockade of pre-synaptic α2 receptors facilitates the release of several neurotransmitters in the central and peripheral nervous system — thus in the corpus cavernosum — such as nitric oxide and norepinephrine. Whereas nitric oxide released in the corpus cavernosum is the major vasodilator contributing to the erectile process, norepinephrine is the major vasoconstrictor through stimulation of α1 receptors on the corpus cavernosum smooth muscle. Under physiologic conditions, however, nitric oxide attenuates norepinephrine vasoconstriction.[47]

Botanical sources of yohimbine; sustainability

Pausinystalia johimbe

The traditional source of yohimbine is the bark of the African tree P. johimbe. It has other uses, but the tree is sought out primarily for its bark; in practice, harvesting the bark kills the tree. Tree density is relatively low (average ≈ 4 harvestable trees/hectare). The high demand for medicines based on the bark has led to the tree's over-exploitation. The bark is traded in local markets and, because it is scarce, it is often adulterated with that of other species which contain little yohimbine.[22] The species is becoming endangered.[48]

Around the year 2000, Cameroon was shipping P. johimbe to Europe at the rate of about 100 tonnes annually. Most bark is collected illegally by local people who are paid 150 CFA francs per kilo (about US$0.10 per pound) for delivery of pre-dried bark at the roadside. In practice they confuse and mix it with P. macroceras ("false yohimbe"), a species that contains little yohimbine.[49]

Aspidosperma quebracho-blanco

Aspidosperma quebracho-blanco is an unrelated tree whose common name is quebracho blanco.[50] It is found in large areas of central South America, particularly the Gran Chaco, where it is often the dominant species in the canopy.[51] It is one of the most widely distributed Argentine arboreal species.[52][53] Traditionally it was logged for fuel, timber and railway sleepers.[53] While in recent times cattle ranching and soya cultivation have led to considerable habitat loss,[54] and while there is still illegal logging, no shortage of the bark is reported. The tree has not been described as endangered: a few members of the genus Aspidosperma are on the IUCN Red List. but the quebracho blanco species is not one of them.[55]

In its bark an alkaloid is found which was given the name Quebrachine. In 1914, two scientific papers claimed quebrachine was chemically identical to yohimbine.[56] This was disputed,[57] and the matter long remained in doubt.[58] However, in 1972, Effler and Effler using modern analytical techniques, including mass spectrometry, UV absorption, IR absorption, and NMR, established that quebrachine and yohimbine are one and the same thing. They wrote:

While it was almost unthinkable in 1914 ... that the same alkaloid was formed in [completely] different plants, recent studies have shown that this is certainly the case for indole alkaloids.[59]

A range of secondary reference works give 'quebrachine' as a synonym for yohimbine.[60][61][62][63][64][65][66][67][68]

Strictly speaking, wrote George Barger, yohimbine should have been given the scientific name quebrachine, seeing that it was first isolated from the quebracho tree and first named in the scientific literature. However the later work on P. yohimbe was better known, so the newer name stuck.[56]

Other plants

Yohimbine has also been isolated from other plant genera in the family Apocynaceae including Lochnera (Catharanthus),[69] Rauvolfia, Amsonia, Vallesia and Vinca; from the family Loganiaceae (genera Gelsemium and Strychnos); and from the family Euphorbiaceae (genus Alchornea).[9]

Doping

There was a case in the World Anti-Doping Agency practice in 2007, when an athlete, who reportedly consumed Yohimbine prior to a given athletic event, was later tested positive for 19-norandrosterone, which is a prohibited substance.[70] However, WADA did not yet list Yohimbine (which can come into a body via an energy drink,[71] also in a form of pre-workout supplement or fat burner[72]) as a prohibited substance, nor did it confirm that its use can increase the endogenous level of anabolic steroids, in particular of 19-norandrostenedione and testosterone.

See also

References

  1. ↑ "Yohimbine pharmacokinetics and interaction with the sympathetic nervous system in normal volunteers". European Journal of Clinical Pharmacology 43 (6): 651–6. 1992. doi:10.1007/BF02284967. PMID 1493849. 
  2. ↑ "Yohimbine. (n.d.)". Collins English Dictionary – Complete and Unabridged. (1991, 1994, 1998, 2000, 2003).. http://www.thefreedictionary.com/yohimbine. 
  3. ↑ "21 CFR Sec. 522.2670 Yohimbine". http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/cfrsearch.cfm?fr=522.2670. 
  4. ↑ Jeske, Arthur H., ed (2013). Mosby's Dental Drug Reference - E-Book (11 ed.). Elsevier Health Sciences. ISBN 978-0323172264. , Appendix H, e83;
  5. ↑ Holt, Stephen; Atkins, Robert C.; Krueger, Robert J.; Sinatra, Stephen T.; Taylor, T.V. (1999). The sexual revolution: natural and healthy alternatives to sex. ProMotion Pub. p. 105. ISBN 978-1579010409. 
  6. ↑ Oxford English Dictionary Online, article "Yohimbe", senses 1 and 2, respectively; Merriam-Webster Online, article "Yohimbe", first and second senses, respectively.
  7. ↑ "Profiling the indole alkaloids in yohimbe bark with ultra-performance liquid chromatography coupled with ion mobility quadrupole time-of-flight mass spectrometry". Rapid Communications in Mass Spectrometry 25 (18): 2591–602. September 2011. doi:10.1002/rcm.5158. PMID 23657953. Bibcode: 2011RCMS...25.2591S. 
  8. ↑ 8.0 8.1 8.2 8.3 8.4 8.5 "Pharmaceutical quantities of yohimbine found in dietary supplements in the USA". Drug Testing and Analysis 8 (3–4): 357–69. 2015. doi:10.1002/dta.1849. PMID 26391406. 
  9. ↑ 9.00 9.01 9.02 9.03 9.04 9.05 9.06 9.07 9.08 9.09 9.10 9.11 9.12 Betz, Joseph M. (2010). "Yohimbe". Encyclopedia of Dietary Supplements (2nd ed.). New York and London: Informa Healthcare. pp. 861–3. ISBN 9781439819289. https://archive.org/details/encyclopediadiet00pcoa. 
  10. ↑ 10.0 10.1 EFSA Panel on Food Additives and Nutrient Sources Added to Food (ANS) (2013). "Scientific Opinion on the evaluation of the safety in use of Yohimbe (Pausinystalia yohimbe (K. Schum.) Pierre ex Beille". EFSA Journal 11 (7): 1–46. doi:10.2903/j.efsa.2013.3302. 
  11. ↑ Dr Betz was described as "a leading P. johimbe expert" by Cohen et al, 357. In 2018 he was appointed acting director of the Office of Dietary Supplements of the. NIH: "JOSEPH M. BETZ, PH.D., ACTING DIRECTOR, ODS". National Institutes of Health: Office of Dietary Supplements. https://ods.od.nih.gov/About/Joseph_Betz.aspx. 
  12. ↑ Betz, 2010, 862.
  13. ↑ "Yohimbine: a clinical review". Pharmacology and Therapeutics 91 (3): 239. 2001. doi:10.1016/S0163-7258(01)00156-5. PMID 11744068. 
  14. ↑ "Mechanisms of penile erection and basis for pharmacological treatment of erectile dysfunction". Pharmacological Reviews 63 (4): 811–59. December 2011. doi:10.1124/pr.111.004515. PMID 21880989. 
  15. ↑ "Yohimbine in the treatment of orgasmic dysfunction". Asian journal of andrology (9): 403 -407. May 2007. doi:10.1111/J.1745-7262.2007.00276.x. PMID 17486282. 
  16. ↑ "Gas chromatographic determination of yohimbine in commercial yohimbe products". Journal of AOAC International 78 (5): 1189–94. 1995. doi:10.1093/jaoac/78.5.1189. PMID 7549534. "Concentrations of yohimbine in the commercial products ranged from < 0.1 to 489 ppm, compared with 7089 ppm in the authentic bark.". 
  17. ↑ "Qualitative and quantitative determination of yohimbine in authentic yohimbe bark and in commercial aphrodisiacs by HPLC-UV-API/ MS methods". Phytochemical Analysis 14 (4): 193–201. 2003. doi:10.1002/pca.699. PMID 12892413. "Twenty commercial aphrodisiac preparations were analysed and the amount of yohimbine measured and expressed as the maximal dose per day suggested on product labels ranged from 1.32 to 23.16 mg.". 
  18. ↑ "Microscopic and UPLC-UV-MS analyses of authentic and commercial yohimbe (Pausinystalia johimbe) bark samples". Journal of Natural Medicines 67 (1): 42–50. January 2013. doi:10.1007/s11418-012-0642-2. PMID 22402817. "Of 12 commercial samples tested, yohimbine was not detected in one; its presence in other samples was found to be in the range 0.1–0.91%.". 
  19. ↑ "Chromatographic fingerprint analysis of yohimbe bark and related dietary supplements using UHPLC/UV/MS". Journal of Pharmaceutical and Biomedical Analysis 61: 142–9. March 2012. doi:10.1016/j.jpba.2011.11.013. PMID 22221902. "Wide variability was observed in fingerprints and yohimbine content among yohimbe dietary supplement samples. For most of the dietary supplements, the yohimbine content was not consistent with the label claims.". 
  20. ↑ "A validated high performance thin layer chromatography method for determination of yohimbine hydrochloride in pharmaceutical preparations". Pharmacognosy Magazine 9 (33): 4–8. January 2013. doi:10.4103/0973-1296.108124. PMID 23661986. "Amount of yohimbine hydrochloride ranged from 2.3 to 5.2 mg/tablet or capsule in preparations containing the pure alkaloid, while it varied from zero to 1.5–1.8 mg/capsule in dietary supplements containing powdered yohimbe bark.". 
  21. ↑ Cohen et al, 368. (Samples did not include other alkaloids characteristic of P. yohimbe.)
  22. ↑ 22.0 22.1 "Pausinystalia johimbe". Timbers 2 of Plant Resources of Tropical Africa. 7. Wageningen, Ne: PROTA Foundation. 2012. pp. 516–519. ISBN 978-9290814955. 
  23. ↑ "Répartition des alcaloïdes dans le Yohimbe (Pausinystalia yohimbe) (K. Schum.) ex Pierre" (in fr). Journal d'Agriculture Traditionnelle et de Botanique Appliquée 7 (4–5): 256–258. 1960. doi:10.3406/jatba.1960.2608. 
  24. ↑ E.g. "Inspections, Compliance, Enforcement, and Criminal Investigations". US Food and Drug Administratiom. https://www.fda.gov/ICECI/EnforcementActions/WarningLetters/ucm402397. 
  25. ↑ "21 U.S. Code § 321 - Definitions; generally". Legal Information Institute. Cornell Law School. https://www.law.cornell.edu/uscode/text/21/321. 
  26. ↑ "Pausinystalia johimbe". Kew World Checklist of Selected Plant Families. http://apps.kew.org/wcsp/namedetail.do?name_id=148191. 
  27. ↑ Year Book of the American Pharmaceutical Association. American Pharmaceutical Association. 1914. p. 564. http://www.mocavo.com/Year-Book-of-the-American-Pharmaceutical-Association-1914-Volume-3/874094/564?browse=true#632. Retrieved 2015-05-04. 
  28. ↑ Witkop, Bernhard (1943). "Zur Konstitution des Yohimbins und seiner Abbauprodukte" (in de). Justus Liebig's Annalen der Chemie 554 (1): 83–126. doi:10.1002/jlac.19435540108. 
  29. ↑ The Alkaloids: Chemistry and Pharmacology. 32. Academic Press. 1988. p. 564. ISBN 978-0-12-469532-0. 
  30. ↑ van Tamelen, E.E.; Shamma, Maurice; Burgstahler, Albert; Tamm, Rudolph; Aldrich, Paul (1958). "The Total Synthesis of Yohimbine". J. Am. Chem. Soc. 80 (18): 5006–5007. doi:10.1021/ja01551a062. 
  31. ↑ "Total synthesis of (+)-yohimbine via an enantioselective organocatalytic Pictet-Spengler reaction". The Journal of Organic Chemistry 76 (21): 8907–12. November 2011. doi:10.1021/jo201657n. PMID 21950549. 
  32. ↑ 32.0 32.1 32.2 "Agonist and antagonist actions of yohimbine as compared to fluparoxan at alpha(2)-adrenergic receptors (AR)s, serotonin (5-HT)(1A), 5-HT(1B), 5-HT(1D) and dopamine D(2) and D(3) receptors. Significance for the modulation of frontocortical monoaminergic transmission and depressive states". Synapse 35 (2): 79–95. February 2000. doi:10.1002/(SICI)1098-2396(200002)35:2<79::AID-SYN1>3.0.CO;2-X. PMID 10611634. 
  33. ↑ 33.0 33.1 "Yohimbine Test Ligand Search". PDSP Ki Database. https://pdsp.unc.edu/databases/pdsp.php?receptorDD=&receptor=&speciesDD=&species=&sourcesDD=&source=&hotLigandDD=&hotLigand=&testLigandDD=&testFreeRadio=testFreeRadio&testLigand=Yohimbine&referenceDD=&reference=&KiGreater=&KiLess=&kiAllRadio=all&doQuery=Submit+Query. 
  34. ↑ 34.0 34.1 "Partial agonist properties of rauwolscine and yohimbine for the inhibition of adenylyl cyclase by recombinant human 5-HT1A receptors". Biochemical Pharmacology 45 (11): 2337–41. June 1993. doi:10.1016/0006-2952(93)90208-E. PMID 8517875. 
  35. ↑ 35.0 35.1 "Yohimbine and rauwolscine inhibit 5-hydroxytryptamine-induced contraction of large coronary arteries of calf through blockade of 5 HT2 receptors". Naunyn-Schmiedeberg's Archives of Pharmacology 323 (2): 149–54. June 1983. doi:10.1007/BF00634263. PMID 6136920. 
  36. ↑ 36.0 36.1 "Further characterization of 5-hydroxytryptamine receptors (putative 5-HT2B) in rat stomach fundus longitudinal muscle". British Journal of Pharmacology 112 (1): 323–31. May 1994. doi:10.1111/j.1476-5381.1994.tb13072.x. PMID 8032658. 
  37. ↑ "Yohimbine (PIM 567)". Inchem.org. http://www.inchem.org/documents/pims/pharm/yohimbin.htm. 
  38. ↑ "Yohimbine". University of Alberta. http://www.drugbank.ca/drugs/DB01392. 
  39. ↑ "Pharmacology of cognitive enhancers for exposure-based therapy of fear, anxiety and trauma-related disorders". Pharmacology & Therapeutics 149: 150–90. May 2015. doi:10.1016/j.pharmthera.2014.12.004. PMID 25550231. 
  40. ↑ "Enhancing exposure therapy for anxiety disorders, obsessive-compulsive disorder and post-traumatic stress disorder". Expert Review of Neurotherapeutics 14 (8): 893–910. August 2014. doi:10.1586/14737175.2014.934677. PMID 24972729. 
  41. ↑ van der Kolk, Bessel A. (1995). "The Treatment of Post Traumatic Stress Disorder". in Hobfoll, Stevan E.; De Vries, Marten W.. Extreme stress and communities: impact and intervention. Boston: Kluwer Academic Publishers. pp. 421–44. ISBN 978-0-7923-3468-2. https://books.google.com/books?id=sVuMSVEY83UC&pg=PA421. 
  42. ↑ "Yohimbe Supplement". National Center for Complementary and Integrative Health. February 2007. https://nccih.nih.gov/health/yohimbe. 
  43. ↑ "Yohimbine in erectile dysfunction: the facts". International Journal of Impotence Research 12 (Suppl 1): S70–74. March 2000. doi:10.1038/sj.ijir.3900508. PMID 10845767. 
  44. ↑ "Pharmacology of penile erection". Pharmacological Reviews 53 (3): 417–50. September 2001. PMID 11546836. 
  45. ↑ "CFR - Code of Federal Regulations Title 21: Regulations on OTC products". U.S. Food and Drug Administration. http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/cfrsearch.cfm?cfrpart=310&showfr=1. 
  46. ↑ "Pharmaceutical quantities of yohimbine found in dietary supplements in the USA". Drug Testing and Analysis 8 (3–4): 357–69. March 2016. doi:10.1002/dta.1849. PMID 26391406. 
  47. ↑ "Regulation of pre-synaptic alpha adrenergic activity in the corpus cavernosum". International Journal of Impotence Research 12 Suppl 1: S20–25. March 2000. doi:10.1038/sj.ijir.3900500. PMID 10845761. 
  48. ↑ "Medicinal and aromatic plants in agroforestry systems". New Vistas in Agroforestry: A Compendium for the 1st World Congress of Agroforestry, 2004. 1. Springer Science and Business Media. 2013. p. 109. ISBN 978-9401724241. 
  49. ↑ Sunderland, Terry C H; Ngo-Mpeck, Marie-Laure; Tchoundjeu, Zacharie; Laird, Sarah A (2002). "Yohimbe (‘’Pausinstalia johimbe’’)". Tapping the Green Market: Certification & Management of Non-Timber Forest Products. Earthscan Publications Ltd. pp. 215–224. ISBN 978-1853838712. 
  50. ↑ "Quebracho" is formed from the Spanish words for "axe breaker'.
  51. ↑ Bucher, E.H. (2012). "Chaco and Caatinga — South American Arid Savannas, Woodlands and Thickets". in Huntley, B.J.; Walker, B.H.. Ecology of Tropical Savannas. Ecological Studies. 42. Springer Science and Business. Media. pp. 54–57. ISBN 978-3642687860. 
  52. ↑ "Nombre científico: Aspidosperma quebracho-blanco" (in es). Herbario Digital. CONICET. https://www.mendoza-conicet.gob.ar/ladyot/herba_digital/fichas_especies/quebracho_blanco.htm. 
  53. ↑ 53.0 53.1 Moglia, Juana Graciela; López, Carlos Raul (2001). "Variabilidad radial de algunos caracteres anatómicos de Aspidosperma quebracho blanco" (in es). Bosque 22 (2): 4. doi:10.4206/bosque.2001.v22n2-01. ISSN 0304-8799. 
  54. ↑ Kent, Robert B. (2006). Latin America: Regions and People. Texts in regional geography. Guilford Press. p. 151. ISBN 978-1572309098. 
  55. ↑ "The IUCN Red List of Threatened Species". https://www.iucnredlist.org/search?query=aspidosperma&searchType=species. 
  56. ↑ 56.0 56.1 Barger, George; Field, Ellen (1915). "Yohimbine (Quebrachine)". Journal of the Chemical Society, Transactions 107: 1025. doi:10.1039/CT9150701025. https://zenodo.org/record/1697152. 
  57. ↑ Allen, Alfred Henry; Sadler, Samuel Schmucker; Lathrop, Elbert C.; Mitchell, C. Ainsworth (1929). Allen's Commercial Organic Analysis. Philadelphia: P. Blakiston's Son & Co.. p. 217. 
  58. ↑ Moyano Navarro, Belzor (1942). "Quebrachina y Yohimbina: Efectos Sobre la Corriente de Acción del Corazón" (in es). Revista de la Universidad Nacional de Córdoba: 369–403. . ('Quebrachine' and 'yohimbine' had different effects on the heart in the dog model; but the suppliers of those reagents were trusted to vouch for their authenticity.)
  59. ↑ "Ûber die Identitat von Quebrachin und Yohimbin" (in de). Chemischer Informationsdienst 4 (14): 921–924. 1972. 
  60. ↑ Abel, G. (2012). Adverse Effects of Herbal Drugs. 3. Springer Science & Business Media. ISBN 978-3642603679. 
  61. ↑ Bosker, Gideon (1995). Emergency Medicine Therapeutics (2 ed.). Mosby, Incorporated. p. 342. ISBN 978-0815109921. 
  62. ↑ Philippsborn, Henry (2006). Elsevier's Dictionary of Vitamins and Pharmacochemistry. Elsevier. p. 599. ISBN 978-0080488790. 
  63. ↑ Staff (1983). Food and Drug Administration Consumer. U.S. Department of Health, Education, and Welfare, Public Health Service, Food and Drug Administration. p. 10. 
  64. ↑ Lewis, Robert A.; Hawley, Gessner Goodrich (2016). Larrañaga, Michael D.; Lewis, Richard J.; Lewis, Robert. eds. Hawley's Condensed Chemical Dictionary. John Wiley & Sons. p. 1438. ISBN 978-1118135150. 
  65. ↑ Jeske, Arthur H., ed (2013). Mosby's Dental Drug Reference - E-Book (11 ed.). Elsevier Health Sciences. pp. Appendix H, e83. ISBN 978-0323172264. 
  66. ↑ Manske, R.H.F.; Meurant, Gerard (1965). The Alkaloids: Chemistry and Physiology. 8. Academic Press. p. 696. ISBN 978-0080865324. 
  67. ↑ Riviere, Jim E.; Papich, Mark G., eds (2013). Veterinary Pharmacology and Therapeutics (9 ed.). John Wiley & Sons. p. 353. ISBN 978-1118685907. 
  68. ↑ Yeung, Albert Y.; Foster, Steven (2003). Encyclopedia of Common Natural Ingredients: Used in Food, Drugs, and Cosmetics (2 ed.). Wiley. p. 431. ISBN 978-0471471288. .
  69. ↑ "[Presence of yohimbine (quebrachin) in the roots of Madagascar periwinkle, Lochnera lancea]" (in fr). Annales Pharmaceutiques Françaises 14 (5): 341–4. May 1956. PMID 13373134. 
  70. ↑ See the Mohadanni case.
  71. ↑ U.S. Anti-Doping Agency Supplement Guide, p. 28.
  72. ↑ Doping substances in dietary supplements

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