Scientific Findings and Achievements in Drug Abuse Research for 2018

From the Blog of Dr. Nora Volkow, Director
National Institute on Drug Abuse
January 7, 2019

Dr. Volkow noted, “As we enter 2019, it is a good time to take stock of what NIDA accomplished over the past year. As always when I look back at the research being done by NIDA grantees and partners, I am amazed at the wealth of knowledge being created from our investments. Here I want to highlight just a few of the many outstanding developments in basic science, new therapeutics, and epidemiology and prevention research from the year that just ended.”

Basic Science Advances

Recent years have seen major advances in the understanding of receptor functioning. In March 2018, a team of researchers at NIDA’s Intramural Research Program (IRP) reported in Nature Communications on an advance in understanding G protein-coupled receptors (GCPRs), a large family of receptors that play an important role in the brain’s response to drugs. These receptors often assemble into larger complexes, but it has been unknown whether those complexes are merely the product of random collision between signaling molecules as they move across the membrane or whether they pre-form into complexes that serve specific functions.

The IRP team found that two common GCPRs in the reward pathway, adenosine A2A and dopamine D2 receptors (along with their G proteins and target enzyme), assemble into preformed macromolecular complexes that act as computation devices processing incoming information and enabling the cell to change its function based on that information. This knowledge could facilitate the development of more precise medication targets.

In June 2018, a team of NIDA-funded researchers at the University of California–San Francisco, along with colleagues in Belgium and Canada, reported in Neuron magazine that they had developed a genetically-encoded biosensor that can detect activation of opioid receptors and map the differences in activation within living cells produced by different opioids. The fact that opioids bind to receptors on structures within the cell—and not just on the cell membrane—was itself a novel finding, but the team also discovered striking differences in how endogenous versus synthetic opioids interact with these structures.

While endogenous peptides activated receptors on membrane-bound compartments within the cell called endosomes, synthetic opioid drugs activated receptor sites on a separate structure called the Golgi apparatus (which acts as a hub for routing proteins to various destinations in the cell). These very different patterns of activation within the cell may lead to greater understanding of why non-peptide opioid drugs produce tolerance as well as the behavioral distortions seen with opioid misuse and addiction whereas the body’s endogenous opioid peptides do not.

The same month, a team led by neuroscientists at UCLA studying narcolepsy reported research in Science Translational Medicine based on their discovery that postmortem brains from individuals who had been addicted to heroin show greatly increased numbers of neurons producing the neuropeptide hypocretin. Hypocretin helps regulate wakefulness and appetite, and a diminished number of cells in the brain producing it is associated with narcolepsy. The researchers went on to conduct a study administering morphine to mice, which as observed in the postmortem study produced increased numbers of hypocretin neurons. The results suggest that increases in these cells and in brain hypocretin could underlie the complaints of sleep problems in patients with an opioid use disorder (OUD). Since insomnia is a factor that contributes to drug taking in OUD and other addictions, strategies to counteract hypocretin signaling might have therapeutic benefits.

Prevention and Treatment

Last year, NIDA-funded research resulted in new therapeutics and apps for opioid use disorder. In May, the FDA approved lofexidine, the first medication approved to treat physical symptoms of opioid withdrawal. In December, the FDA cleared the first mobile health app intended to help retain patients with OUD in treatment, called reSET-O. It uses interactive lessons to deliver a community reinforcement approach therapy and enables users to report cravings and triggers to their health care provider between office visits, along with whether or not they have used Suboxone. NIDA funded the clinical trial that led to this app’s approval. A version called reSET was approved in 2017 to help with behavioral treatment of several non-opioid substance use disorders.

NIDA-funded research in epidemiology and prevention also added greatly to the knowledge of new drug trends in 2018. Last month’s striking findings on monitoringthefuture.org alerted us to escalating use of vaping devices among adolescents. Although most adolescents in 2017 claimed they used vaping devices only to vape flavors, this year most reported they used them to vape nicotine. Alarmingly, there was also an increase in vaping of cannabis.

Several other studies published in 2018 increased our understanding of factors that may lead youth to experiment with vaping. For example, a longitudinal cohort study by researchers at Yale and reported in Addictive Behavior found that exposure to ads for e-cigarettes on social media sites like Facebook significantly increased the likelihood of subsequent e-cigarette use among middle and high school students in Connecticut. In another study published in Preventive Medicine, the researchers also found that higher socioeconomic status was associated with greater exposure to e-cigarette advertising (which in turn was associated with increased likelihood of use)—important data that can help with targeting prevention efforts. Other work by UCSF researchers and published in Pediatrics found that e-cigarette use in adolescents was positively associated with being a smoker of conventional cigarettes, lending further support to the view that these devices are not diverting youth from smoking cigarettes but may be having the opposite effect in some users.

Looking To The Future

This year the Adolescent Brain Cognitive Development (ABCD) Study successfully completed recruitment of 11,874 participants, ages 9-10, who will be followed for 10 years, through young adulthood. The study, which is being conducted at 21 research sites around the country, is using neuroimaging to assess each individual’s brain development while also tracking cognitive, behavioral, social, and environmental factors (including exposure to social media) that may affect brain development and other health outcomes. The first release of anonymized data was made available so that both ABCD and non-ABCD researchers can take advantage of this rich source of information to help answer novel questions and pursue their own research interests.  Last year alone, the data resulted in more than 20 publications.

 

How Heroin Kills

The following information appeared in The Sunday Item, April 3, 2016, Sunbury, Pennsylvania.

Teresa Stoker gently pulls a sterling silver necklace from beneath the neck of her gray sweatshirt and holds it out beyond her chin. Ashes of 27-year-old Mark Stoker are piled inside a tiny cylinder, strung next to an imprint of her youngest son’s right thumbprint. His two siblings keep their brother’s ashes in keepsake key chains. Their mother has one of those, too. Mark died February 4, 2016 of a heroin overdose inside a New Columbia motel – one of 13 tri-county residents dead or suspected to have died of a drug overdose in 2016, according to coroners from Northumberland, Snyder and Union counties.

Mark was alone when motel staff found him after he failed to check out of his room. He was alone the day before, overdosed again in heroin and dumped by an acquaintance in the parking lot of a Burger King in Williamsport, PA, rain pouring onto his unconscious body, until passersby came to his aid and dialed 9-1-1.

He was supposed to be at his mother’s home in Shamokin Dam that day. They were supposed to have dinner and watch TV together. That had been the routine for days. He had stayed off heroin for six months, but he was growing irritable. His suboxone prescription was running short. He didn’t have consistent rides to counseling. He tried to make it work. He sliced the medicated film in half. As his supply dwindled, he sliced it in fours.

When Teresa pulled into her driveway on February 3rd, she could see through the blinds hung in the front window. “I knew he wasn’t in there,” she says.

Two months after his death, Mark’s family is left to reconcile love and pain, guilt and forgiveness – within themselves and within their own relationships fractured by a loved one’s fatal drug addiction. “He was the link that brought us together, and he was the one that pulled us apart,” says his sister and eldest sibling, Desiree. “He wasn’t long for this world,” adds Teresa. “He fought this to the very end,” says his brother Matt. “Mark didn’t really have a choice.”

The Stoker kids’ father died early in their lives. Mark was only 2 years old. Matt wonders if it was the impetus for mental health issues Mark would develop in life, particularly depression. Anxiety and depression are often evident in the psyche of a drug addict, according to the National Institute on Drug Awareness. “Addiction is a mental health issue,” says Dr. Rachael Levine, Pennsylvania’s physician general, who is among the officials at the forefront in addressing the Keystone State’s heroin and opioid addiction crisis. “It is not a moral failing.”

Mark sought help, and sometimes he sought it himself. He was no stranger to rehab. He’d been in and out of treatment several times, both in Pennsylvania and elsewhere. His family stood by his side the best they could, the only way they knew how. They encouraged him to lead a clean life, showed pride when he landed new jobs, sat bedside when he was hospitalized for an overdose. “Sometimes I look back and think we were fooling ourselves,” Matt says.

Matt and Desiree were the academics in the family. The former is enrolled in the physician assistant program at Pennsylvania College of Technology, and the latter is a registered nurse at Geisinger Medical Center in Danville, PA. Mark was no fool, either. His mind was for mechanics. He once rebuilt his own motorcycle after he wrecked it. Then he sold it and traded up for a better ride. His career path was in electrical work. On one job, he was hanging by a harness from a helicopter 200 feet above the ground repairing high-voltage lines. His family describes him as witty and charming, kind and sensitive, resilient and rebellious.

A quick learner, fearless in life’s pursuit, Mark hit dirt bike jumps taller than himself before he was a teen. He took quickly to Black Diamond slopes when he began to ski and bagged an eight-point buck on his first hunt. He was just 10 when he picked up on how to drive a stick shift. Accidents along the way created a need for pain relief. It’s very important to note that the American Society of Addiction Medicine found 4 in 5 new heroin users started by abusing prescription painkillers. Count Mark among the 80 percent. According to Mark’s mother, he was given pain meds at 14 when he had a wisdom tooth extracted. He took painkillers at 16 after having his gallbladder removed. Again, he took narcotic pain medication at 18 after being involved in a motorcycle accident.

Mark was 23 in 2012 when he developed painful kidney stones. His behavior suddenly changed. He became withdrawn, choosing to spend more time than normal alone in his bedroom. He was in legitimate need of relief from pain, but looking back, this is when his family says they first recognized signs of addiction. He’d been abusing oxycodone he was getting from three separate doctors. Maybe he needed relief the next summer when he stole Vicodin from his mother’s medicine cabinet.

It was September of that same year when Mark’s family first saw him experience a heroin overdose. He had borrowed his sister’s car. She found him slumped over in the driver’s seat as the engine idled – eyes glazed, sweat pooled in a cup holder. Mark’s sister dialed some of his recent calls on his cell phone. Someone told her, “He might be doing heroin.” She flipped out. The pock marks on the back of Mark’s hands weren’t bug bites as she thought on first glance. They were injection sites.

There would be more overdoses for Mark between September 2013 and the night he died in February 2016. Once his mother got a call from a Virginia state trooper. Mark overdosed in a hotel room while he was out of state on a job. Another time he was dumped at the doors of Evangelical Community Hospital in Lewisburg, PA, “dead on arrival,” as Teresa says. Attempts at recovery followed. Twenty-eight days at a Virginia facility didn’t take. The Stokers were more hopeful after a 28-day stay at Father Martin’s Ashley in Maryland, but again it didn’t help. He walked out of a rehab in White Deer, PA one week after he checked himself in.

Jobs, friendships, girlfriends – all lost by Mark to addiction, an addiction that strained an already complicated relationship, and ultimately led to his loss of parental rights to his daughter. He spoke often about the little girl, wrote about her in his journal. Teresa holds dear the few photographs she has of the two together.

A study on addiction by the Center for Rural Pennsylvania determined only 1 in 8 Pennsylvanians can afford treatment services. Geisinger Health System’s latest needs assessment says lack of insurance, cost of care, and transportation are barriers to treatment. More importantly, there simply aren’t enough providers to meet demand.

Mark had health insurance through the Health Insurance Marketplace. His mother says it didn’t cover the $150 monthly cost for suboxone, or the $100 cost per session for addictions counseling. His mother was in counseling herself, and with Mark out of work, she was covering all the bills. “We all knew he should be on [suboxone]…but we couldn’t afford it,” Teresa says.

And so the afternoon of February 4th, one day after Mark’s life was saved after he was found in the parking lot of the fast-food restaurant, came a familiar phone call to Teresa. One the whole family expected and equally feared. It was the state police. They didn’t tell her, but she knew. This time, Mark was dead.