A drug overdose epidemic continues to tighten its grip on the nation. While the opioid crisis is in the limelight, there are multiple other substances lurking in the shadows. They may not attract as much attention, but they contribute to the staggering number of overdoses nationwide.
We’re taking a critical look at the substances fueling the epidemic—from well-known drugs like fentanyl and fentanyl analogues to lesser-known emerging threats that toxicologists, psychiatrists, and other healthcare professionals are starting to flag with more regularity.
How has COVID affected their misuse? What are the latest treatment recommendations? Is there hope for improvement, and where is there potential for psychiatrists to help? Download the report here or read on to explore these questions with us.
An epidemic by the numbers
Between December 2020 and December 2021, more than 107,000 overdose deaths were reported in the United States. Over the years, drug overdose death rates have only escalated.
In men, the age-adjusted drug overdose death rate shot up from 14.8 per 100,000 in 2009 to 29.6 per 100,000 in 2019. In women, this measure increased from 9.1 per 100,000 in 2009 to 13.7 per 100,000 in 2019.
Minority groups are impacted most by overdose deaths. One study in JAMA Network Open found that between March and August 2021, the highest overdose death rates occurred in American Indian or Alaska Native men aged between 15 and 34 years, as well as Black and American Indian or Alaska native men aged between 35 and 64 years. In every age and ethnic group, overdose deaths were higher in men compared with women.
The epidemic is mainly fueled by fentanyl and fentanyl analogues, methamphetamine, and cocaine (adulterated or combined). But substance abuse and overdose involves many other culprits, including the lesser-discussed benzodiazepines and emerging threats like the gamma-aminobutyric acid (GABA)–mimetic agent phenibut, a neuropsychiatric drug which was taken by early Soviet cosmonauts to induce calm and well-being. Today, it plays an increasing role in serious disability and long-term impairment due to overdose.
The plight of phenibut abuse
Phenibut misuse represents an emerging health crisis. Although some physicians may have limited awareness of the drug—which is not approved by the FDA—its rise in popularity and ease in ordering online have made this agent a threat to public health.
What is phenibut?
With a predilection for GABA-B vs GABA-A receptors, phenibut (β-phenyl-γ-aminobutyric acid) is a GABA analog that goes by many names, including phenigamma, Anvifen®, and Fenibut®. It readily crosses the blood-brain barrier, and its effects are akin to baclofen and gabapentin.
Soviet researchers first synthesized the drug in the 1960s, and Russian physicians still prescribe it for its antidepressant, mood-enhancing, and cognitive-enhancing (ie, nootropic) properties.
A legal gray area
Although phenibut is not defined as a dietary supplement in the United States, it is sold online as a treatment for anxiety, and to promote sleep and relaxation. Ease of procuring this unregulated drug has contributed to its rise in popularity, according to experts. In contrast, the European Union and Australia have not approved its use.
High abuse potential
Taken at lower doses (ie, < 1 g), phenibut’s short-term effects include a sense of calm and well-being. At higher doses, however, phenibut use and misuse results in sedation, respiratory depression, and decreased levels of consciousness.
Across the country, emergency cases of phenibut-associated dissociation, respiratory depression, and psychosis are on the rise.
Beyond the short-term risks, long-term consequences may also result from phenibut exposure, including dependence–with patients often complaining it’s impossible to stop taking the drug. Anxiety, agitation, and acute psychosis frequently accompany withdrawal.[4,5]
The dangers of exposure
In a 2020 report, the CDC assessed the frequency of phenibut-related exposures in the US based on call data to US poison centers. Phenibut exposures referred to any type, not just poisonings or overdose, with authors also taking into account various demographic factors.
US poison control centers reported 1,320 cases of phenibut exposure between 2009 and 2019 in all 50 states and the District of Columbia.
In total, 58.4% of exposures involved adults aged between 18 and 34 years. Unintentional exposures–including in children—made up 21.1% of the calls. The number of exposures ballooned after 2015, when “phenibut” became a capture term. Oral formulations including tablets or powder accounted for the lion’s share of exposures.
"Educational efforts to increase awareness among the public and clinicians regarding the emerging popularity and dangers of phenibut might help prevent adverse health effects and outcomes, including death."
— Graves JM, Dilley J, Kubsad S, et al
The most common adverse effects were agitation (30.4%), drowsiness/lethargy (29.0%), tachycardia (21.9%), and confusion (21.3%). Coma occurred in 6.2% of cases, with one coma occurring in an adolescent. In about half of the cases, the exposure did not result in long-term impairment, but substantial disability did occur in 12.6% of cases. Overall, there were three deaths involving phenibut exposure.
“Educational efforts to increase awareness among the public and clinicians regarding the emerging popularity and dangers of phenibut might help prevent adverse health effects and outcomes, including death,” the authors wrote.
From barbiturates to benzodiazepines
Benzodiazepines had an auspicious beginning as a hopeful replacement prescription for dangerous barbiturates. Although barbiturates had a powerful anxiolytic effect, they also had potent adverse effects and well-known dosing difficulties. Overdose on barbiturates resulted in central nervous system depression, coma, or death.
Fast potential for abuse
It wasn’t long, however, before benzodiazepines proved to be highly addictive on their own. Reactions to these drugs occur more slowly than for barbiturates, but experts have observed that, among patients taking the drug for 4 weeks, 50% required an increase in dosage to experience the same degree of relief as previously. Withdrawal symptoms are intense and include tension, anxiety, panic attacks, hand tremors, and seizures.
Dose-related side effects include amnesia and central respiratory depression. When taken in large quantities, benzodiazepines result in a dopamine rush, which floods the user with sensations of pleasure and reward.
The rates of benzodiazepine prescription have been on the rise. Between 1996 and 2013, the number of prescriptions rose by 67% to 135 million per year.
The first benzodiazepine, chlordiazepoxide, was synthesized in 1955, which was then followed by the discovery of diazepam in 1963. By the late 1950s, the brickwork was in place to replace barbiturates with benzodiazepines, and these newer agents eventually also overtook the use of opiate derivatives. By the 1970s, benzodiazepines were the most abused drugs.
Subsequently, benzodiazepines were flagged by the FDA, and benzodiazepine dependence was recognized by the American Psychiatric Association in 1990.
Benzodiazepines work by binding GABA-A receptors and dampening brainstem arousal pathways. Benzodiazepines open ion channels, thus causing chloride ions to rush in. This increase in membrane polarization inhibits neuron firing and leads to central nervous system depression.
Benzodiazepines are differentiated by their half-life: there are long-acting forms such as diazepam, intermediate-acting forms such as alprazolam and clonazepam, and short-acting drugs like midazolam.
Fears of an impending epidemic
Experts fear that the increasing number of prescriptions for benzodiazepines—a number that rivals the 190 million prescriptions per year for opioids—points to an impending benzodiazepine drug epidemic. As with opioids, a high number of benzodiazepine prescriptions can result in drug diversion and the illicit sale and consumption of these drugs.
Deaths from opioid overdoses still outnumber those involving benzodiazepines, with 46,700 deaths attributable to opioid overdose in 2017 (when the White House declared an opioid epidemic) compared with 11,000 for benzodiazepines in 2016. Nevertheless, the rise in deaths linked to benzodiazepines has been exponential.
Shortly thereafter, the FDA released a statement warning against combined prescription of benzodiazepines and opioids, as patients were often receiving both for various reasons.
One explanation for the benzodiazepine overprescription and misuse could be that patients are inclined to seek mental health care from primary care practitioners rather than from specialists. Pressed for time and lacking specialty training, primary care practitioners may not be able to adequately assess and evaluate a patient’s need for and understanding of the drugs.
In addition, primary care physicians can feel pressured by patients who are long-time users to simply renew their prescription for a benzodiazepine.
Send in the psychiatrists
A common thread that runs through all these potential overdose scenarios is that it’s crucial to integrate care with an addiction psychiatrist. One solution might be to refer all patients who may need a benzodiazepine prescription for a detailed assessment by a psychiatrist.
Another potential solution is to embed a psychiatrist in the primary care setting. They can provide insight and perform a robust examination to determine not only the need for benzodiazepines but also the management of other psychiatric medications that primary care physicians may feel uncomfortable prescribing (eg, SSRIs and antipsychotics). Currently, various academic centers offer integrated psychiatric consultation and primary care, including Yale Medicine.
The curse of fentanyl and synthetic opioids
Starting in 2013, the synthetic opioid fentanyl rapidly entered the illicit drug market. The number of deaths due to fentanyl is skyrocketing.
During the 12 months that ended in June 2020, 48,000 of 83,335 overdose deaths in the US were due to fentanyl. This is 29 times the rate in 2012. The perils of fentanyl also plague various European countries and Australia.
In 2020, more than 56,000 people died from overdose due to synthetic opioids, with counts through June 2021 signaling an acceleration of overdose deaths during the pandemic.
Why so lethal?
Fentanyl is mixed with heroin or cocaine to heighten the euphoric effect. As a result, its potency is significantly higher when activating the μ-opioid receptor (MOR) at 80-100 fold in comparison to morphine, and 30-50 fold in comparison to heroin.
The higher lipophilicity of fentanyl results in rapid and higher uptake by the brain when compared with morphine or heroin. This makes the drug a powerful analgesic and highly addictive due to its potent rewarding effects. Fentanyl overdose results in severe respiratory depression, which is evident from slow irregular breathing, as well as sedation, acute respiratory distress, slowing of circulation, seizures, and coma.Related: Nonfatal opioid overdose rates are climbing. Here's what you can do to help
What you can do
The CDC recommends that HCPs expand the use of naloxone–a fast-acting MOR antagonist used for short-term reversal of opioid overdose–when treating opioid use disorder. HCPs should keep in mind that multiple doses of naloxone may be needed during an overdose because of the increased potency of fentanyl. Some formulations are associated with delayed toxicity, meaning that prolonged dosing of naloxone may be needed in the ED.
Other guidance includes facilitating access to a Medication-Assisted Treatment (MAT) team, which integrates medication treatments, counseling, and behavioral therapies. ED physicians should make sure that they prescribe naloxone and connect patients with case management or a peer-navigator network for treatment. The NIH also suggests that family and friends of addicted individuals have naloxone on hand.Related: Methamphetamine use is up in rural areas. Here’s what you need to know.
Better treatments urgently needed
Currently, the treatment for fentanyl opioid use disorder (fOUD) is the same as for opioid use disorder (OUD). This approach includes the use of methadone (ie, full MOR agonist), buprenorphine (ie, partial MOR agonist), and naltrexone (ie, MOR antagonist). Although these treatments are the gold standard for OUD, they may not be optimal for fOUD. More research is needed.
“Clinical cases and anecdotal reports indicate that it is much more challenging to treat patients with fOUD than with other OUD,” wrote an NIH researcher in World Psychiatry. “There are greater difficulties in initiating buprenorphine treatment, resulting from buprenorphine‐precipitated withdrawal and lower rates of abstinence and retention after six months of buprenorphine treatment.”
"Clinical cases and anecdotal reports indicate that it is much more challenging to treat patients with fOUD than with other OUD."
— Nora D. Volkow
The author also highlighted the slow clearance of fentanyl due to accumulation in fatty tissues, which could necessitate slower detoxification before the initiation of buprenorphine or naltrexone. Higher rates of tolerance and physical dependence resulting from repeated fentanyl exposure could also require higher doses of methadone or buprenorphine compared with other types of OUD.
Finally, withdrawal symptoms secondary to fentanyl detoxification could be treated with alpha‐adrenergic drugs such as lofexidine and clonidine, as for other types of OUDs.Read Next: Groundbreaking research for treatment of substance use disorders
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