From the Editor

Is xylazine the new fentanyl?

In the first selection, Dr. Rahul Gupta (of the University of Pennsylvania), who serves as the US Director of National Drug Control Policy, and his co-authors write about xylazine in The New England Journal of Medicine. They describe the emergence of this medication, intended for veterinarian uses, as a substance of abuse. They note its presentation and ask research questions. “Our goal is for the designation of xylazine as an emerging threat and subsequent actions to begin to address this threat before it worsens and undermines efforts to reduce illicit fentanyl use in the United States.” We consider the paper and its implications.

In the second selection, from JAMA Psychiatry, Viktoriya L. Nikolova (of King’s College London) and her co-authors look at probiotics – an area of increasing interest for those with mood and anxiety problems. They report on the findings of a small RCT involving people with depression who took an antidepressant but had an incomplete response. “The acceptability, tolerability, and estimated effect sizes on key clinical outcomes are promising and encourage further investigation of probiotics as add-on treatment for people with MDD in a definitive efficacy trial.”

And in the third selection, Charles Fain Lehman (of the Manhattan Institute) comments on the new drug crisis in a long essay for National Affairs. Lehman notes the rise of the synthetic agents (think fentanyl replacing heroin) and its impact on people, particularly in terms of overdoses. “Today’s drug cycle is different from previous ones, measured not just in the number of people addicted, but the number dead. Reducing the growth of that figure, now more than ever, is a vital task for policymakers to undertake.”


Selection 1: “Xylazine – Medical and Public Health Imperatives”

Rahul Gupta, David R. Holtgrave, Michael A. Ashburn

The New England Journal of Medicine, 15 June 2023

Increasing use of xylazine, most often in combination with other drugs such as fentanyl, is a rapidly growing threat to human health in the United States. Xylazine is an α2-agonist in the same drug class as clonidine, lofexidine, and dexmedetomidine. It was initially studied for use in humans as an antihypertensive agent, but development for human use was discontinued because of adverse effects. Xylazine was approved by the Food and Drug Administration for use as a sedative in veterinary medicine in 1972 but isn’t approved for use in humans.

So begins a paper by Gupta et al.

They note the rise of this new substance, with first reports of use in Puerto Rico in 2001. “Xylazine appears to have entered the illicit drug supply in the northeastern United States as an additive to fentanyl.” They discuss the types of use: “It can be consumed orally or by smoking, snorting, or intramuscular, subcutaneous, or intravenous injection. The drug’s reported duration of effect is longer than that of fentanyl; adulteration of fentanyl with xylazine therefore probably enhances the euphoria and analgesia induced by fentanyl and reduces the frequency of injections.”

The authors observe its growing popularity. “Xylazine was found in more than 90% of illicit drug samples tested in Philadelphia in 2021 and was identified in forensic toxicology samples from 36 of 49 states that were tested in June 2021. As of March 2023, fentanyl mixed with xylazine had been found in drug seizures in 48 states.”

They discuss the presentation. “Patients presenting with xylazine intoxication may have central nervous system depression, hypotension, and bradycardia. Clinicians may not recognize the contribution of xylazine to a person’s symptoms, since many aren’t aware of growing use and rapid point-of-care testing for xylazine isn’t widely available. Respiratory depression has been reported in people using xylazine, probably because the drug increases the risk of opioid-induced respiratory depression. Naloxone can reverse opioid-induced respiratory depression but doesn’t reverse the effects of xylazine.”  They also note the effects on skin. “In addition to its acute effects, xylazine is associated with severe necrotic skin ulcerations…”

How to treat withdrawal? “Limited data are available to guide clinical decision making related to the treatment of xylazine withdrawal in inpatient settings. Some institutions are exploring the use of dexmedetomidine infusions for xylazine-withdrawal symptoms in the intensive care unit, whereas others are exploring the use of clonidine and lofexidine in inpatient units.” 

They close with a call for action. “There is an urgent need for more robust evidence on treatment options for acute xylazine intoxication, management of withdrawal symptoms, wound care, and long-term management of xylazine-related substance use disorder.”

A few thoughts:

1. This is a concise and readable paper.

2. Xylazine appears to be used in combinations of substances, creating highly addictive cocktails. 

3. The paper focuses on the United States. A recent Health Canada paper suggests problems here, too. And, as seen in the US, xylazine is often mixed with other drugs: “79% of exhibits containing Xylazine contained 2 to 4 other substances…” That paper can be found here:

4. We seem to have entered into a new era of substance disorders with the rise of the synthetic substances. For a careful consideration of this, please see Selection 3.

The NEJM Perspective can be found here:

Selection 2: “Acceptability, Tolerability, and Estimates of Putative Treatment Effects of Probiotics as Adjunctive Treatment in Patients With Depression: A Randomized Clinical Trial”

Viktoriya L. Nikolova, Anthony J. Cleare, Allan H. Young, et al.

JAMA Psychiatry, 14 June 2023  Online First

Approximately 60% of people with major depressive disorder (MDD) experience some degree of nonresponse to first-line treatments, and approximately one-third continue to experience symptoms despite further treatment. Increasing understanding of the involvement of the microbiota-gut-brain axis in the pathophysiology of MDD has made it a promising target for novel treatments, such as probiotics.

So begins a Brief Report by Nikolova et al.

Here’s what they did:

  • “In this single-center, double-blind, placebo-controlled pilot randomized clinical trial, adults aged 18 to 55 years with MDD taking antidepressant medication but having an incomplete response were studied.” 
  • “A random sample was recruited from primary and secondary care services and general advertising in London, United Kingdom.”
  • The intervention: “Multistrain probiotic (8 billion colony-forming units per day) or placebo daily for 8 weeks added to ongoing antidepressant medication.”
  • “The pilot outcomes of the trial were retention, acceptability, tolerability, and estimates of putative treatment effect on clinical symptoms…” Scales used: HAMD-17, HAMA, GAD-7.

Here’s what they found:

  • 24 were randomized to probiotic and 25 to placebo.
  • Demographics. 80% were female, and the mean age was 31.7 years.
  • Effect. “Standardized effect sizes (SES) from linear mixed models demonstrated that the probiotic group attained greater improvements in depressive symptoms according to HAMD-17 scores (week 4: SES, 0.70…) and IDS Self Report scores (week 8: SES, 0.64…) as well as greater improvements in anxiety symptoms according to HAMA scores (week 4: SES, 0.67…; week 8: SES, 0.79…), but not GAD-7 scores… compared with the placebo group.”
  • Adverse events. None were reported.

A few thoughts:

1. This is a good Brief Report with interesting data.

2. How to understand the results? “Compared with the placebo group, the probiotic group exhibited greater improvement in depressive symptoms with moderate effect sizes, which are comparable with those reported in earlier meta-analyses. Participants in the probiotic arm experienced, on average, a reduction of 1 severity grade on both depression rating scales.”

3. The authors are reasonable in their assessment: the results are “promising.”

4. Like all studies, there are limitations. The authors note several, including: “we cannot ascertain whether the observed effects are specific to the interaction with SSRIs or generalizable to other treatments.”

5. Some view probiotics with a skeptical eye (including me). That said, it should be noted that this intervention is quite innocuous. Participants seemed to agree: the adherence rate was 97.2%.

The full JAMA Psych Brief Report can be found here:

Selection 3: “How to Think about the Drug Crisis”

Charles Fain Lehman

National Affairs, June 2023

Almost nobody is taking America’s drug crisis seriously. To be sure, the ever-mounting deaths attract headlines. They get a mention in the State of the Union, or on the campaign trail. But based on the outcomes, policymakers appear to have more or less given up.

Some numbers put the problem in perspective. After Covid-19, drugs are now the leading driver of America’s steadily declining life expectancy. A reported 111,219 Americans died from a drug overdose in 2021. That figure has risen more or less unabated, and at an increasing pace, since the early 1990s. Back in 2011, 43,544 Americans died from a drug overdose – less than half the 2021 figure. Ten years earlier, in 2001, it was 21,705 – less than half as many again. And the problem keeps getting worse: The 2021 figure is nearly 50% higher than it was in 2019.

So begins an essay by Lehman.

“Drug overdose is now the leading cause of non-medical death in the United States. As of 2021, it was only slightly less deadly than all homicides, suicides, and motor-vehicle fatalities combined. Drugs still cause addiction, of course, and addiction still hurts addicts and society. But, likely for the first time ever, the primary harm of today’s drug crisis is death.”

He writes about the shift in drugs. “Historically, illicit drugs – heroin, cocaine, marijuana, etc. – were derived from plants grown in fields or greenhouses. But licit pharmacology has long been able to use simple, widely available precursor chemicals to synthesize the active ingredients in these substances. This sidesteps the complex processes of farming altogether. At some point in the past several decades, drug-trafficking organizations learned to use the same techniques at scale. Using precursors sourced primarily from China, they now synthesize a variety of opioids – the class of drugs that includes heroin.”

He focuses on opioids. “The most widely known of these is fentanyl, a synthetic opioid conventionally used in anesthesia that is 50 times stronger than heroin. Some are stronger still – carfentanil, the most potent opioid known thus far, is roughly 100 times stronger than fentanyl. In 2021, synthetic opioids were involved in roughly two out of every three overdose deaths.”

“Why have these drugs taken over the market? Because they’re a much better value proposition for sellers. Synthetic drugs significantly reduce production costs, both because chemistry is less labor- and input-intensive per unit produced than farming and because lab production is much easier to obscure from interdiction efforts that drive up costs. Furthermore, because the potency per dose is higher, drug-smuggling operations can move a smaller amount of fentanyl than heroin for the same profit.”

Lehman comments on ways forward. For example, he champions opioid agonist therapy. “As of 2020, survey data suggest that roughly 18 million Americans had in the past year suffered from an illicit drug-use disorder, including 4.2 million whose disorder involved a drug other than marijuana. Just 2.6 million people, however, reported actually receiving treatment that year, including 800,000 who received medication-assisted treatment (MAT).” 

Lehman wonders about more coercive treatment. “[J]ail inmates can be diverted into drug-court programs that offer a suspended sentence in exchange for compliance with treatment. Such programs have been shown to significantly reduce recidivism. Additionally, given the criminal-justice system’s outsized role in effective treatment, policymakers should think twice before decriminalizing small possession, as the state of Oregon has. If police cannot arrest users, they cannot divert them into treatment.”

He also mulls more policing: “supply-reduction operations – everything from busting street dealers to shutting down cartels – reduce the availability of drugs, making it harder for would-be users to use and driving up the price, thereby reducing the number of doses a person with a given amount to spend on drugs can consume.” But he notes their cost and limitations: “The shift to synthetics has put law enforcement at a distinct disadvantage by dramatically reducing drug prices – recent estimates suggest that fentanyl prices have fallen rapidly, by roughly 50% from 2016 to 2021. It has also made it much harder to detect and therefore interdict drugs.”

He advocates prevention, and likes the Youth in Iceland program. “It’s been credited with a dramatic reduction in teen drinking and substance use in that country. The program involves an all-of-society effort, including regular survey surveillance, a national curfew for 13- to 16-year-olds, state funding for extracurricular activities as a substitute for situations that lead to alcohol and drug use, and parent contracts to encourage their involvement.”

A few thoughts:

1. This is a long, detailed essay covering everything from America’s first drug crisis (after the Civil War) to policy recommendations. 

2. The above summary doesn’t capture the detail and nuance of the essay which stretches past 6 000 words.

3. The description of the shift in illicit drugs (and the resulting deaths) is excellent. Has the drug market changed forever? Lehman argues that it’s a matter of economics.

4. The author makes several recommendations, including promotion of opioid agonist therapy. The essay doesn’t put that much emphasis on other evidence-based interventions, such as residential treatment. One, of course, doesn’t exclude the other.

5. The author thinks there is a role for involuntary treatment. Past Readings have weighed such an approach – while recognizing the controversy and debate around such ideas. In a New York Times essay, David Sheff argues: “Many people in the traditional recovery world believe that we must wait for people who are addicted to hit bottom, with the hope that they’ll choose to enter treatment. It’s an archaic and dangerous theory.” That essay can be found here:

The full National Affairs essay can be found here:

Reading of the Week. Every week I pick articles and papers from the world of Psychiatry.