Yohimbine

Yohimbine, also known as quebrachine, is an indole alkaloid derived from the bark of the African tree Pausinystalia johimbe and from the bark of the unrelated South American tree Aspidosperma quebracho-blanco. It is a veterinary drug used to reverse xylazine.
Substances purported to be extracts from the yohimbe tree have been marketed as dietary supplements for various purposes, especially for erectile dysfunction, but they contain highly variable amounts of yohimbine, if any; no published clinical evidence supports their efficacy for treating sexual dysfunction or any disease.
In the United States, it is illegal to market an over-the-counter supplement product containing yohimbine as a treatment for any supposed health effect without having approval from the Food and Drug Administration. In the United Kingdom, yohimbine is an unlicensed drug, rarely and specifically compounded as a "prescription-only medicine", while yohimbine herbal supplements are banned from manufacturing as dangerous substances.

Uses

Poison warning and variable content in over-the-counter supplements

In 2022, the Tennessee Poison Center warned that use of yohimbine supplements may have fatal effects due to the possibility for high, unregulated amounts of yohimbine in over-the-counter supplement products. Due to inaccurate product labeling and the potential for serious adverse effects, yohimbine supplements have been banned in many countries. Use of such products has been associated with cardiovascular problems and seizures.
The European Food Safety Authority Panel on Food Additives determined that it was not possible to conclude about the safety or to establish a health-based guidance value for yohimbine in supplement products. They wrote:
One study found that samples of brands sold in American brick-and-mortar stores contained highly variable amounts of yohimbine, with some brands of "yohimbe" not containing yohimbine from the P. johimbe tree, and other products containing no yohimbine at all. Labeling claims were often misleading.
In analyses by other laboratories for products sold in the US, in other countries, and on the internet, highly variable content levels of yohimbine were revealed.
Yohimbe sold in markets in West Africa where the tree grows may be adulterated with other species of the genus Pausinystalia, which contain little yohimbine. The amounts of alkaloid found even in genuine P. johimbe bark vary considerably, depending on the source of the bark.

FDA warning letters

During the 21st century, the FDA issued multiple warning letters to American manufacturers of yohimbe supplements for making false health claims and interstate marketing of such products as misbranded, unapproved drugs.

Sexual dysfunction and aphrodisiac

There is no evidence that yohimbe herbal supplements are effective as an aphrodisiac or as an OTC replacement for sildenafil for erectile dysfunction. Prescriptions for it are rare, and most United States pharmaceutical manufacturers have discontinued production of prescription capsules and tablets. In Canada during 2019, yohimbe products were removed from the market out of concern their use for sexual enhancement, weight loss, or as an exercise aid would pose serious health risks.
It 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.
In the United Kingdom, supplement preparations of yohimbe are banned as introducing a considerable risk for adverse effects. The drug form of yohimbine, called Yohimbine hydrochloride - 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 - a formulation that cannot be sold, supplied or advertised as a retail product.
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.
In the United States, "yohimbe" preparations are sold as 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".

Other uses

Yohimbine has been used to increase peripheral blood flow and to dilate the pupil of the eye.

Adverse effects

s of yohimbine in humans at high doses include hypertension, tachycardia, agitation, hypervigilance, anxiety, tremors, nausea, and urinary frequency. The drug is described as producing a psychoactive state of considerable anxiety along with tenseness, restlessness, and irritability and as being "extremely unpleasant", at least at the assessed doses. In animals, yohimbine likewise produces effects suggestive of severe anxiety. Yohimbine has been used in animals as a model of anxiety in the evaluation of novel anxiolytics.

Drug interactions

Yohimbine has extensive interactions with prescription drugs, some with severe health consequences, including sudden hypotension, irregular heart rate, heart failure, and death.
Barbiturates and benzodiazepines can reduce the anxiety produced by yohimbine. Conversely, combination with imipramine, which is notably known to act as a norepinephrine reuptake inhibitor, has been reported to augment the restlessness and anxiety of yohimbine and to convert them into panic.

Pharmacology

Yohimbine has high affinity for the α₂-adrenergic receptor, moderate affinity for the α₁ receptor, 5-HT_1A, 5-HT_1B, 5-HT_1D, 5-HT_1F, 5-HT_2B, and dopamine D₂ receptors, and weak affinity for the 5-HT_1E, 5-HT_2A, 5-HT_5A, 5-HT₇, and dopamine D₃ receptors. It behaves as an antagonist at α₁-adrenergic, α₂-adrenergic, 5-HT_1B, 5-HT_1D, 5-HT_2A, 5-HT_2B, and dopamine D₂, and as a partial agonist at 5-HT_1A. Yohimbine interacts with serotonin and dopamine receptors in high concentrations.

Molecular target	Binding affinity	Pharmacologic action	Species	Source
SERT	1,000	Inhibitor	Human	Frontal cortex
5-HT_1A	346	Partial agonist	Human	Cloned
5-HT_1B	19.9	Antagonist	Human	Cloned
5-HT_1D	44.3	Antagonist	Human	Cloned
5-HT_1E	1,264	Unknown	Human	Cloned
5-HT_1F	91.6	Unknown	Human	Cloned
5-HT_2A	1,822	Antagonist	Human	Cloned
5-HT_2B	43–143.7	Antagonist	Human	Cloned
5-HT₇	2,850	Unknown	Human	Cloned
α_1A	1,680	Antagonist	Human	Cloned
α_1B	1,280	Antagonist	Human	Cloned
α_1C	770	Antagonist	Human	Cloned
α_1D	557	Antagonist	Human	Cloned
α_2A	1.05	Antagonist	Human	Cloned
α_2B	1.19	Antagonist	Human	Cloned
α_2C	1.19	Antagonist	Human	Cloned
D₂	339	Antagonist	Human	Cloned
D₃	3,235	Antagonist	Human	Cloned

Yohimbine selectively blocks the pre-synaptic α₂-adrenergic receptors. Blockade of post-synaptic α₂-adrenergic 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-adrenergic 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-adrenergic receptors on the corpus cavernosum smooth muscle. Under physiologic conditions, however, nitric oxide attenuates norepinephrine vasoconstriction.
Yohimbine binds to the a₂ adrenergic receptor at a ratio of 40:1 and is the only a₂ adrenergic receptor antagonist with no imidazoline receptor activity.

Chemistry

Yohimbine is a polycyclic cyclized tryptamine and yohimban derivative.

Related compounds

Other related compounds include ajmalicine, alstonine, corynanthine, deserpidine, mitragynine, rauwolscine, spegatrine, reserpine, and rescinnamine.

Natural occurrence

''Pausinystalia johimbe''

Yohimbine should not be confused with yohimbe but often is. Yohimbe is the common English name for the tree species P. johimbe and, by extension, the name of a medicinal preparation made from the bark of that tree, sold as an aphrodisiac. 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; and, while it has been described as the most active of these, it constitutes only 15% of the total alkaloid content. Others include rauwolscine, corynanthine and ajmalicine; the bark also contains non-alkaloids about which virtually nothing is known.
Yohimbe, thus a complex mixture, has been studied far less thoroughly than yohimbine, the pure compound. Pharmaceutical grade yohimbine is usually presented as the hydrochloride, which is more soluble.
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. 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. The species is becoming endangered.
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 for delivery of pre-dried bark at the roadside. In practice they confuse and mix it with P. macroceras, a species that contains little yohimbine.