Xylazine has been found to be adulterating pills in America, and doctors will need to understand this new threat. First, xylazine is not “krokodil,” although it produces somewhat similar-looking skin ulcers.  Krokodil is a pseudonym for desomorphine, which is created from a precursor chemical called alpha-chlorocodide. Desomorphine is dihydrodesoxymorphine and was developed in Germany in 1932. It is a very fast but short-acting, semi-synthetic opioid used mainly in Russia.  Xylazine is completely different.

Xylazine was developed as an antihypertensive in 1962. In Germany again. It is not an opioid and is not based on the morphine molecule, but it does, in some studies, seem to bind the kappa-opiate receptor weakly. Xylazine is a near tricyclic, with a gap left in the middle ring. It is frequently mixed with other drugs like opiates to enhance their effects or with cocaine to ameliorate some of that drug’s more unpleasant effects. It has even been found in THC e-cigarettes in the United Kingdom.

So, how does Xylazine work? Once taken orally, xylazine spreads throughout the body in about half an hour, where it acts as an alpha-2  adrenergic agonist.  We usually think of adrenergic agonists as increasing alertness and blood pressure, but it’s more complicated than that. Because xylazine works on alpha-2 receptors, it has a paradoxical effect. It actually suppresses the release of these catecholamines, which was confusing to me.

Alpha-2 adrenergic receptors or adrenoreceptors are found in both the peripheral and central nervous system on both pre- and post-synaptic neurons and are usually activated by norepinephrine and epinephrine.  When the presynaptic alpha-2 neurons are activated, norepinephrine release onto the postsynaptic neuron where alpha-1 receptors reside is inhibited, reducing the activity of the post-synaptic neuron.  This prevents a “runaway” effect from these stimulatory neurotransmitters.

The effect is often referred to as sympatholytic, which means it reduces or blocks the sympathetic nervous system response, creating hypotension, bradycardia, sedation, analgesia, and muscle relaxation. Activation of alpha-2 adrenergic receptors also inhibits the release of other neurotransmitters, including glutamate, the major excitatory neurotransmitter in the brain, enhancing its overall sedative effect.

Medications with similar actions include tricyclic antidepressants (like trazodone),  phenothiazines (promethazine), and clonidine. Especially clonidine, which is also an alpha-2 agonist and is very similar to xylazine. There are three types of alpha-2 adrenoreceptors: a, b, and c.  Alpha-2a and 2c are in the locus ceruleus, and activating them shuts off norepinephrine in that area, creating the sedative effect. While in the dorsal horn of the spinal cord, alpha-2a, and c activation produces an analgesic effect.

The alpha-2b type is found in the smooth muscles of blood vessels, controlling blood pressure by vasodilation. Xylazine activates alpha-2 over alpha-1 by a factor of 160x. The selectivity for the subtypes of alpha-2 is still being worked out, but we do know that the activation of alpha-2b receptors in the skin, especially in an area of injection, causes vasoconstriction, which can lead to ischemia, leading to the pathognomonic skin ulcers.

These can occur from any administration of the drug and do not require skin injection to manifest but almost always occur with subcutaneous injection. Rapid and repeated use of xylazine at very high doses, in animals and humans, seems to exhaust the hypotensive action, creating a rebound hypertensive emergency.  This is something to be aware of as more Americans are unknowingly being poisoned by this drug every day and are at high risk of dying.

I stress poisoning because it’s important to remember that these are not “overdoses” as we usually think of them, as people do not know which “oxycodone” pills have been adulterated.  According to a CDC report, the rate of deaths involving xylazine has increased by 35x. I emphasize involvement because it does not mean there is a proven cause and effect.  Just because something is present doesn’t mean it was responsible for the death.

Multidrug intoxications are notoriously hard to treat, especially now with this new combination of fentanyl and xylazine. That’s because some medications work synergistically to multiply their effect rather than just being additive. Physicians can use this to reduce the overall dose of any one medicine in a practice called rational polypharmacy. In rational polypharmacy, we combine two medications that we know will amplify each other at lower doses to avoid the side effects associated with high-dose therapy.

It can also be used by illicit drug factories to create more potent combinations. That is what is happening with fentanyl and xylazine. In 2018, in the entire United States, there were only 102 deaths where xylazine was found with fentanyl. By 2021that became 3,468 and we should expect it to become more common. When 1,176 counterfeit pills were evaluated, most of them fell into three categories: Oxycodone (686 pills), alprazolam (brand name Xanax, 312 pills), and amphetamines (174 pills).

Terrifyingly, the laboratory analysis showed that almost all the counterfeit oxycodone pills seized in 2022 contained fentanyl.  Fentanyl was also detected in 2.6 percent of the Xanax pills.  None of the amphetamine pills contained fentanyl.  Xylazine was also found in almost all of the fake oxycodone pills. Out of 137 pills containing xylazine, 135 (98.5 percent) were counterfeit oxycodone while xylazine was detected with fentanyl in 136 of 137 pills.”

Dr. Kimberly Sue, an addiction medicine doctor at Yale Medicine in New Haven, Conn., said that “… for the majority of people, they don’t know they’re using it and they don’t intend to be using it …” Another complication is that xylazine does not respond to Narcan (naloxone), which is finally being made somewhat available about three decades later than it should have. This could dramatically limit EMT and ER treatments when patients are found alive.

The combination of fentanyl with a new drug that cannot be treated with Narcan added to a medical environment where patients are abandoned after the DEA locks up their doctors for daring to try to treat pain and addiction, is a perfect storm for even more deaths. But it is worse than that. Xylazine alters mRNA expression of protein phosphorylating AMPK signaling molecules, which could cause persistent changes in the brain.

A study from 2022 found a critical role for AMPK in addiction, specifically to cocaine, through actions in the motivation and reinforcement center, the nucleus accumbens. Finding that “AMPK-CRTC1 signaling regulates cocaine reinforcement and motivation.” This could imply that xylazine, when added to any habit-forming substance, could potentiate the risk of developing a full addiction, dramatically increasing the dangers of its use.

But all is not lost. A vaccine has been developed by researchers at Scripps Research in La Jolla, California. This could be used after a non-fatal overdose to guard against the effects of relapse.  Can we make more of these vaccines? They have one for cocaine. Of at least one thing, I am sure. Addiction is more complicated than politicians would lead you to believe, and we need more doctors willing to try to help these patients, not fewer.

L. Joseph Parker is a distinguished professional with a diverse and accomplished career spanning the fields of science, military service, and medical practice. He currently serves as the chief science officer and operations officer, Advanced Research Concepts LLC, a pioneering company dedicated to propelling humanity into the realms of space exploration. At Advanced Research Concepts LLC, Dr. Parker leads a team of experts committed to developing innovative solutions for the complex challenges of space travel, including space transportation, energy storage, radiation shielding, artificial gravity, and space-related medical issues. 

He can be reached on LinkedIn and YouTube.