\n<\/p>\n
On June 11, 2018, seeking relief from chronic pancreatitis pain, Ashley Romero took what she believed to be half a pill of Percocet. Within minutes, she was dead.<\/p>\n
The pill, which Romero\u2019s boyfriend had acquired on the black market, was packed with fentanyl, a synthetic opioid that can be fatal in doses the size of a dozen grains of salt. Romero left behind a then seven-year-old son. The next day, her boyfriend fatally shot himself.<\/p>\n
\u201cTwo families, from this little half a pill,\u201d says Andrea Thomas, Romero\u2019s mother, sadly musing on the devastation. In the seven years since her daughter\u2019s death, Thomas has become an antifentanyl advocate, pushing for initiatives that range from education programs to teach young people about the insidious ways fentanyl shows up in the drug supply to efforts to restrict the flow of precursor chemicals for the opioid from overseas.<\/p>\n
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Recently Romero has taken interest in an emerging innovation: an antifentanyl vaccine. Developed by academic researchers with Department of Defense funding and licensed by biotech company ARMR Sciences, this vaccine will be tested in humans for the first time beginning in January or February. If it works to keep the deadly molecule out of the brain, the hope is that it can prevent fentanyl overdose\u2014and deliberate use. And that\u2019s important, Romero says, because most people who use drugs don\u2019t want to become addicted to something as dangerous as fentanyl.<\/p>\n
\u201cIf the public understood the whole picture of fentanyl, this would be a go-to for many people,\u201d she says.<\/p>\n
Medications for substance use disorders can carry stigma: People may grumble about heroin users trading one drug for another by using maintenance medications such as methadone to help ease cravings and withdrawal symptoms. Yet the dizzying death toll of the opioid crisis, which killed nearly 80,000 Americans in 2023, down 4 percent from the death rate in 2022, may be shifting some of those attitudes. Naloxone (sold under the brand name Narcan) is now available over the counter and has undeniably saved thousands of lives. The tendrils of the epidemic have touched families across racial and socioeconomic groups, and a 2018 Associated Press\u2013NORC Center for Public Affairs Research survey found that more Americans view opioid use disorder as a medical condition than see it as a character flaw or lack of willpower.<\/p>\n
Now researchers are developing and testing new medications that could help people win their battles against addictive substances. Some of these, such as the potential vaccine that blocks the effects of fentanyl, are aimed at helping people stop using altogether. Others ease symptoms of withdrawal to make quitting easier or even to just help people reduce their use\u2014a harm-reduction approach that has typically not won medications approval from the Food and Drug Administration. But these days abstinence isn\u2019t the only measure of success, a shift in mindset that could give people with drug problems more options in the future.<\/p>\n
\u201cWe\u2019re at a stage in our society where we\u2019re starting to look at individuals\u2019 lived experience, to look at what they\u2019re asking for,\u201d says Margaret Haney, a Columbia University neurobiologist, who is studying medication options for cannabis addiction. \u201cIt\u2019s always been very top-down.\u201d<\/p>\n
As of 2023, about 48.5 million Americans had a substance use disorder, and about 8.9 million of those cases involved opioids. Only about a quarter of those with a substance use disorder received treatment of any sort, much less medication. For some substances, including stimulants and marijuana, there simply is no medication option.<\/p>\n
Even so, medication is not a cure-all. Substance use disorders are complicated, and people who struggle with addiction often have other problems that require support. Data from the 2023 National Survey on Drug Use and Health, for example, found that people with mental illness were more than twice as likely to have used illicit substances in the past year compared with those without such a condition. Medication is one tool among many, experts agree.<\/p>\n
Withdrawal from an addictive substance is often the first hurdle in treatment. And it\u2019s hard, \u201cthe hardest thing that you\u2019ll do, probably,\u201d says Andrew Huhn, an associate professor of psychiatry and behavioral sciences at the Johns Hopkins School of Medicine, who researches opioid withdrawal medications. Medications that can ease the symptoms of withdrawal can make long-term recovery more likely.<\/p>\n
Users of opioids such as heroin or oxycodone already have options such as buprenorphine or methadone, which cling to opioid receptors in the brain and reduce withdrawal symptoms. Yet most people relapse at least once when they try to quit opioids\u2014and often do so within the first month of treatment. Those relapses can be fatal, especially if former users with decreased tolerance start again at the same doses they used before or if they encounter a dose laced with fentanyl. ARMR Sciences\u2019 new approach would guard against these particular overdoses by vaccinating against fentanyl.<\/p>\n
The problem with fentanyl is twofold: it\u2019s up to 50 times stronger than heroin (and 100 times stronger than morphine), and it\u2019s often slipped into street drugs or illegally sold prescription meds without the buyer\u2019s knowledge. So opioid users can easily overdose, and individuals can succumb without ever seeking it out. That\u2019s where the vaccines come in. Fentanyl doesn\u2019t normally activate a person\u2019s immune system\u2014the target of vaccines. University of Houston researcher Colin Haile, however, has shown in animal studies that he can coax the body\u2019s immune system to make antibodies that block the drug. To get that response, Haile linked a piece of the fentanyl molecule to a deactivated diphtheria toxin and a compound distilled from toxins produced by the Escherichia coli bacterium. That complex is recognized by the immune system, which makes antibodies that recognize the fentanyl molecule. These antibodies cling to fentanyl in the bloodstream and prevent it from entering the brain: no high, no overdose risk.<\/p>\n
The researchers envision the vaccine as helpful for people in recovery who are taking maintenance medications to block opioid receptors in the brain but who need an extra barrier to getting high or avoiding an overdose. A three-shot series would continue to block fentanyl even if someone stopped taking their other medications, perhaps saving their life, should they seek out or encounter fentanyl during a relapse.<\/p>\n
\u201cThis gives them another chance of getting on the wagon to sobriety,\u201d Haile says.<\/p>\n
Phase I trials will start enrolling participants at a site in the Netherlands in January or February. These trials are designed to look for safety problems with the vaccine, but researchers will also be testing volunteers\u2019 blood for antifentanyl antibodies. They hope these antibodies will be long-lasting in people; vaccination in rats, Haile says, blocked fentanyl from entering the brain for six months, which is a good chunk of a lab rat\u2019s lifespan. If the vaccine is safe and moves on to phase 2 trials, vaccinated volunteers would be given medical doses of fentanyl under supervision to test for efficacy.<\/p>\n
Company CEO Collin Gage envisions military and first responders as an initial market. Police and EMTs often worry about encountering fentanyl at work, Haile says. The drug is not effectively absorbed through the skin, but it is theoretically possible to feel some effects if it accidentally gets into the eyes or mouth. There are also concerns that troops could encounter fentanyl as a chemical weapon. In 2002 the Russian military used aerosolized carfentanil, a veterinary tranquilizer, to neutralize Chechen rebels who were holding hostages in a theater in Moscow. The vaccine could also be used by people in recovery, as well as people who use nonopioid street drugs that might be laced with fentanyl.<\/p>\n
Thomas says that some parents might hesitate to give their kids an antidrug vaccine but that families that are struggling with addiction will likely be open. \u201cWhy would we not be using every resource we have right now to save lives?\u201d she says. (Thomas has co-founded an advocacy group, ARMOUR Families, with Gage to support similar research innovations against fentanyl, but ARMOUR Families is not funded by ARMR Sciences.)<\/p>\n
Even if it proved effective, a vaccine would not reduce cravings or withdrawal symptoms. Johns Hopkins\u2019s Huhn is tackling one of the most insidious side effects of opioid withdrawal\u2014insomnia\u2014with an antiwakefulness medication called suvorexant. Between 50 and 85 percent of people recovering from opioid use have insomnia, Huhn says. And in many cases, the sleep problems can persist for months or years. Lack of sleep reduces a person\u2019s brain function and increases cravings, and it may be a factor in relapse.<\/p>\n
\u201cWe\u2019ve always said: if somebody doesn\u2019t get a night of sleep, or maybe they miss two nights of sleep, they\u2019re gone,\u201d Huhn says. \u201cWe know they\u2019re going to leave treatment.\u201d<\/p>\n
But typical insomnia medications can be habit-forming or might interact with opioids, making them poor candidates for treating people with opioid use disorder. Suvorexant, which is already approved to treat insomnia in the general population, binds to orexin receptors in the brain that regulate wakefulness and other basic functions such as appetite. \u201cIt\u2019s more of an antiwakefulness medication than a sedative,\u201d Huhn says. \u201cIt probably doesn\u2019t pack the same punch that Ambien would, as far as putting you to sleep. But it allows you to fall asleep easier, and then it allows you to stay asleep.\u201d<\/p>\n
In a 2022 trial in people withdrawing from opioid use disorder with the help of buprenorphine and naloxone, suvorexant improved sleep by an average of 90 minutes a night. Huhn and his colleagues are in the midst of a multisite phase 3 clinical trial looking at the efficacy of the medication in people in outpatient treatment. The hope, he says, is not just to promote quitting drugs but to also optimize recovery.<\/p>\n
\u201cWe often determine the success of treatment by saying, \u2018This person quit, or they didn\u2019t,\u2019\u201d he says. \u201cBut did they quit but they\u2019re miserable, and it\u2019s harder than it needs to be? Are we really doing the best we can by people?\u201d<\/p>\n
Suvorexant isn\u2019t the only already approved treatment that might be expanded into use against addiction. At the University of Cambridge, neuropsychiatrist Valerie Voon is testing deep-brain stimulation (DBS) for combating addiction. Already approved for improving some of the movement symptoms of Parkinson\u2019s disease, DBS involves implanting electrodes in the brain and delivering a constant buzz of high-frequency electric stimulation. In the case of addiction, Voon says, the target is the nucleus accumbens, a brain region involved in motivation\u2014and drug craving.<\/p>\n
\u201cIt\u2019s overactive when you show someone an addiction cue, and it\u2019s overactive in subjective reports of craving,\u201d Voon says. The hope is that DBS will calm that activity, just as it does the overactivity in movement regions of the brains of people with Parkinson\u2019s. The researchers have surgically implanted electrodes in three people with alcohol use disorder and plan to do six more surgeries by the end of spring. They\u2019ll then study whether stimulation changes people\u2019s risk-taking behaviors, decision-making and alcohol craving.<\/p>\n
An advantage of an approach like DBS is that it could theoretically work regardless of the relevant substance. While alcohol, nicotine and opioids all have at least some medication options on the market, there are no medications available to people with addictions to cannabis or stimulants, a category that includes everything from methamphetamine to black-market Adderall to cocaine.<\/p>\n
These drugs don\u2019t kill as easily as opioids, but their effects on the brain are much more complicated. Stimulants, for example, ping receptors that are deeply enmeshed in the brain\u2019s reward system. If you give someone with an opioid addiction a medication such as methadone, it can cling to the opioid receptors in the brain and block the dangerous effects. There\u2019s no real way to disentangle the more addictive effects of stimulants from their basic reward function, though, says Courtney Miller, a neurobiologist at the University of Florida.<\/p>\n
\u201cYou can\u2019t antagonize the same receptors and processes that stimulants hit because you end up with anhedonia,\u201d she says. \u201cPut really simply, you just induce depression in everyone, and no one would take it.\u201d<\/p>\n
Since the 1970s researchers have explored potential medications against stimulants, including a cocaine vaccine that Haile worked on that didn\u2019t make it past clinical trials. With the diphtheria and E. coli\u2013derived compounds used in the fentanyl vaccine, Haile is now working to revive a new version of the cocaine vaccine in animal tests. Miller is taking another approach, studying a small molecule that targets a protein called nonmuscle myocin II. This protein plays a role in remodeling neuron-to-neuron connections during learning. In methamphetamine addiction, it goes into overdrive in the amygdala, a brain region involved in fear and learning. In mice, Miller has found, inhibiting nonmuscle myocin II can restabilize neuronal connections and break the feedback loop that motivates drug seeking. A single dose stops mice from seeking out meth for a month, Miller says.<\/p>\n
Cannabis is similar to stimulants in that its effects on the brain are multifaceted\u2014in fact, the endocannabinoid system has receptors all over the body, especially in immune tissue. Cannabis doesn\u2019t induce dependence as easily as a drug like heroin does, but the legalization of pot has brought with it increasingly concentrated strains, Columbia\u2019s Haney says. People trying to pull back their usage can experience cravings, irritability, appetite loss and sleep problems. \u201cOne of the sad things is that they\u2019re very hard on themselves,\u201d Haney says. \u201cThey\u2019re like, \u2018Why can\u2019t I do this? It\u2019s just cannabis.\u201d<\/p>\n
Haney has been studying AEF0117, an inhibitor of some cannabis receptors that reduces the high induced by cannabis. She and her colleagues have found that AEF0117 reduces cannabis intoxication, enjoyment and consumption. But a not-yet-published, three-month multisite clinical trial with more than 300 participants failed to increase the likelihood that people would use cannabis one day or fewer per week, the FDA\u2019s benchmark for approving pharmacotherapy for substance use, Haney says.<\/p>\n
To many in the field, it is that benchmark, not the complexity of cannabis or meth, that is holding back new treatments.<\/p>\n
\u201cThis is a chronic and relapsing condition, and unlike pretty much any other condition, we expect our patients to be perfect in treatment,\u201d says William Stoops, a professor of behavioral science at the University of Kentucky College of Medicine. \u201cWe don\u2019t expect someone with type 1 diabetes to have perfect blood sugar all the time, and we don\u2019t kick them out of treatment if they don\u2019t\u2026. But for some reason, for addiction, as a field, we have said forever that complete abstinence is the indicator.\u201d<\/p>\n
There are some indications that the FDA might be softening that stance, Haney says. In 2023 the agency released guidance stating that it was open to clinical end points other than abstinence for medications for stimulant use disorder. The trick now, Stoops says, is to build the evidence for those end points, showing, for example, that a reduction in cravings has an important effect on quality of life or that using fewer days a week correlates with better physical health.<\/p>\n
For cannabis users in particular, many don\u2019t want to quit entirely, Haney says. They simply don\u2019t want the drug to take over their life. And listening to what people are looking for in treatment could lead not just to new medications but also to a reappraisal of old options.<\/p>\n
\u201cIt\u2019s my suspicion,\u201d Haney says, \u201cthat we have tossed out many medications that might have been useful.\u201d<\/p>\n","protected":false},"excerpt":{"rendered":"
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