Why is Fentanyl so Dangerous?

image of vial with fentanyl label

The Drug Enforcement Agency (DEA) has a simple answer to the question many people ask themselves when they read about the opioid crisiswhy is fentanyl so dangerous – which they’ve shared far and wide for the past several years:

One Pill Can Kill

While that statement from the DEA appears, at first blush, like an exaggeration designed to scare people away from fentanyl and illegal drugs in general, it is absolutely not an exaggeration. Yes, it’s meant to scare people away from fentanyl, and for good reason: one pill really can kill.


Here are the facts on the drug. According to the DEA, fentanyl is:

  • 50 times more powerful than heroin
  • 100 times more powerful than morphine
  • Strong enough to cause death with a dose only 2 milligrams (mg)

To put that last bullet point into perspective, consider these facts:

  • A pinch of salt contains 150-300 mg
  • 2 mg of fentanyl looks roughly like a sprinkle of powdered sugar
  • 2 mg of fentanyl takes up less space than the exposed lead at the end of a pencil

In addition, the DEA warns people that international drug traffickers use illegal pills to manufacture millions off counterfeit pills every year, then distribute the pills to street-level dealers, who sell them as real – but diverted – prescription medication. Traffickers design the pills to look like common medications such as Adderall, Xanax, Vicodin, Percocet, Oxycontin, and various other prescription medications, and sell them both in person and through online sources which makes them easily accessible to anyone with an internet connection.

To learn more about fentanyl from the Centers for Disease Control (CDC) and the DEA, please download these fact sheets:

CDC Fentanyl Fact Sheet

DEA Fentanyl Fact Sheet

Now we’ll share new information, based on a research effort conducted in Switzerland, that offers insight about why fentanyl is so dangerous.

Fentanyl Acts on More Areas of the Brain Than Previously Thought

The fundamental brain processes that lead to the disordered use of substances, such as alcohol use disorder (AUD) or opioid use disorder (OUD) involve what we call the reward network in our brain, also known as the mesolimbic system. Here’s how research published by the National Institutes of Health (NIH) describe the reward system:

“Reward is a natural process during which the brain associates diverse stimuli, [including] substances, situations, events, or activities with a positive or desirable outcome. This results in adjustments of an individual’s behavior, ultimately leading them to search for that particular positive stimulus.”

That’s the positive reinforcement component of the disordered use of substances. The second part of the puzzle revolves around negative reinforcement. Ingesting opioids causes euphoria. However, after an individual develops a physical dependence on a substance and then stops taking the substance, what happens is something most of us know about: withdrawal.

Withdrawal is characterized by uncomfortable physical, psychological, and emotional components. Physical aspects of withdrawal include nausea, chills, sweating, gastrointestinal pain/distress, high blood pressure, muscle/joint pain, and elevated heart rate. Psychological and emotional components of withdrawal include agitation, restlessness, intense cravings for opioids, insomnia, and anxiety.

When a person continues to take opioids to avoid experiencing withdrawal symptoms, that’s the negative reinforcement component of the disordered use of substances.

This new research offers important new information on the positive and negative reinforcement components of addiction. The study authors, in the paper “Distinct µ-Opioid Ensembles Trigger Positive and Negative Fentanyl Reinforcement,” describe the concept behind their research:

“Until now, it was thought that the mechanisms of both positive and negative reinforcements takes place in the same brain area, the mesolimbic system. Conversely, our hypothesis suggests that the origin of negative reinforcement is to be found in cells that express the mu receptor elsewhere in the brain.”

Let’s learn more about what they mean.

The Reward System and the Fear/Anxiety System

Opioid medications and illicit opioids attach to specific receptors in the nervous system in the human body, called mu opioid receptors.

These receptors are common in the mesolimbic system, specifically in the ventral tegmental area (VTA). Researchers know receptors in this area are related to positive reinforcement, because when they eliminated those cells in lab animals, the animals no longer sought opioids in behavioral experiments.

The research team identified a group of brain cells in another brain region, the central amygdala (CeA), that also express mu opioid receptors. This was new information for neuroscientists. What they learned next was more important than that discovery, though. When they eliminated those cells in the CeA in lab animals, the animals no longer showed symptoms of opioid withdrawal in behavioral experiments.

Why is that an important discovery, and how does that help us understand why fentanyl is so dangerous?

Because the central amygdala is the brain area associated with feelings of anxiety and fear.

Therefore, fentanyl – and other opioids – carry a one-two punch that we previously didn’t understand completely. Positive reinforcement originates in the VTA, and negative reinforcement originates in the CeA. We can now say that one reason fentanyl and opioids are so dangerous is because they act on more brain areas than we previously thought.

How Does This Help Us Help People With Fentanyl Addiction?

The current gold-standard treatment for opioid use disorder (OUD) – which includes fentanyl addiction – is medication-assisted treatment (MAT). This approach uses medications directed at mu opioid receptors in the reward system of the brain. This new research indicates that a significant driver of ongoing addiction is the fear/anxiety system in the brain. Here’s how a press release from the University of Geneva, where the research was conducted, describe the results:

“These discoveries will make it possible to refine substitution treatments and advance research into analgesics without addiction liability.”

In plain language, this new knowledge on how opioids act in the brain may help us – in years to come – develop MAT approaches with medications that target brain areas like the VTA not previously implicated in addiction or withdrawal, and help us develop new, non-opioid pain medications that are less likely to involve risk of misuse, disordered use, and addiction.

Keep an eye on this blog for any new information on this topic. As soon as we learn anything new, we’ll report it here.

The materials provided on the Pinnacle Blog are for information and educational purposes only. No behavioral health or any other professional services are provided through the Blog and the information obtained through the Blog is not a substitute for consultation with a qualified health professional. If you are in need of medical or behavioral health treatment, please contact a qualified health professional directly, and if you are in need of emergency help, please go to your nearest emergency room or dial 911.