Corynine (Yohimbine): A Comprehensive Reference
1. Identity and Nomenclature
Corynine is a historical and synonymous name for the alkaloid more widely known as yohimbine. Yohimbine is a monoterpenoid indole alkaloid with potent pharmacological effects obtained from several biological sources; it is also called quebrachine, aphrodine, corynine, and hydroaerogotocin. The name "corynine" derives from the tree genus Corynanthe, an older taxonomic synonym for the plant now predominantly classified as Pausinystalia yohimbe.
Yohimbine is the principal indole alkaloid derived from the bark of the Yohimbe Tree (Pausinystalia yohimbe = Corynanthe yohimbi) (Rubiaceae). It is also found in the Rauwolfia root and the dried bark of Aspidosperma quebracho.
Yohimbine is a nitrogenous organic compound with the chemical formula C21H26N2O3 and a molecular weight of 354.44 g/mol. It is a 17α-hydroxyyohimban-16α-carboxylic acid methyl ester. Tryptophan and the secoiridoid monoterpene secologanin are the biosynthetic sources of this pentacyclic monoterpenoid indole alkaloid.
Structurally, yohimbine features a pentacyclic ring system with five chiral carbon atoms (C3, C15, C16, C17, and C20) and two nitrogen atoms. This intricate chemical structure, featuring five chiral centers and two nitrogen atoms, contributes to the diversity of yohimbine stereoisomers, such as rauwolscine and corynanthine, each exhibiting subtle differences in their physical properties and interactions with various receptors.
1.1 Synonyms and Accepted Names
- IUPAC name: Methyl 17α-hydroxy-yohimban-16α-carboxylate
- Synonyms: Corynine, Quebrachin, Quebrachine, Antagonil, Aphrodine, Aphrodyne, Johimbin
- CAS number (yohimbine HCl): Yohimbine hydrochloride (CAS: 146-48-5) was isolated for the first time from the bark of the Pausinystalia yohimbe tree in West Africa.
- Molecular formula: C21H26N2O3
1.2 Primary Botanical Source
The genus Pausinystalia belongs to the Rubiaceae. The principal species of medicinal interest is Pausinystalia yohimbe (K. Schum.) Pierre ex Beille, sometimes spelled as P. johimbe or P. yohimba. Another Latin binomial for this species is Corynanthe yohimbe K. Schum., sometimes spelled as C. johimbe. Vernacular names are yohimbe, yohimbehe (English); Yohimbe (German); yohimbe, yohimbé, yohimbéhé (French). The commercially available plant part is the stem bark.
Yohimbe is an evergreen tree native to central and western Africa. Pausinystalia yohimbe bark contains the alkaloid yohimbine at a concentration of approximately 6%.
1.3 Additional Botanical Sources
Corynine/yohimbine is not exclusive to P. yohimbe. Yohimbine is an indole alkaloid found in numerous botanical sources. It is the predominant alkaloid in extracts from the bark of the Pausinystalia yohimbe tree, and can also be found in Rauwolfia root. Corynanthe-type alkaloids are abundant and widely distributed in plants. They are mainly found in the genera belonging to the Apocynaceae, Bruceaceae, and Rubiaceae families.
1.4 Common Dosage Forms and Preparations
Yohimbine is clinically utilized as a prescription drug with its main dosage forms in powder and tablets, and is also available for purchase on the Internet as an herbal supplement and oral liquid. Yohimbe bark extract and yohimbine are marketed as food supplements. Preparations commercially available include standardized bark extracts, yohimbine hydrochloride tablets and capsules, and crude powdered bark. The amount of yohimbine in dietary supplements may vary; some yohimbe products contain very little yohimbine.
2. Traditional and Historical Use
Yohimbe is an evergreen tree native to central and western Africa. It has a compound called yohimbine in its bark. The bark has been used traditionally as an aphrodisiac and sexual performance enhancer, as well as a mild hallucinogen.
Yohimbine hydrochloride was isolated for the first time from the bark of the Pausinystalia yohimbe tree in West Africa. Humans have traditionally used this plant as a stimulant and aphrodisiac, particularly as an herbal remedy to help with erectile dysfunction.
Yohimbe (also called yohimbine) is a popular herbal medicine that has been used in Africa for numerous health conditions, including cough, fever, and heart disease. In Western countries, yohimbe has been used to treat sexual dysfunction.
Yohimbine is found in the bark of Pausinystalia johimbe (synonymous with Corynanthe johimbe). It has been used in traditional medicines in the treatment of angina and hypertension, but is more commonly employed in organic/psychogenic impotence, and used as an aphrodisiac.
The traditional method of use involved the preparation of bark decoctions consumed orally. Yohimbine has traditionally been used in African folk and Western medicine to increase feelings of energy and vitality in both animals and humans.
3. Key Constituents and Active Compounds
3.1 Alkaloid Profile of the Source Plant
In addition to yohimbine and its isomers (α-yohimbine, β-yohimbine, allo-yohimbine), the alkaloids of Pausinystalia yohimbe bark include ajmaline, dihydroyohimbine, corynantheine, dihydrocorynantheine, and corynanthine (rauhimbin).
The bark's alkaloid diversity means that whole-bark preparations differ pharmacologically from purified yohimbine (corynine). Yohimbine has two stereoisomers (rauwolscine and corynanthine) that differ little in their physical properties or in their effects on serotonin and dopamine receptors. The three isomers, however, do differ significantly in their affinity for the alpha-1 and alpha-2 adrenoceptor subtypes.
3.2 The Corynanthe Alkaloid Class
Corynanthe alkaloids can be classified into the following groups: simple corynanthe, yohimbine, oxindole corynanthe, mavacurane, sarpagine, akuammiline, strychnos, and ajmaline-type alkaloids. Corynanthe alkaloids have been recently isolated from plants belonging to the families of Apocynaceae, Loganiaceae, and Rubiaceae, and most of them possess excellent biological activities.
Corynanthe alkaloids are highly abundant natural bioactive substances of various core structures possessing important properties such as nerve excitation and antimalarial and analgesic effects.
4. Mechanisms of Action
4.1 Primary Adrenergic Mechanism
Yohimbine (corynine) has also been called quebrachine, aphrodine, corynine, and hydroaerogotocin. It is a potent selective α2-adrenoceptor (AR) antagonist with weaker α1-antagonist activity, as demonstrated by radioreceptor ligand binding assays and by pharmacological studies.
The pharmacological activity of yohimbine is mediated by the combined action of the central and peripheral nervous systems. It selectively blocks the pre- and postsynaptic α2-adrenergic receptors and has a moderate affinity for α1 and α2 subtypes. Yohimbine also binds to other behaviourally relevant monoaminergic receptors in the following order: α-2 NE > 5HT-1A > 5HT-1B > 1-D > D3 > D2 receptors.
Yohimbine may exert its beneficial effect on erectile ability through blockade of central alpha-2-adrenergic receptors, producing an increase in sympathetic drive secondary to an increase in norepinephrine release and in firing rate of cells in the brain noradrenergic nuclei.
The α2-adrenoceptor antagonism has downstream consequences for multiple physiological systems. Being a derivative of indolylalkylamine, yohimbine selectively blocks α2-adrenergic receptors. It weakens the negative feedback mechanism of norepinephrine release in nerve endings. It has a sympathomimetic effect and can also cause sympathomimetic activity.
4.2 Mechanism in Erectile Function
Effects on erectile dysfunction may result from inhibition of presynaptic-α1-adrenoceptor activity in cavernous smooth muscle cells and impact on NO and cGMP formation involving endothelium and endothelial NO synthase activity, which is testosterone-dependent.
4.3 Pharmacokinetics and Metabolism
The major metabolic pathway involves hepatic oxidation, primarily mediated by cytochrome P450 enzymes, specifically CYP2D6 and CYP3A4. CYP2D6 plays a crucial role in the 11-hydroxylation of yohimbine, forming 11-hydroxyyohimbine, a pharmacologically active metabolite. Genetic polymorphisms in CYP2D6 can significantly influence yohimbine metabolism, leading to substantial interindividual variability in its clearance and clinical effects. Individuals with certain CYP2D6 genotypes may exhibit impaired metabolism, resulting in higher plasma concentrations and an increased risk of adverse effects.
Other metabolic pathways include oxidation to 10-hydroxyyohimbine and other minor metabolites. The kidneys excrete yohimbine and its metabolites, with less than 1% of the administered dose found unchanged in the urine after 24 hours. Yohimbine has a relatively short half-life of less than 1 hour, indicating rapid clearance from the plasma.
Variations between individuals are known with regard to the pharmacokinetics after oral administration of drugs which, like yohimbine HCl, are primarily metabolised through CYP2D6, and genetic variations for CYP2D6 with varying consequences have been described: defective alleles, alleles leading to a reduced metabolic rate, amplification of alleles with increased metabolic rate and changes to alleles with no functional consequences.
5. Scientific Evidence by Area of Use
5.1 Erectile Dysfunction
Erectile dysfunction (ED) is the indication for which corynine/yohimbine has received the most rigorous clinical investigation. Yohimbine, a pharmacologically well-characterized alpha-2-adrenoceptor antagonist with activity in the central and peripheral nervous system, has been used for over a century in the treatment of erectile dysfunction. In-depth, systematic studies in animals have shown that the drug has a remarkable positive effect on sexual performance. Meta-analyses of the few controlled, randomized human studies have consistently shown an advantage of yohimbine over placebo. Despite such a long history and encouraging activity, the drug has not yet been subjected to scientifically rigorous human clinical trials.
A systematic review and meta-analysis identified a pool of randomized placebo-controlled trials. A systematic review of literature on yohimbine for erectile dysfunction identified 7 trials involving 419 patients, all of which showed evidence of efficacy; adverse events were uncommon. The dosing used in the included trials ranged: yohimbine (5 to 10 mg, 3 times per day) or yohimbine hydrochloride (5, 5.4 or 6 mg given 3, 4, or 8 times per day) orally for a period of 2 to 10 weeks was used in the treatment groups, compared with placebo, in men suffering some form of erectile dysfunction aged 18 to 70 years.
A more recent systematic review confirmed this signal. A total of eight studies out of 543 were included in this review. Both yohimbine alone (odds ratio [OR] = 2.08, 95% CI 1.30–3.32, P = .002) and in combination (OR = 6.35, 95% CI 3.01–13.41, P < .001) showed a significantly greater probability of erectile function improvement compared to the placebo group.
However, results have not been uniformly positive. A randomized controlled trial in organically impotent men found that a randomized, controlled study with partial cross-over of yohimbine versus placebo in 100 organically impotent men showed a positive response in 42.6 per cent of the patients receiving yohimbine versus 27.6 per cent in the placebo group; although favorable to the test medication these values did not reach statistical significance (p = 0.42).
The overall picture remains qualified: although relevant basic pharmacological and animal research information has been available for over 15 years, recent studies were designed with a lack of insight and complete disregard of those fundamental studies. Dose-response investigations are not available, alternative routes of administration (i.e. sublingual) have not been investigated, nor has continuous versus 'on-demand' administration been explored. Synergistic activity with other drugs was last studied nearly four decades ago. Assessment of various populations was carried out in very limited cohorts. In short, properly designed trials in humans have not been done.
Regulatory status varies: in the United States, yohimbine chloride is approved by the Food and Drug Administration under 49 different brands. In the United Kingdom, supplement preparations of yohimbe are banned as introducing a considerable risk for adverse effects. The drug form of yohimbine HCl — which is not licensed as a medicine for any condition — may rarely and specifically be compounded by a pharmacist as a prescription-only medicine for treating delayed ejaculation.
Evidence strength: Moderate. Meta-analyses demonstrate statistically significant benefit over placebo in several small-to-medium RCTs, but individual trials show mixed results and methodological limitations are well-documented. No large definitive RCT exists.
5.2 Weight Loss and Body Composition
Yohimbe is promoted for erectile dysfunction, athletic performance, and weight loss. There is very little research in people on the effects of yohimbe as a dietary supplement. But studies have documented the risks of taking it. There is not enough evidence for definite conclusions to be reached about yohimbe's effectiveness for any health condition.
The proposed mechanism underlying fat-loss effects centers on α2-receptor blockade. Alpha-2-adrenoceptors are expressed in adipose tissue and, when activated, inhibit lipolysis. Blocking them with yohimbine is hypothesized to promote fat mobilization during caloric restriction or exercise.
Key human trials have produced inconsistent results. In an early randomized double-blind study in obese women: yohimbine significantly increased the mean weight loss in patients on a low-energy diet: 3.55 ± 0.24 kg (yohimbine) vs. 2.21 ± 0.37 kg (placebo), P < 0.005. With yohimbine, a steady level of effort-induced energy expenditure and sympathetic system activity was maintained. No significant effect of yohimbine on lipolysis was observed under the experimental conditions of this study.
A study in elite male soccer players showed a more limited effect on body composition: fat mass was significantly lower in the yohimbine versus placebo trial at post-supplementation assessment (7.1 ± 2.2 vs. 9.2 ± 1.9%; p < 0.05). There were no changes in exercise performance indicators (bench and leg press, vertical jump, dribble and power test results, shuttle run). The results indicate that supplementation with yohimbine combined with resistance training does not significantly alter the body mass, muscle mass, or performance indicators in professional soccer players. Nonetheless, yohimbine supplementation appears to be suitable as a fat loss strategy in elite athletes.
In contrast, a six-month randomized double-blind trial in men found no effect: forty-seven men with a mean age of 42 years were assigned in random, double-blind fashion to treatment with either placebo or high-dose yohimbine (peak dose, 43 mg/day). Thirty-three subjects completed the six-month program. Variables assessed included body weight and body mass index, total cholesterol and HDL, body fat, and fat distribution as measured by both waist-to-hip ratio and CT scan. Treatment with yohimbine had no effect on any variable in comparison with the control group.
A systematic review drawing on three high-quality clinical trials using yohimbine to reduce body weight found conflicting results and could not conclude that yohimbine use is effective. In a study among athletes, yohimbine 20 mg daily for 21 days had no effect on body mass or muscle mass, but did decrease body fat.
Evidence strength: Weak to inconsistent. A small number of human trials show mixed results — some positive findings on fat mass reduction but generally without effect on body weight, muscle mass, or exercise performance. No large-scale RCT supports efficacy for weight management.
5.3 Orthostatic Hypotension
In patients with orthostatic hypotension, yohimbine produces a pressor effect by engaging residual sympathetic tone.
A double-blind, crossover, placebo-controlled clinical study examined yohimbine in patients with antidepressant-induced orthostatic hypotension: a double-blind, crossover, placebo-controlled study tested the effect of low doses (4 mg three times daily) of yohimbine in 12 patients with depression with clomipramine-induced orthostatic hypotension. Yohimbine, a selective alpha-2-adrenoceptor antagonist, had a favorable effect in orthostatic hypotension and induced a significant increase in blood pressure.
Yohimbine increased norepinephrine, epinephrine, muscle sympathetic nerve activity, blood pressure, and heart rate in neurally-mediated syncope patients compared with baseline. Yohimbine was more effective than pyridostigmine at improving orthostatic hypotension in a study population that included multiple system atrophy, pure autonomic failure, and Parkinson disease.
Evidence strength: Preliminary. Data from small clinical studies suggest a pressor benefit in orthostatic hypotension, particularly in the context of drug-induced hypotension, but findings are from limited trials and this remains an exploratory indication.
5.4 Xerostomia (Drug-Induced Dry Mouth)
Yohimbine 6 mg given 3 times a day has been used in xerostomia trials. Data from a pharmacokinetic study describe an interaction between yohimbine and tricyclic antidepressants and show that a relatively low dose (4 mg) of yohimbine could be useful in the treatment of dry mouth due to tricyclic antidepressants.
Early research suggests that taking yohimbine, the active ingredient in yohimbe, improves symptoms of dry mouth in people taking antidepressants. The effect of yohimbe bark itself on dry mouth is not clear.
Evidence strength: Preliminary. A small number of clinical studies support the pro-salivary effect of yohimbine specifically in patients on xerogenic drugs (principally tricyclic antidepressants). Broader evidence is lacking.
5.5 Female Sexual Dysfunction
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.
Evidence strength: Insufficient. The available clinical trial data do not support efficacy in female sexual dysfunction.
5.6 Athletic Performance
Commercially, yohimbine is used in multi-ingredient exercise performance supplements despite minimal research on health and performance implications. Early research suggests that taking yohimbine daily for 21 days does not improve exercise performance or build muscle mass in soccer players. The effect of yohimbe bark on exercise performance is not clear.
Evidence strength: Insufficient. Current evidence does not support performance enhancement effects.
5.7 Other Investigated Areas
Yohimbine has also been used in studies investigating disorders including autonomic failure and orthostatic hypotension. Effects on the CNS including reductions in fear and increased impulsivity have been reported. Data are also limited on the use of yohimbine for PTSD, orthostatic hypotension, athletic performance, and xerostomia.
Emerging evidence suggests that the combination of yohimbine with traditional antidepressants, such as the selective serotonin reuptake inhibitor fluoxetine, may hold promise in accelerating the antidepressant response in clinical settings. This remains highly preliminary.
6. Body Systems and Health Areas
- Cardiovascular system: Alpha-2-adrenoceptor blockade raises blood pressure and heart rate through increased sympathetic drive; investigational use in orthostatic hypotension.
- Central nervous system: Noradrenergic and serotonergic receptor interactions; effects on anxiety, fear conditioning, and arousal documented in preclinical and limited clinical settings. Effects on the CNS including reductions in fear and increased impulsivity have been reported.
- Reproductive / urogenital system: Historically and pharmacologically linked to male erectile function via α-adrenoceptor modulation in cavernous tissue.
- Metabolic / adipose tissue: Proposed fat-mobilizing action via α2-adrenoceptor blockade in adipose tissue, with inconsistent human evidence.
- Exocrine (salivary) system: Yohimbine is used to increase peripheral blood flow and to dilate the pupil of the eye. Early clinical evidence supports effects on salivary gland secretion, particularly relevant in drug-induced xerostomia.
- Autonomic nervous system: Used as a research tool to probe α2-AR-mediated autonomic regulation; clinical effects on blood pressure and norepinephrine dynamics are well-documented in pharmacological studies.
7. Dosage Forms and Reported Dosages
The following dosages are reported from published clinical studies and should not be interpreted as recommendations:
- Erectile dysfunction: A mean dose of 0.4 mg/kg body weight or 30 mg daily, and a maximum of 50 mg, has been used in erectile dysfunction studies. Yohimbine (5 to 10 mg, 3 times per day) or yohimbine hydrochloride (5, 5.4 or 6 mg given 3, 4, or 8 times per day) orally for a period of 2 to 10 weeks was used in the systematic review's constituent trials.
- Organic erectile dysfunction (single-study): Yohimbine showed modest effectiveness at the doses used in the trial (18 mg per day).
- Body weight / fat loss: In studies investigating effects on body mass, yohimbine 20 mg daily has been used. In one study, overweight female subjects received yohimbine (yohimbibinum hydrochloricum) 5 mg 4 times per day (20 mg/day) for three weeks after subjects had started a weight loss diet.
- Xerostomia: Yohimbine 6 mg given 3 times a day has been used in xerostomia trials.
- Orthostatic hypotension: A double-blind, crossover, placebo-controlled study tested the effect of low doses (4 mg three times daily) of yohimbine in 12 patients with depression with clomipramine-induced orthostatic hypotension.
- General ergogenic / fat-burning context: Although optimal dosing strategies have not been established, many studies recommend the effective oral dose of yohimbine as 2.5–5 mg. However, multiple doses have been empirically tested, ranging from 2.5 to 20 mg, making definitive dosage recommendations elusive.
- Body weight dosing referenced: Total daily dosages of 0.2 mg/kg body weight have been successfully used to increase fat burning without significant implications on cardiovascular parameters like heart rate and blood pressure.
8. Safety Considerations and Drug Interactions
8.1 Adverse Effects at Standard Doses
At normal dosages, the most common side effects of yohimbine include gastrointestinal symptoms, dizziness, nervousness/anxiety, and increased blood pressure and heart rate. Though yohimbine is effective, side effects may include anxiety, nervousness, and an elevated heart rate, and the reported dose of yohimbine in many supplement formulas doesn't match the actual dose.
The adverse effects of yohimbine at low doses are relatively mild and include temporary hypertension and tachycardia; however, there have been few reported cases of serious adverse effects in sport and exercise when the safety dosage is dramatically exceeded.
8.2 Serious and High-Dose Adverse Effects
The adverse effects of yohimbine include gastrointestinal distress, hypertension, tachycardia, manic reactions, bronchospasm, palpitations, insomnia/anxiety, chills/cold/shivering, sweating, flushing, and headaches, which can be attributed to its central adrenergic activity.
At higher doses or in susceptible individuals, more severe adverse effects can occur. These may include cardiac arrhythmias, myocardial infarction, seizures, and renal failure. Yohimbine can also exacerbate pre-existing psychiatric conditions like agitation, anxiety, and panic disorders.
Clinical trials report few serious adverse reactions. There are case reports of rash, lupus-like syndrome, bronchospasm, severe hypotension, dysrhythmia, heart failure, and death.
According to the FDA Center for Food Safety and Nutrition (CFSAN), 275 cases of poisoning caused by dietary supplements were monitored in San Francisco within one year (2006), and yohimbine products accounted for 18% of supplement-related symptomatic cases.
8.3 Interindividual Variability and CYP2D6 Polymorphism
Genetic polymorphisms in CYP2D6 can significantly influence yohimbine metabolism, leading to substantial interindividual variability in its clearance and clinical effects. Individuals with certain CYP2D6 genotypes may exhibit impaired metabolism, resulting in higher plasma concentrations and an increased risk of adverse effects.
Variations between individuals are known with regard to the pharmacokinetics after oral administration of drugs which, like yohimbine HCl, are primarily metabolised through CYP2D6. The safety factor for substances primarily metabolised through CYP2D6 should accordingly be raised for interindividual differences in toxicokinetics (Standard: 3.16) to 18, and in children even to 45.
8.4 Drug Interactions
Yohimbine can interact with medications that affect the adrenergic and serotonergic systems, such as antidepressants, antihypertensives, and stimulants. Concurrent use with these medications may potentiate or alter yohimbine's effects, increasing the risk of adverse events.
Specific interaction categories documented in the literature include:
- Antidepressants (MAOIs and tricyclics): Do not take with antidepressant medications or with foods containing high amounts of tyramine such as cheese, red wine, or liver, or with decongestants, diet aids, or phenylpropanolamine-containing products.
- Antihypertensive drugs / α2-agonists (e.g., clonidine): Blood pressure medicines and α2-agonists (e.g., clonidine): yohimbine can counteract these and raise blood pressure.
- Stimulants: Combining with stimulants and CYP2D6 inhibitors may increase the risk of adverse effects.
- CYP2D6 inhibitors: Because yohimbine is metabolized primarily by CYP2D6, inhibitors of this enzyme can raise plasma yohimbine concentrations significantly.
8.5 Contraindications
Yohimbine should not be used if a person has high blood pressure, heart disease, arrhythmias, Parkinson's disease, seizure disorders, kidney, thyroid, or liver disease, sexual organ inflammatory disorders, ulcers, or psychiatric disorders.
Yohimbine should not be used in the presence of renal or hepatic dysfunction. It is contraindicated in pregnancy. It should not be used during pregnancy or lactation.
It is important to note that yohimbe products are among supplements with the largest number of documented contraindications, toxic effects, and severe events requiring hospitalization.
8.6 Supplement Labeling and Quality Concerns
An analysis of 49 yohimbine supplement brands sold in the US showed that only 4% provided accurate information about the quantity of yohimbine and known adverse effects.
Research suggests that the quantity and quality of yohimbine supplements varies greatly. Many yohimbine-containing supplements don't state the amount of yohimbine they contain.
Yohimbine has been studied as a potential treatment for erectile dysfunction, but there is insufficient evidence to rate its effectiveness. Nevertheless, the quantity of yohimbine in dietary supplements, often advertised as promoting sexual function, has been found to overlap with prescription doses of yohimbine.
References
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