How yohimbine and sildenafil citrate (Pfizer’s Blue) work
For erections to occur, there must be vasodilation of penile tissue. All medications for erectile dysfunction have a vasodilatory effect. But apart from this, erectile dysfunction medications work very differently. It is surprising how many physiological processes, which are quite independent from each other, actually contribute to erections.
Sildenafil citrate works on an enzymatic level. It suppresses the enzyme phosphodiesterase type 5 (PDE5), which naturally occurs in erectile tissue. Phosphodiesterase type 5 (PDE5) breaks down the body chemical known as cyclic GMP (cGMP). Cyclic GMP is produced during arousal and causes the muscular and vascular changes that lead to an erection. Men who don’t produce a sufficient amount of cyclic GMP will have problems achieving an erection. Likewise, men with high levels of the enzyme PDE5 will have problems maintaining one.
Sildenafil citrate doesn’t produce the same results in all men. This is because, for cyclic GMP to do its job in the first place, there have to be specific receptors and intact downstream pathways. Men whose genetic program provides for a comparatively generous number of receptor sites and healthy endothelial function are likely to produce better erections than those with a smaller number or vascular damage. It is a variation in the human race that cannot always be fully corrected by sildenafil citrate.
Unlike sildenafil, Tongkat Ali is not an acute, direct vasodilator. Its pro-sexual effects are primarily attributed to its influence on the endocrine system (such as modulating free testosterone and reducing SHBG) and its adaptogenic, stress-reducing properties. While healthy testosterone levels support overall endothelial function and nitric oxide synthase activity over the long term, Tongkat Ali does not trigger an acute, immediate chain reaction of nitric oxide and cGMP proliferation in the genital area in the same direct pharmacological manner as PDE5 inhibitors. Its effects are systemic and build over time, rather than acting as an immediate mechanical trigger for an erection.
The vasodilatory and pro-sexual effect of yohimbine is based on an entirely different physiological mechanism. The Mosby RxList reference to pharmaceutical drugs describes yohimbine as follows (this description is practically identical to the package brochure text of some older prescription yohimbine brands):
“Yohimbine blocks presynaptic alpha-2-adrenergic receptors. Its action on peripheral blood vessels resembles that of reserpine, though it is weaker and of short duration. Yohimbine’s peripheral autonomic nervous system effect is to increase parasympathetic (cholinergic) and decrease sympathetic (adrenergic) activity. It is to be noted that in male sexual performance, erection is linked to cholinergic activity and to alpha-2 adrenergic blockade, which may theoretically result in increased penile inflow, decreased penile blood outflow or both. Yohimbine exerts a stimulating action on the mood and may increase anxiety. Such actions have not been adequately studied or related to dosage although they appear to require high doses of the drug. Yohimbine has a mild anti-diuretic action, probably via stimulation of hypothalamic centers and release of posterior pituitary hormone.
“Reportedly, Yohimbine exerts no significant influence on cardiac stimulation and other effects mediated by beta-adrenergic receptors; its effect on blood pressure, if any would be to lower it; however, no adequate studies are at hand to quantitate this effect in terms of yohimbine dosage.”
Medical Correction: The claims in the above quote that yohimbine decreases sympathetic activity and lowers blood pressure are pharmacologically inaccurate. Systemically, yohimbine is a sympathomimetic agent. By blocking presynaptic alpha-2 autoreceptors, it prevents the negative feedback loop of norepinephrine, thereby increasing the release of norepinephrine and increasing sympathetic tone. This is why it frequently causes tachycardia and hypertension. Its pro-erectile effect is likely due to central nervous system arousal and the local blockade of alpha-2 receptors on the smooth muscle of the corpus cavernosum (which normally maintain flaccidity), not a systemic shift to parasympathetic dominance.
Contrary to the older literature quoted above, modern scientific studies and clinical experience clearly show that yohimbine can result in a rise in blood pressure. The Expanded Commission E Monographs, published by the American Botanical Council, list hypertension as a possible side effect:
“Therapeutic administration of yohimbine can cause nervous excitation, tremor, sleeplessness, anxiety, increased blood pressure, tachycardia, nausea, and vomiting. In case of existing liver and kidney diseases, yohimbe preparations should not be used. Interactions with psychopharmacological herbs have been reported.”
To understand the pharmacological action of yohimbine, the following has to be considered.
A large number of bodily (physiological) processes are outside of a person’s voluntary control. They are controlled by the autonomic nervous system. This includes, for example, breathing, digestive processes, heartbeat, and blood pressure. Much of the autonomic nervous system functions via two pathways: the sympathetic and the parasympathetic nervous systems. These two parts of the nervous system largely use separate but parallel nerve cords.
The sympathetic division is responsible for the body’s reaction to stress factors (fight or flight). When the sympathetic system is active, heart rate and blood pressure will increase, respiration becomes faster, blood vessels to the heart will be dilated, and there will be increased blood flow to the muscles. This is, by and large, accompanied by a constriction of arterial blood vessels in the extremities and digestive tract.
The parasympathetic division rules in restful situations (rest and digest). When stress situations subside, parasympathetic nerve impulses will slow the heart rate, decrease blood pressure, slow breathing, stimulate digestion, induce salivation, and dilate peripheral blood vessels.
For nerve impulses from the brain or central nervous system to reach their destinations, they have to be transmitted from nerve cell to nerve cell on a specific pathway. The transmission between nerve cells is effected by neurotransmitters, which are emitted by an upstream nerve cell. For the signal to reach the next downstream nerve cell, there have to be synaptic receptors on which neurotransmitters can bind.
The primary neurotransmitter active on the sympathetic pathway is norepinephrine. The primary neurotransmitter active on the parasympathetic pathway is acetylcholine. Norepinephrine is not just a neurotransmitter but also a hormone; it is secreted by the adrenal medulla. While neurotransmitters primarily function to connect nerve cells across synapses, hormones are messenger molecules that act on body parts at some distance from where the hormone originates via the bloodstream.
In contrast, prostaglandins are local messenger molecules that act in the environment where they originate. A prostaglandin that causes vasodilation of penile tissue is alprostadil (prostaglandin E1). Alprostadil is an additional medication that can be injected or applied topically to induce erections.
A large number of neurologically active pharmaceuticals actually do not affect nerve cells themselves but rather the neurotransmitters in between. Yohimbine is such a pharmaceutical. It blocks the receptor sites for the neurotransmitter norepinephrine. More specifically, yohimbine blocks presynaptic alpha-2-adrenergic receptors. By blocking these autoreceptors, yohimbine prevents norepinephrine from inhibiting its own release. This results in a surge of norepinephrine, which stimulates unblocked alpha-1 and beta-1 receptors, leading to systemic sympathetic activation (increased heart rate and blood pressure). However, in the penis, the local blockade of alpha-2 receptors on the smooth muscle prevents the vasoconstriction that maintains flaccidity, which, combined with central arousal, can facilitate an erection.
Adrenergic blockade can be effected not just by yohimbine but by a considerable number of other pharmaceutical agents as well. However, most other adrenergic blocking drugs, such as beta-blockers, are known to impair sexual function rather than enhance it.
To evaluate the effect of adrenergic blockade, we have to be aware of the differentiation among adrenergic receptors. Four main kinds of receptors have been identified: alpha-1, alpha-2, beta-1, and beta-2. They all are binding sites for the adrenal hormones/neurotransmitters epinephrine and norepinephrine. The physiological effect depends on which specific receptor is stimulated or blocked.
Heart function and blood pressure are closely correlated to beta-1 and alpha-1 receptors. Your typical medication for high blood pressure is a beta-blocker or an alpha-1 blocker.
Beta-blockers are known to cause erectile dysfunction. The primary mechanism for this is that non-selective beta-blockers block beta-2 adrenergic receptors (which normally mediate vasodilation). This leaves alpha-1 adrenergic receptors (which mediate vasoconstriction) unopposed, making it physically difficult to achieve the vasodilation necessary for an erection. Additionally, beta-blockers can cause central nervous system side effects like fatigue, which lower libido.
Yohimbine, as an alpha-2 antagonist, causes an increase in plasma levels of norepinephrine. Because the alpha-2 receptors are blocked, this excess norepinephrine freely binds to unblocked beta-1, beta-2, and alpha-1 receptors. This systemic stimulation of beta-1 and alpha-1 receptors is what leads to the side effects of hypertension and tachycardia (an abnormally fast heartbeat).
Most of the literature on yohimbine recommends daily use, in order to keep unwanted side effects like nervousness and insomnia at bay. The rationale for such a recommendation is derived from the body's ability to adapt to continuous receptor stimulation.
Practically all hormones and neurotransmitters have the effect of down-regulating their own receptors or inhibiting their own production via negative feedback loops.
The hypothalamus measures plasma levels of various hormones. However, it is important to correct a common endocrine misconception: the hypothalamus-pituitary-adrenal (HPA) axis (via Corticotropin-releasing hormone and ACTH) regulates the adrenal cortex, which secretes cortisol. The adrenal medulla, which secretes epinephrine and norepinephrine, is not regulated by ACTH; it is innervated directly by preganglionic sympathetic nerve fibers. Therefore, the reduction of yohimbine's side effects over time is not due to HPA axis feedback shutting down the adrenal medulla, but rather due to the central nervous system and peripheral receptors down-regulating or adapting to the continuous presence of elevated norepinephrine.
The few physicians who do prescribe yohimbine in the age of phosphodiesterase inhibitors usually tell their patients that problems such as restlessness and insomnia subside after several days into a yohimbine cycle. This is likely due to receptor desensitization and central nervous system adaptation, rather than a halt in adrenal medulla secretion.
Apart from presynaptic alpha-2-adrenergic receptor blockade, there may be other elements that contribute to the sexuality- and erection-enhancing power of yohimbine. It has been noted that yohimbine has a mild anti-diuretic action, possibly via the release of the posterior pituitary hormone vasopressin (antidiuretic hormone, ADH). Vasopressin is known to have some centrally mediated sexually stimulating effects, and its release may contribute to yohimbine's overall profile. Finally, while some older literature suggests yohimbine has MAO-inhibiting properties, modern pharmacology considers its MAO-inhibiting activity to be clinically negligible at therapeutic doses.