On Fentanyl, the Opioid Crisis, Psychedelics, and Cannabis Risk: A Q&A with Dr. Nora Volkow

Q&A With Nora Volkow, M.D.

Director of the National Institute on Drug Abuse (NIDA)

BBRF Scientific Council

Dr. Volkow, in a recent paper in the American Journal of Psychiatry, you and a co-author noted that the increased prevalence of more powerful opioids and drug mixtures in the illicit market has led to an unprecedented number of deaths and overdoses. When did this all start? What are the roots of this phenomenon? Why are opioids more powerful and more dangerous these days?

To be honest, I think it is a combination of innovation and greed. Innovation in terms of the ability to generate increasingly more powerful chemicals and the ability to synthesize them in ways that are quite simple, so that they can be synthesized rapidly without the need for advanced technologies. Greed, because manufacturing extremely potent synthetic opioids like fentanyl enables illegal drug manufacturers and dealers to maximize their profits.

Part of this, then, is the fact that it’s easier than ever to illegally manufacture extremely powerful synthetic opioids, much more potent than previously popular opioid drugs.

Yes, and the other part is that compounds like fentanyl also generate much greater returns on investments for drug dealers and manufacturers than heroin or cocaine. Those crop-derived drugs require cultivation, which is costly. And in the case of heroin, there is the extra step of extracting morphine from the crop and transforming it into heroin.

With fentanyl and other synthetic opioids, the combination of simple synthesis and the increased revenue from sales is driving widespread prevalence. A key point is that because fentanyl is so extraordinarily potent, you need to manufacture much smaller volumes of it. Also, most illicit drugs are brought into this country from abroad. It’s much easier to smuggle smaller volumes without being detected than bringing in pounds and pounds of drugs like cocaine or heroin.

Fentanyl is highly addictive. Many people initially get exposed to it, unknowingly, because it is mixed into other drugs, such as heroin. And because fentanyl is so potent, sometimes 50 times more potent than heroin, someone who uses fentanyl rapidly becomes tolerant to heroin (or other drugs) that don’t contain fentanyl. For such people, fentanyl-free heroin doesn't do the trick anymore. They then seek out increasingly more powerful drugs such as fentanyl or drugs laced with it.

Fentanyl, being an opioid, interacts with the endogenous opioid receptors found in large numbers all throughout the body, including the brain. So they're interacting with the same receptors as the "older opioids," right?

Correct. Exactly the same receptors. The differences rely on two factors. First, fentanyl is an incredibly potent drug. Meaning, you don’t need to use a lot of fentanyl to experience significant effects. A very small amount of fentanyl has a massive effect. In addition to potency, the second important factor is affinity. Some drugs bind with higher affinity to cellular receptors than others. When they bind with higher affinity, there is a greater probability that the drugs “stick” to the binding site. Fentanyl has both extremely high affinity for the receptors and extremely high intrinsic efficacy. So it activates, and it activates maximally. Other powerful drugs, such as heroin, do not have the same efficacy or affinity as fentanyl.

What is the half-life of fentanyl in the body compared to other opioids? In other words, does it linger?

Fentanyl has a relatively short half- life, around 60 minutes. But fentanyl accumulates in the fat tissues. So if you use fentanyl regularly, you end up having a “depot” of fentanyl in your body. And so when you take fentanyl [if you’ve taken it regularly], the effects are much longer lasting because you you’re not starting from zero. You're starting from a slow-release compartment, the fat “depot.”

The other characteristic that makes fentanyl so addictive is that it gets into the brain very rapidly. We just discussed how drugs may have higher or lower affinity for receptors and greater or lower potency. However, drugs also differ in the speed with which they get into the brain.

Fentanyl gets into the brain rapidly. The faster a drug gets into the brain, the more rewarding it is, and the quicker it is likely that someone may feel the untoward effects. Respiratory depression is an effect of opioid use, and in the case of fentanyl it appears extremely fast. This is challenging because even though we have a medication that's very effective for reversing overdoses—naloxone (marketed as Narcan)—we need to administer it much faster for fentanyl than for heroin. The window for saving the overdosed person is much shorter than with heroin. You have to intervene right away.

Stimulation of one class of endogenous opioid receptors— mu-opioid receptors—in cells in the brainstem inhibits breathing and is the mechanism that drives opioid overdoes.

Yes. And if you suspect someone has overdosed on fentanyl, and you give them naloxone, they may start breathing again and become conscious. However, multiple healthcare providers have documented that due to the “depot effect,” after a person becomes conscious, they may lose consciousness again and stop breathing. This is called re-narcotization. In other words: the beneficial effects of Narcan are shorter-lasting than the duration of the respiratory depressant effect of fentanyl. With less potent opioids naloxone can cover someone for 60 minutes. But someone with a depot supply of fentanyl can re-narcotize several times. In order to protect that person from overdosing, we need to give higher doses of naloxone or alternatively repeat the doses every 60 minutes. It's easier to repeat if you are in the ER or the hospital. However, if repeated doses are not possible, you want to give the person a higher dose of naloxone because it prolongs the concentration of naloxone in the blood.

What is NIDA’s priority regarding the crisis with high- potency opioids like fentanyl? You're not the federal drug enforcement agency, so arresting manufacturers or dealers is not your mission. But what can your agency do, and what are you trying to do with respect to the fentanyl, and more broadly, the opioid crisis?

First of all, NIDA needs to come up with tools and strategies for a person who gets exposed to fentanyl, knowingly or not. We need to discover interventions to reverse those overdoses.

We do research to develop tools like Narcan, and now we've also developed tools that can get into the brain faster than naloxone/Narcan and that can have a longer duration of effect. We need other strategies that stimulate respiration and medications that help people with substance use disorders control their cravings and withdrawal and can protect them from overdosing.

We are also developing therapeutics for addiction to cocaine, methamphetamine, and prescription drugs. People have a higher risk of overdosing because cocaine, methamphetamine, and illicitly manufactured prescription medications are being contaminated with fentanyl.

Protecting people goes beyond doing research on how to treat them. For example, say you have a young person who occasionally consumes simulant drugs to prepare for a college exam or uses medications for the reward, i.e., the “high,” and you want to protect them from overdosing. What types of interventions should one develop to prevent people who are at an extremely high risk of being contaminated with fentanyl from starting to take drugs—the kind of drugs that can kill them after a single exposure?

That’s one avenue of research. There are other areas of research about how to deploy interventions that we know work. Medications that treat opioid addiction and overdose, although effective, are often not being given to people who actually need them. Our research looks into how we can change that.

The medicines that treat opioid use disorder have been around, the three very effective ones— methadone, buprenorphine and naltrexone—for a long time. But the percentage of people who seek treatment themselves is extremely low, less than 20%. So this is a real social problem.

The drugs work, but there are many impediments to people seeking treatment. There is just a tremendous stigma against people who take drugs. If I am a person taking drugs and I'm mistreated when I go to my provider, I’m not going to bring it up.

But there are other issues around the medications we use to treat opioid addiction. You've heard it many times—the incorrect idea that “methadone is just exchanging one [opioid] drug for another.” That's an incorrect, yet common, belief. There are many programs, like Narcotics Anonymous, that provide help to people, but many of these programs are unwilling to accept someone who is being treated with methadone or buprenorphine. These issues interfere with the proper deployment of therapeutics.

Another aspect that makes addiction a stigmatized condition is that many psychiatrists or other healthcare providers don't want to treat people with opioid addiction because the reimbursement that they get is not sufficient.

Why is someone treating Alzheimer's getting a higher reimbursement than someone treating addiction? This is not justified by the level of clinician involvement. That's why I say stigma plays an extremely important role, and the stigma also has driven the lack of priority given to education in healthcare systems. Whether you are in medical school or in nursing or in other specialties, addiction is not deemed to be a condition that is the responsibility of healthcare providers. So healthcare professionals are not prepared for it or not prepared to do it.

Again, knowing this, what is NIDA’s approach?

What do we do as an agency is to fund research documenting the benefits of education and treatment. We seek to provide evidence that employing and engaging nurses, emergency department physicians, infectious disease doctors, primary care physicians, has specific benefits. We have also been extremely proactive on doing research on how addiction and overdose brings justice settings into the picture.

Recently, evidence from research has started to change the culture, as we see more of those in the justice system willing and open to consider treatments. The research has shown it's very effective. The rise of telehealth has made it easier, for example, to deliver treatments in jails and prisons, which in the past was not possible because of the lack of in-person clinicians.

One other component I want to highlight is prevention.

I always ask: why are we in the current situation? What has made us so vulnerable as a country that we're taking these drugs? Why is it that we have such a big problem with drugs in the United States?

This is a key question that we need to ask ourselves. Then we can target prevention to address that vulnerability.

This gets at the classic [2015] paper by Case and Deaton about the “deaths of despair” in America, many of which are deaths due to opioid misuse and overdose.

I suppose it's so much larger than the question of science alone. It goes far beyond science into the social fabric and how people feel about their lives.

But we need to tackle it! It's part of the science in my view. We now have tools that allow us to start to address the questions that we’ve known all along. For example, we know in the field of addiction that individuals who have had adverse childhood experiences are at much higher risk of developing addiction. What are these adverse childhood experiences doing to the human brain and physiological organs that ultimately drive these behaviors?

Also, it is possible to study how discrimination, neglect, poverty, and other socioeconomic factors affect the brain throughout the lifespan, most importantly in the transition from childhood into adulthood. What are these structural factors that influence our brains and our wellbeing?

Many BBRF grants are exploring this really important question of what happens to the brain when a child is abused or neglected or exposed to violence—these terrible things that clearly perturb brain biology.

They do perturb brain biology. Researchers are starting to identify how impactful these factors are in brain development. Among the areas of research, for example, it has become clear how underrepresented groups that have been discriminated against, like Black Americans or Native Americans, are negatively influenced by the social determinants of health.

So we've generated a system that is putting underrepresented groups at a tremendous disadvantage that starts to impact their brain development. We're focusing on brain, but I'm sure that other NIH Institutes are addressing the issues in the heart and the immune system, and other parts of the body.

In a “Viewpoint” article for JAMA Psychiatry this past October, you and Dr. Josh Gordon, the Director of the National Institute of Mental Health and a fellow BBRF Scientific Council member and former grantee, wrote about the prospect of psychedelics as therapeutics for psychiatric disorders.

In that piece you wrote that “it is clear that psychedelics are not wonder drugs,” and noted that “the hype has gotten ahead of the science.” You say that this is reminiscent of what happened with medical cannabis.

Yes, there is a similarity in the response to renewed interest in psychedelics to treat psychiatric disorders. We love fairy tales. We all want happy endings.

The hype comes from two sides. As an investor you say, "This looks very promising." And you want to get ahead of the curve. Your cognitive appraisal will go toward exaggerating and believing the positives more than the negatives. We all do that.

If you are a patient, you're going to gravitate toward stories that tell you that there is a solution. We all have the cognitive dissonance that if we see something that is potentially desirable, like a treatment that could be a cure, our cognitive ability shuts down the critical aspects of cognition.

When you put together the opportunity for investors to make money, the desperation of patients, and the lack of regulation of how these messages are communicated, you generate the hype we are observing right now. Just as we saw for medical cannabis, we see a lot of people exposing themselves to treatments with psychedelics for which there is at present no conclusive evidence.

For the benefit of our readers: in your "Viewpoint" article you and Dr. Gordon note that one important research question that needs to be explored is whether the positive subjective experiences that some people report with psychedelic drug use “are intrinsic to or separable from” the putative therapeutic effects of these drugs. Does the benefit, when there is one, come from the drug or the talk therapy that follows the experience? How are the two related? You also note the need to study the “contextual factors” which may impact people’s experiences. There is as yet “no standard protocol” for administration of drugs such as psilocybin, yet it is widely thought that support during a psychedelic drug experience may have a great deal to do with what someone who uses these drugs may gain afterward from the experience.

Our position has been that right now, there is not sufficient evidence to show that psychedelics are beneficial. On the other hand, there may be evidence—depending on the condition—that other [non-psychedelic] medications are beneficial. It makes sense to actually opt for a therapeutic that is shown to work as opposed to one for which there is a lot of hype.

We are the evidence-based agency. We're funding researchers to evaluate the potential benefits, for example, that psilocybin may have for the treatment of depression or addiction. Or the potential that MDMA may have for the treatment of PTSD.

The same applies to cannabis. We are predominantly funding research as it relates to its potential benefits for pain and addiction. Other NIH Institutes hopefully are going to start funding more research as it pertains to other reasons why people are using it.

In recent years we have reported on a number of papers, including one that you and others published this past May in Psychological Medicine. In that paper you showed that in a sample of nearly 7 million people born in Denmark in the last 50 years, young males “might be particularly susceptible to the effects of cannabis.” You estimated that one-fifth of over 45,000 schizophrenia cases among young males in that sample of 7 million people might have been prevented if those who did develop schizophrenia had not had cannabis use disorder.

How worried are you about this?

I'm definitely worried because the concern is that more and more people are using cannabis. Cannabis use in young people has been pretty stable. Regular use in the U.S. is close to 6%. (“Regular use” means almost every day.) But the transition period from adolescence to adulthood is one of a very high rate of use of cannabis. And in that transition, we're seeing what appear to be very negative effects. One that has attracted a lot of attention for many decades is schizophrenia-related psychosis.

The other thing we need to keep our eye on is that in people with suicidal behaviors, the prevalence of cannabis use is much higher than in those that without suicidal behaviors. Independent studies show that there appears to be a higher association of suicidal thinking and behaviors among people that consume cannabis, and it's even higher among those with cannabis use disorder.

This doesn't mean that there is a causal linkage. But the association is there, and it's strong. We need to determine if people are using cannabis to medicate suicidal thinking or whether cannabis could trigger suicidal behaviors. We need to understand those dynamics. NIDA and others have a mission to research these important questions.

Interview By Peter Tarr, Ph.D.

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