Drug addiction is by no means a modern problem. Historians have found references to various types of drug addiction in the earliest known recordings of human history (1,2). Since the beginning, people have often viewed drug addiction as a moral failing of the individual, rather than as a disease that can be treated with pharmacological interventions. Starting in the 20^th century, however, new scientific findings finally began to shift the blame away from the individual as studies revealed how drugs of abuse hijack the brain’s reward circuitry (3,4). Yet, widespread stigma still exists today that harms individuals with substance use disorders and hinders efforts to develop effective pharmaceutical treatments. 

Because of this, “companies don't necessarily want to be associated [with it],” said Nora Volkow, an addiction scientist and director of the National Institute on Drug Abuse. “Industry is not interested in developing medications for addiction.” 

Beyond stigma, developers of addiction therapeutics also face unique challenges compared to other brain disorders. “Drugs of abuse attack parts of the brain that are very important from an evolutionary or survival point of view,” said Eric Nestler, a neuroscientist at the Icahn School of Medicine at Mount Sinai. To be able to treat addiction, Nestler added, “you need to figure out a way to somehow act on those brain reward circuits that prevents the actions of drugs of abuse or reverses the damaging effects of drugs of abuse, without interfering with those pathways' normal functioning for rewards that we need for survival.”

Despite the complexities involved in developing treatments, Nestler and Volkow emphasized that the science is at an advanced stage. “It’s particularly frustrating that, despite the fact that we've learned so much about addiction, it has been very difficult to translate that into new treatments,” Nestler said.

There are a limited number of medications for opioids, nicotine, and alcohol. But for drugs that fall under the categories of cannabis, polysubstance, or stimulants like cocaine and methamphetamine, there are no FDA-approved options at all. Unfortunately, these addictions can be deadly. While naloxone can rapidly treat opioid overdoses, no medications can reverse the effects of a stimulant drug overdose. 

Despite the hurdles, researchers are developing many new treatment strategies for these often-neglected substance use disorders that target genes, recruit the immune system, or engineer new small molecule drugs.

“I’m very optimistic that we will get there, it's just going to require more time and harder work,” said Nestler. 

An extremely efficient enzyme 

One strategy to treat drug addiction is to prevent the drug from reaching the brain in the first place. Psychiatrist Michael Hooten and immunologist Kah Whye Peng at the Mayo Clinic are testing a souped-up version of a butyrylcholinesterase enzyme that breaks down cocaine in the blood so rapidly that it never has a chance to travel to the brain. Their version of the enzyme gets a boost from five genetic mutations that increases its activity by 1,000 times. 

Their colleague Stephen Brimijoin, a former pharmacologist at the Mayo Clinic who retired, started this work. Brimijoin’s group showed that infusing the engineered human version of the enzyme into rodents led them to stop self-administering cocaine (5). 

But to deliver the enzyme in humans, Peng and Hooten’s team is using a gene transfer approach that introduces the genetic mutations into liver cells — possibly for life. Since liver cells don’t have a high turnover rate, theoretically they should continue to synthesize the mutated enzyme indefinitely. “Basically, you just have these little engines in the liver continually expressing the enzyme,” said Hooten. “Once you get through the initial phase, then you can move forward in time hopefully without any adverse consequences and still retain a very high level [of the enzyme to] protect you during those vulnerable periods of relapse, which might be one year, two years out from abstinence.” 

So far, their team has demonstrated that the gene transfer therapy is safe in rodents and nonhuman primates. The only potential concern they foresee is whether the enzyme might also metabolize other drugs too quickly and diminish their effects. “There are a couple of depolarizing drugs for muscle relaxation [and] paralysis during surgery that are actually hydrolyzed by esterases, and so they may be affected. But there's 15 other drugs that [anesthesiologists] can use,” said Hooten. “So, I think that would be a minor concern for the vast majority of people.”

They have now moved into a Phase 1 clinical trial to test the safety of their approach in people with cocaine use disorder, and they hope to test its efficacy in preventing cocaine usage in a Phase 2 trial. “We hope it happens in humans, but human psychology is obviously slightly different,” said Peng.

Peng and Hooten also acknowledged that a gene transfer therapy that may last a lifetime could seem like a drastic measure. At the same time, many drug addictions are lifelong battles. Therapies that wear off too quickly could make someone vulnerable to relapse. “When you talk to people like me or other people who are not users, it's like, ‘Oh, gosh, I will not take something so severe as gene transfer,’ … but there might be different motivations and struggles that we don't understand,” said Peng. Hooten agreed, adding, “The folks that we'll be targeting, these folks are at risk of death. These are people with very, very severe cocaine use disorder.”

Editing the epigenome

Rather than targeting genes with a permanent gene therapy, researchers in Nestler’s laboratory study how drugs of abuse lead to epigenetic changes. “The way we would look at addiction is that addiction is mediated — not completely, but in part — by the ability of drugs of abuse … to disrupt gene expression patterns that normally occur in the brain,” said Nestler.

In 2018, Nestler’s team used RNA sequencing and machine learning to study mice that were addicted to cocaine to find gene expression patterns that were most closely related to cocaine use (6). They identified a gene called Retinoid X receptor alpha (RXRα), which is a transcription factor that regulates the activity of other genes. They recently published work showing that RXRα changes the electrical activity of neurons in the nucleus accumbens, a key part of the brain’s reward circuitry, and plays a major role in driving addiction-like behavior in mice (7). Nestler’s group is now investigating whether existing RXRα inhibitors could treat cocaine addiction. But they aren’t stopping there. “We don't see addiction being mediated by one mechanism, RXRα. We think it’s important, but it's one of many important factors,” he said. “It's brute force to analyze one [inhibitor] at a time to figure out which one is going to be the best therapeutic. There's just no other way to do that now.”

Elizabeth Heller, a former postdoctoral scholar in Nestler’s laboratory who is now at the University of Pennsylvania, is also studying ways to target the epigenome to treat drug addiction. Instead of traditional gene editing, her group is at the forefront of studying a new epigenetic editing technique. Heller’s team used a non-cutting CRISPR tool that activates gene expression to increase the level of nuclear receptor subfamily 4 group A member 1 (Nr4a1) in neurons, which led to less drug-seeking behavior in mice (8). 

The disease of addiction is really a disease of both drug taking and abstinence. It's actually the cycling between those two stages that categorizes it as a disorder. 
– Elizabeth Heller, University of Pennsylvania

Heller emphasized that the important part of this treatment is that it targets gene activity that begins during a period of abstinence from the drug. “The disease of addiction is really a disease of both drug taking and abstinence. It's actually the cycling between those two stages that categorizes it as a disorder,” said Heller. Her work highlighted that Nr4a1 regulates gene expression during the abstinence period before drug-taking begins again. When Nr4a1 was active, the mice were less interested in cocaine, suggesting that it may work as a therapeutic to keep users in the abstinence period for a long enough time that they may never relapse again. 

“It's a little variable by substance, but in general, if they can stay abstinent for like eight months — especially if they can stay abstinent for a year — the likelihood of lifetime abstinence is way high. So, it’s this threshold,” said Heller. It means that after enough time has passed, eventually the brain does have a process to return to homeostasis, where the effects of the drug are reversed, Heller explained. “The ideal situation would be, can we find gene expression patterns that might function in this delayed time point to finally reverse the effects of the drug? And if we find them, [could we] start those processes earlier during the abstinence period to return the system to homeostasis earlier?” said Heller.

Controlling cannabinoid activity

For drugs like cannabis, scientists working on addiction treatments often face bewildered responses from the public. “There's been a mismatch between the scientific, the medical, and the popular [perception of cannabis]. The scientists, we knew that cannabis was not good many, many years ago,” said Pier Vincenzo Piazza, a neuroscientist and the Chief Executive Officer of Aelis Farma. Piazza cofounded the company in 2013 to develop novel therapeutics for cannabis-related disorders and other brain conditions. “When we started developing our treatment in France, people would laugh. They would say, 'Why do you want to develop a treatment for a disease that does not exist?'

But for some users of cannabis, addiction is indeed their reality. Piazza said that many of the users in their studies smoke between five to 15 joints per day. Many prior cannabis addiction treatments blocked cannabinoid receptor 1 (CB1), which is where the active ingredient of marijuana, tetrahydrocannabinol (THC), binds in the brain. But that quickly led to problems. “CB1 is one of the most expressed neurotransmitter receptors in the brain. It's everywhere,” said Piazza. “The molecules of the previous generation, these antagonists, they blocked access of cannabis, …  but also they blocked access of the natural molecule that stimulates these receptors.” These drugs thus caused serious adverse effects, including anxiety and depression, in clinical trials (9). 

Aelis Farma is working on a different approach based on Piazza’s earlier discovery of a natural mechanism that the brain uses to counteract over-activation of CB1 receptors (10). In response to high concentrations of THC, the steroid hormone pregnenolone binds to CB1 receptors, but it doesn’t completely block them from activating at all. Instead, only “the effects that are linked to overactivation, the intoxicating effects of cannabis, are blocked,” said Piazza. 

However, pregnenolone can’t be a therapeutic drug on its own because its half-life is too short, so Piazza’s team modified the structure of the hormone into new drug molecules called signaling specific inhibitors of the cannabinoid type 1 receptor (CB1-SSi). “The mechanism is so new that we have to call it a new name,” said Piazza. 

Aelis Farma recently published the results of their Phase 2a study showing that their new CB1-SSi drug, AEF0117, was tolerated well, significantly decreased the subjective effects of cannabis, and decreased the use of cannabis compared to placebo (11). 

They will receive the results of the Phase 2b study in September, and plan to move forward with a Phase 3 trial after that. “I would be very surprised if the Phase 2b is completely negative,” said Piazza. 

Immunity from addiction

A natural way to keep drug molecules in the blood from reaching the brain is to send the immune system to attack them first. Using a vaccine approach, researchers train immune cells to watch out for drugs of abuse and to bind to them before they can go latch onto receptors in the brain. But just like vaccines targeted to infectious diseases can take weeks or months to be effective, vaccines against drugs of abuse do too — which puts individuals at risk of relapse. 

Kim Janda, a chemist at Scripps Research, said that it may work to first use monoclonal antibodies that bind to the drug in the short term. “[With] a monoclonal, if you infuse it, you have immediate production. So, I've always been in the mindset that you infuse a monoclonal [that lasts] up to six weeks, and at the same time you vaccinate them, and then boost. And when the monoclonal wanes off, the vaccine would kick in,” he said.

Janda’s team has developed several immunotherapy approaches to target drugs without any currently approved therapies like methamphetamine, cocaine, and cannabinoids (12,13). His team is now working towards treating polysubstance addictions too. “We're trying to develop these antibodies that have multiple arms that could pick up multiple drugs at the same time,” said Janda. 

The journey to approval

At the Sanford Burnham Prebys Medical Discovery Institute, medicinal chemist Nicholas Cosford and pharmacologist Douglas Sheffler are developing molecules that target metabotropic glutamate receptors (mGlu) to treat addictions to drugs like cocaine, methamphetamine, and polysubstance use disorders. “The drugs we've been working on, they work really well in pretty much everything we've thrown them at,” said Sheffler. The researchers are still only studying animal models for now, but their work has shown that targeting mGlu₂ and mGlu₃ can reverse a relapse (14,15). 

They don’t know yet if it will work better to target mGlu 2, 3, or both. But even after they complete the preclinical work in rodents, Sheffler said it will be extremely difficult to move the drugs into clinical trials and apply for FDA approval. For drugs that would treat substance use disorders, “there is no existing FDA regulatory pathway for approval of anything other than really alcohol or nicotine, because nothing's ever been approved,” he said. “What are your primary endpoints and secondary endpoints going to be for the clinical trial? No one's ever done it.”

Since the path to approval is easier for drugs that target nicotine, Sheffler and Cosford are preparing for with a Phase 2 clinical trial to test a positive allosteric modulator of mGlu₂ to treat nicotine addiction. If that gets approved, they hope it might be possible to more easily get the same drug approved to treat a stimulant use disorder too. “We could take the same exact molecule and try to run another clinical trial and get it approved for opioids, or get it approved for methamphetamine, or something else. But the key is you have to get it approved,” said Sheffler.

The difficulties of engineering a new molecule from scratch and then successfully obtaining FDA approval suggests it could be worthwhile to test out drugs that are already on the market to treat other conditions. “Something that has everybody very, very excited is the possibility that medications that are being used for obesity or diabetes, that are based on emulating glucagon-like peptides, may be useful for the treatment of substance use disorders,” said Volkow.

Heath Schmidt, a neuropharmacologist at the University of Pennsylvania, was one of the earliest researchers to study the effects of GLP-1 agonists on drug addiction about a decade ago. “There's a lot of overlap in the brain between the circuits that regulate feeding and drug-seeking behaviors,” said Schmidt. Based on his reading of early papers looking at GLP-1 related to drug addiction, Schmidt added, “it suggested to me that GLP-1 signaling in the brain is regulating the hedonic value of food. And if it's doing that in these circuits — the same circuits that regulate drug seeking — then perhaps targeting that system would also reduce drug seeking in our models.”

There is no existing FDA regulatory pathway for approval of anything other than really alcohol or nicotine, because nothing's ever been approved. 
– Douglas Sheffler, Sanford Burnham Prebys Medical Discovery Institute

Researchers in Schmidt’s group have published several papers in rodents showing that the use of GLP-1 agonists significantly decreased their drug-seeking behavior of cocaine (16,17). Now, the team is trying to investigate how it works. “We have evidence and so do others that these GLP-1-receptor-based medications are reducing the ability of drugs of abuse to increase dopamine signaling in the brain,” he said. “If that's a driver of relapse or cravings, you can envision that that's kind of a neurochemical mechanism underlying the efficacy of these drugs. But it's probably complex, and there's a lot more going on there.”

At the same time, regardless of which drug it is, Volkow said that the FDA regulatory system needs to change, specifically by removing the remaining stigma around drug addiction. One of the current FDA requirements for new therapies for drug abuse is that the treatment leads to two weeks of abstinence from the substance. “The regulatory system also is a reflection of these stigmatized perceptions [because] the person is doing an illegal activity, and therefore any consumption is utterly unacceptable. Whereas my view is that drugs right now are so dangerous that if I can get a reduction in the amount of drugs that a person consumed, you're reducing the risk of them having an overdose just by pure statistics,” she said. “We need to change those attitudes in order to really exploit the advances that we have in science that could turn into very useful medications.”

With many promising candidates in the pipeline, scientists today are excited, but still cautious. “I'm optimistic enough to think that eventually, we'll get there,” said Cosford. “It's just really difficult … the big pharma companies are just not currently interested.” 

That’s not to say they won’t be in the future. Volkow added, “We’re starting to see new entrepreneurship and small companies being built up to develop the field of substance use disorder, which we didn't have before. It's still very limited, but I'm excited because we didn't have it in the past. And, there is increased recognition that this is something that we need to solve and address.”

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