Summary: Researchers report Yohimbine, a dietary supplement derived from tree bark, shows potential in the treatment of sleep apnea, especially for those with anxiety disorders and high blood pressure.
Obstructive sleep apnea, which causes people to briefly stop breathing while asleep, affects an estimated 5 percent of the population, not including the many more who don’t even realize they suffer from the disorder.
Patients are sometimes treated with a machine that blows air into the patient’s airway through a face mask, but no drug treatments exist. In an advance that may change that, MIT researchers have discovered that a dietary supplement called yohimbine reverses the root cause of obstructive sleep apnea in an animal model.
Yohimbine, a chemical derived from the bark of the African yohimbe tree, has a long history of use by humans as an aphrodisiac, and more recently it has been used by bodybuilders to burn fat. It is not FDA-approved for any of these uses, however. Chi-Sang Poon, a principal research scientist at MIT’s Institute for Medical Engineering and Science (IMES), says that while the results of the obstructive sleep apnea study are promising, people should not begin taking the drug on their own, especially those who also suffer from heart disease, high blood pressure, or anxiety disorders.
“People who have these problems could be at risk if they use yohimbine,” says Poon, the senior author of the study. “Before clinical trials are done, it is not advisable for the general public to try this on their own.”
Gang Song, an IMES research scientist, is lead author of the paper, which appears in the Feb. 23 issue of the journal JCI Insight.
“Back to normal”
Obstructive sleep apnea is caused by a narrowing of the airway that cuts off breathing, and people who are obese are at higher risk for the disorder. This closing of the airway often occurs during sleep, especially REM sleep, when most of the body’s muscles are relaxed, including the tongue. If the tongue falls back into an already narrow airway, it can cut off the flow of air.
The most effective treatment is a device known as a continuous positive airway pressure (CPAP) machine, which delivers a stream of compressed air into the airway to prevent it from closing.
“It works very well, but the problem is everybody hates it,” Poon says. “It’s very uncomfortable and inconvenient. Almost half of the people prescribed never use it.”
Because of this, many scientists have been trying to develop a drug treatment for obstructive sleep apnea, which would be easier for patients to tolerate. One drug target that researchers have sought to exploit is the hypoglossal nerve, which controls the tongue. Scientists had hoped that stimulating this nerve during sleep would help prevent the tongue from falling back, but none of the drugs they have tried have been successful.
The MIT team decided to take a different approach. Previous research had suggested that the hypoglossal neurons that control the tongue are stimulated by a part of the brain known as the pons, located in the brain stem. Two particular groups of neurons in the pons, known as A5 and A7, had been thought to contribute to hypoglossal neuron activation. In experiments performed on rats, the MIT team found that obstructive apnea that is artificially imposed while the animals are not asleep can actually make this A5 and A7 activation of hypoglossal neurons become even stronger, and stay strong long afterward.
“It is as though these neurons can ‘learn’ from the obstructive apnea experience and remain vigilant against it later,” Poon says.
The activity of A5 and A7 usually drops dramatically during sleep, especially REM sleep, and that’s where the problem begins. “It is as if these cells become sleepy and ‘forget’ to do their job,” Poon says, so the researchers sought to find a way to re-activate these neuron groups. They decided to try yohimbine, which is known to inhibit norepinephrine receptors found on these cells that constrain their excitation of hypoglossal neurons. This approach was counterintuitive, Poon says, because the cells’ activity is already suppressed during sleep, and blocking these receptors would be like beating a dead horse.
However, no one had ever actually tried that, and Poon decided to take a chance and see what would happen. Through a mechanism not fully known yet, the researchers found that yohimbine treatment targeting A5 and A7 surprisingly stimulated the hypoglossal neurons and restored their vigilance against obstructive sleep apnea in rats.
“It worked wonders,” Poon says. “Everything seemed to get back to normal again.”
“A centuries-old drug”
The researchers are now hoping to work with pharmaceutical companies to refine the drug and begin tests in patients. Determining effective and safe dosage levels will be a critical step, says Poon, who cautions against anyone trying the drug on their own.
“Yohimbine is a centuries-old drug that people have been using for other reasons,” he says. “The drug itself is relatively safe in healthy subjects, but in patients that have heart disease, hypertension, or stroke, or have anxiety problems, they could be at risk because nobody has done long-term studies to show how safe the drug is for these patients.”
Funding: The research was funded by the National Institutes of Health.
Source: Anne Trafton – MIT
Image Source: NeuroscienceNews.com image is credited to MIT News.
Original Research: Full open access research for “α2-Adrenergic blockade rescues hypoglossal motor defense against obstructive sleep apnea” by Gang Song and Chi-Sang Poon in JCI Insight. Published online February 23 2017 doi:10.1172/jci.insight.91456
α2-Adrenergic blockade rescues hypoglossal motor defense against obstructive sleep apnea
Decreased noradrenergic excitation of hypoglossal motoneurons during sleep causing hypotonia of pharyngeal dilator muscles is a major contributor to the pathogenesis of obstructive sleep apnea (OSA), a widespread disease for which treatment options are limited. Previous OSA drug candidates targeting various excitatory/inhibitory receptors on hypoglossal motoneurons have proved unviable in reactivating these neurons, particularly during rapid-eye-movement (REM) sleep. To identify a viable drug target, we show that the repurposed α2-adrenergic antagonist yohimbine potently reversed the depressant effect of REM sleep on baseline hypoglossal motoneuron activity (a first-line motor defense against OSA) in rats. Remarkably, yohimbine also restored the obstructive apnea–induced long-term facilitation of hypoglossal motoneuron activity (hLTF), a much-neglected form of noradrenergic-dependent neuroplasticity that could provide a second-line motor defense against OSA but was also depressed during REM sleep. Corroborating immunohistologic, optogenetic, and pharmacologic evidence confirmed that yohimbine’s beneficial effects on baseline hypoglossal motoneuron activity and hLTF were mediated mainly through activation of pontine A7 and A5 noradrenergic neurons. Our results suggest a 2-tier (impaired first- and second-line motor defense) mechanism of noradrenergic-dependent pathogenesis of OSA and a promising pharmacotherapy for rescuing both these intrinsic defenses against OSA through disinhibition of A7 and A5 neurons by α2-adrenergic blockade.
“α2-Adrenergic blockade rescues hypoglossal motor defense against obstructive sleep apnea” by Gang Song and Chi-Sang Poon in JCI Insight. Published online February 23 2017 doi:10.1172/jci.insight.91456
Yohimbe (Corynanthe yohimbe ) is an herb derived from the bark of the yohimbe tree found primarily in the West African nations of Cameroon, Gabon, and Zaire. The major active constituent of the bark is yohimbine. In prescription doses, the active ingredient is yohimbine hydrochloride.
Yohimbe has been used for centuries in African folk medicine to treat fevers, leprosy, coughs, and as a local anesthetic. But its most popular use has been as an aphrodisiac and a mild hallucinogen. It has been widely used in Europe for about 75 years to treat male erectile dysfunction, formerly called impotence . The U. S. Food and Drug Administration (FDA) approved yohimbe as a treatment for impotence in the late 1980s. It is sold as an over-the-counter dietary supplement and as a prescription drug under brand names such as Yocon, Aphrodyne, Erex, Yohimex, Testomar, Yohimbe, and Yovital.
There is no clear medical research that indicates exactly how or why yohimbe works in treating impotence. It is generally believed that yohimbe dilates blood vessels and stimulates blood flow to the penis, causing an erection. It also prevents blood from flowing out of the penis during an erection. It may also act on the central nervous system, specifically the lower spinal cord area where sexual signals are transmitted. Studies show it is effective in 30-40% of men with impotence. It is primarily effective in men with impotence caused by vascular, psychogenic, or diabetic problems. It usually does not work in men whose impotence is caused by organic nerve damage. In men without erectile dysfunction, yohimbe in some cases appears to increase sexual stamina and prolong erections.
Yohimbe is also used for weight loss, although not to the extent it is used for treating impotence. Some alternative health practitioners believe it is more effective and safer than the stimulant ephedra (also known as ma huang ) in achieving weight loss. Yohimbe is often prescribed for weight loss by natural health practitioners at Bastyr University in Kenmore, Washington. “It’s my number one choice for weight loss,” Lise Alschuler, medical director of the school’s natural health clinic, said in a January 1998 article in Vegetarian Times. “I prescribe it in very small doses and slowly increase intake while monitoring patients’ tolerance levels.” Dosing starts at 1 mg of yohimbine three times a day.
A 1994 study by the Eastern Virginia Medical School also found yohimbine may be effective in treating narcolepsy . While the study involved only eight people with the sleep disorder, seven of them given yohimbine were able to stay awake for an eight-hour work day. The researchers believe yohimbine works by counteracting the brain chemistry that causes narcolepsy, and remains effective even after a few weeks of regular use.
The usual dosage of yohimbine extract to treat erectile dysfunction is 5.4 milligrams (mg) three times a day. It may take three to six weeks for it to take effect. In the event of side effects, dosage is usually reduced to one-half a tablet three times a day, then gradually increased to one tablet three times a day. Prescription yohimbe containing yohimbine is standardized at 5.4 mg per tablet. The retail price for a name brand yohimbe is generally $18-36 for 30 tablets. A generic prescription for yohimbine is about $6-12 for 30 tablets. Most yohimbe sold over the counter is in tablet or capsule form and contains 500-1,000 mg of yohimbe bark, and contains only a small percentage of the active ingredient yohimbine. The strength of yohimbe bark extract sold over the counter varies greatly and may not be a reliable source of yohimbine. A 1995 study by the FDA looked at 26 over-the-counter yohimbe products and did not find any that had enough yohimbine to effectively treat erectile dysfunction. Yohimbe bark extract is also sold over the counter in combination with other herbs and dietary supplements. The best way to ensure that a patient is getting enough active ingredient to treat erectile dysfunction is to ask a physician for a prescription yohimbe product.
Since yohimbe can cause confusion, dizziness , and disorientation, it should not be taken while operating machinery, driving, or performing hazardous activities. It should not be taken by people with chronic health problems, such as heart, liver, or kidney disease, diabetes, glaucoma, hypertension (high blood pressure), or mental illness. Children, women, or men with prostate problems should not use yohimbe. Persons should consult their physician or health care practitioner before they start taking yohimbe.
There can be several serious side effects associated with yohimbe. An allergic reaction is possible with symptoms such as difficulty breathing, throat constriction, hives , and swelling of the face, lips, or tongue. It can also cause an irregular or rapid heartbeat, and disorientation. Minor side effects can include dizziness, anxiety , shaking, headaches, skin flushing, and irritability.
Yohimbe is also reported to have produced hallucinogenic properties in some people. The effects have been compared to the drug LSD and can last from two to four hours. These effects include audio and visual hallucinations, and feelings of euphoria. They usually occur when yohimbe is taken in higher than recommended doses.
Yohimbe should not be used by people who are taking tranquilizers, antidepressants, sedatives, antihistamines, amphetamines or other stimulants, including caffeine . Since yohimbe is a short-term monoamine oxidase (MAO) inhibitor, it should not be taken with hypertension medication. It should not be taken with food or drink that contains high amounts of tyramine, such as wine, beer, cheese, cured meats, dried fish, bananas, red plumbs, oranges, dried fruit, avocado, tomato, eggplant, and soy sauce. Doing so can cause a rise in blood pressure. Yohimbe should not be used with other prescription erectile dysfunction drugs, such as Viagra.