Yohimbine or Synephrine: What Is the Difference

Yohimbine and synephrine often stand side by side in the composition of fat burners, and they are frequently considered interchangeable «thermogenics». But pharmacologically these are substances with opposite logics of action: one blocks the receptors that inhibit noradrenaline release, the other itself weakly stimulates adrenergic receptors. The editors examine what follows from this for effectiveness and safety.

Where Yohimbine and Synephrine Come From

Yohimbine is an indole alkaloid from the bark of the West African tree Pausinystalia johimbe. Traditionally the bark was used as an aphrodisiac, and yohimbine hydrochloride was for a long time used in medicine to treat erectile dysfunction, until more effective drugs appeared. In veterinary practice yohimbine is used to bring animals out of sedation caused by alpha-2 agonists.

Synephrine, or more precisely p-synephrine, is a protoalkaloid from the peel of bitter orange (Citrus aurantium). It belongs to the phenylethylamines and in structure resembles adrenaline and octopamine. It gained popularity in weight-loss supplements after the ban on ephedra in the United States in 2004.

Chemically these substances have almost nothing in common. Yohimbine is a complex polycyclic molecule, synephrine is a small amine. They also differ in how they are obtained in supplements: synephrine is usually introduced as a standardized bitter orange extract, and yohimbine as an extract of yohimbe bark or in the form of the hydrochloride.

They have one thing in common: both substances affect the adrenergic system, which regulates lipolysis, heart rhythm and blood pressure. But they do this in fundamentally different ways.

To Block or to Stimulate: The Difference in Mechanisms

Yohimbine is a selective antagonist of alpha-2 adrenergic receptors. These receptors act as a «brake»: on nerve endings they limit the release of noradrenaline, and in fat tissue they suppress lipolysis. By blocking them, yohimbine simultaneously increases noradrenaline release and removes the inhibition of fat breakdown in adipocytes.

An interesting feature is the dependence on hormonal background. Insulin suppresses lipolysis, so yohimbine's effect on the mobilization of fatty acids is most pronounced on an empty stomach or during physical activity. Alpha-2 receptors are more densely represented in some «problem» fat depots, which gave rise to the popular but poorly proven idea of local fat burning.

Synephrine acts differently: it is itself a weak agonist of adrenergic receptors. According to the review by Stohs and colleagues (2011), its affinity for the alpha-1, alpha-2, beta-1 and beta-2 receptors is low, and part of its metabolic effects may be associated with beta-3 receptors. It does not block the «brakes», but only gently presses the «gas».

By increasing noradrenaline release, yohimbine affects the brain and cardiovascular system much more strongly: agitation, anxiety and increased blood pressure appear. Synephrine, because of its poorer penetration into the brain and low affinity for cardiac receptors, has a milder profile.

What Is Known About Effectiveness

For yohimbine there are several small studies in humans. Galitzky and colleagues (1988) showed that oral yohimbine in healthy men increases the level of free fatty acids in the blood, that is, it enhances the mobilization of fats. In the study by Ostojic (2006), footballers who took yohimbine for 21 days had a greater reduction in body fat percentage than the placebo group, with no changes in performance indicators.

However, these studies are small, short and conducted on specific groups, so their results should not be transferred to everyone. The mobilization of fatty acids by itself does not mean that they will be oxidized: without an energy deficit, fat may simply return to the depot.

For synephrine the data are even more modest. Individual small works recorded a slight increase in resting energy expenditure or fat oxidation during exercise, but many studies were conducted with multi-component products, and the contribution of synephrine specifically cannot be assessed separately.

So in both cases it is a matter of a small auxiliary effect, not an independent weight-loss agent. Yohimbine has somewhat more convincing data on fat mobilization, but, as we will see, a substantially narrower safety window.

Side Effects and the Safety Window

Yohimbine is known for its narrow therapeutic window: the difference between the dose that produces an effect and the dose that causes unpleasant or dangerous reactions is small. The review by Cimolai and Cimolai (2011) describes anxiety, panic attacks, tremor, tachycardia, increased blood pressure, insomnia, nausea, and with overdose — severe cardiovascular and neurological reactions that required emergency care.

Yohimbine is capable of provoking panic attacks in predisposed people — this property has even been used in studies of anxiety disorders. Therefore it is especially not recommended for people with anxiety conditions, bipolar disorder and post-traumatic stress disorder.

Synephrine, according to reviews by Stohs and colleagues, at doses from studies in healthy adults does not significantly increase pulse and blood pressure. At the same time side effects can occur when combined with caffeine and other stimulants, and in the literature there are reports of cardiovascular events against the background of multi-component products.

• Both substances should preferably not be combined with MAO inhibitors, antidepressants and other stimulants without the agreement of a physician.
• Both are contraindicated during pregnancy, breastfeeding and in adolescence.
• Yohimbine is additionally contraindicated in anxiety disorders and unstable blood pressure.

Supplement Quality and Regulatory Status

A serious problem of the yohimbine market is inaccurate labeling. Cohen and colleagues (2016) analyzed supplements sold in the United States and found that in many products the amount of yohimbine differed substantially from that stated, while some contained it in pharmaceutical quantities, whereas the label listed only bark extract. For a substance with a narrow safety window such uncertainty is especially dangerous.

In a number of European countries the circulation of yohimbine in food products and supplements is restricted or prohibited, while in some states yohimbine hydrochloride is dispensed as a medicine. Therefore availability and legality depend on the country.

Synephrine as part of bitter orange extract is legally sold in most countries as a supplement ingredient, although individual regulators set restrictions on its content or its combination with caffeine.

In sport neither yohimbine nor p-synephrine is included in the WADA Prohibited List; synephrine is included in the Monitoring Program. However, the risk of supplement contamination with undeclared stimulants remains, so athletes should choose products with independent certification.

Editorial Conclusions

Yohimbine and synephrine belong to the same category of «fat burners» only conditionally. Yohimbine is an antagonist of alpha-2 receptors that enhances noradrenaline release and shows itself best on an empty stomach; synephrine is a weak agonist of adrenergic receptors with a milder action.

Yohimbine has somewhat more convincing data on fat mobilization, but a significantly higher risk of anxiety, increased blood pressure and problems with product quality. Synephrine is safer, but its effect is mostly modest.

Neither substance replaces a calorie deficit and training, and the decision about taking them should be made taking into account one's state of health.

We recommend reading our materials on fasted cardio and lipolysis, on the comparison of yohimbine with caffeine, and on how to evaluate the composition of fat burners.

References

1. Galitzky J, Taouis M, Berlan M, et al. Alpha 2-antagonist compounds and lipid mobilization: evidence for a lipid mobilizing effect of oral yohimbine in healthy male volunteers. Eur J Clin Invest. 1988;18(6):587–594.
2. Ostojic SM. Yohimbine: the effects on body composition and exercise performance in soccer players. Res Sports Med. 2006;14(4):289–299.
3. Cimolai N, Cimolai T. Yohimbine use for physical enhancement and its potential toxicity. J Diet Suppl. 2011;8(4):346–354.
4. Cohen PA, Wang YH, Maller G, et al. Pharmaceutical quantities of yohimbine found in dietary supplements in the USA. Drug Test Anal. 2016;8(3–4):357–369.
5. Stohs SJ, Preuss HG, Shara M. A review of the receptor-binding properties of p-synephrine as related to its pharmacological effects. Oxid Med Cell Longev. 2011;2011:482973.
6. Stohs SJ, Preuss HG, Shara M. The safety of Citrus aurantium (bitter orange) and its primary protoalkaloid p-synephrine. Phytother Res. 2011;25(10):1421–1428.
7. World Anti-Doping Agency. Prohibited List та Monitoring Program. Montreal: WADA; актуальні редакції.