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.

 

Youth in Crisis

Research tells a statistical horror story of what is happening every day in America regarding our youth. 1,000 unwed teenage girls become mothers. 1,106 teenage girls get an abortion. 4,219 teenagers contract a sexually transmitted disease. 500 adolescents begin using drugs. 1,000 adolescents begin drinking alcohol. 135,000 kids bring a gun or other weapon to school. 3,610 teens are assaulted, 80 of which are raped. 2,200 teens drop out of high school. 2,750 kids watch their parents separate or get a divorce. 90 kids are taken from their parents’ custody and placed in foster care, a group home, or institutional care. 7 kids age 10-19 are murdered. 7 juveniles age 17 and under are arrested for murder. 6 teens commit suicide. Every day!

Many of America’s 28 million teens face struggles and crises that most adults would find difficult to bear. For example, one in eight has an alcoholic parent. One in five lives in poverty. More than one in five (22%) live in single-parent homes. More than on in fifty live with no parent at all. Moreover, research and experience reveal that teens in evangelical churches are by no means immune to such problems. A survey of twenty-three national Christian youth leaders involved in denominational and parachurch ministries identified such issues as premarital sex, pornography, sexual abuse, emotional abuse, abortion, parental divorce, alcoholism, drug addiction, and suicide as issues faced by their kids – church youth, Christian youth. Issues those leaders consider both important and urgent for today’s youth and the adults who care for them.

Youth leaders helped identify the fifty most basic, pressing problems faced by adolescents today. Problems that range from emotional issues (like loneliness and depression) and relational issues (such as love, dating, and peer pressure) to sexual issues, abuse, addictions, and vocational issues (like finding God’s will and choosing a career or ministry).

The teen years are vital to establishing a strong foundation for adulthood. Problems such as addiction, mental illness, violence, pregnancy and suicidal thoughts are tough enough to face as adults. They are compounded in teens by emotional immaturity, lack of experience and judgment, impulsiveness, confusion, bullying, broken homes, academic pressures, and finding their place in society. Kids are quite vulnerable at this phase of their development. It is truly sinful that some adults prey on these vulnerabilities. What can be more evil than trafficking drugs to teens, taking advantage of their sexual curiosity, or manipulating them through playing on their emotions? Working with adolescents as an addictions counselor or mental health worker can be both frustrating and challenging, but it is some of the most vital work we can undertake as adults.

Drunkenness is a sin. The Bible is clear on this point. But once a person is an alcoholic, once he has allowed his will to be taken hostage by alcohol, he is sick. He can no longer help himself. To tell an alcoholic to shape up and stop drinking is like telling a man who has just jumped out of a nine-story building to fall only three floors. It just isn’t going to happen. If we define alcoholism as a physical disease, without including a spiritual dimension, we completely miss the fact that alcoholism affects a person physically, mentally and spirituality. An alcoholic will not get well unless he is treated on all three levels.

There is no single reason for teenagers to start using drugs and alcohol. They see their parents and other adults drinking alcohol, smoking, and, sometimes, abusing other substances. Also, the teen social scene often revolves around drinking and smoking pot. Sometimes friends urge one another to try a drink or smoke something, but it’s just as common for teens to start using a substance because it’s readily available. They see all their friends enjoying it. In their mind, they see drugs and alcohol as a part of the normal teenage experience.

Many factors influence whether an adolescent tries drugs, including the availability of drugs within their neighborhood or school, and whether their friends are using them. Family environment is also important. Exposure to violence, physical or emotional abuse, mental illness, or drug use in the household, increase the likelihood that an adolescent will use drugs. Also, an adolescent’s inherited genetic vulnerability, personality traits like poor impulse control or a high need for excitement, mental health conditions (such as depression, anxiety, or ADHD), and believing drugs are cool or harmless, make it more likely that an adolescent will use drugs.

Most teens do not escalate from trying drugs to developing an addiction or other substance use disorder, but even experimenting with drugs is a problem. Drug use can be part of a pattern of risky behavior, including unsafe sex, driving while intoxicated, or other hazardous, unsupervised activities. In cases when a teen does develop a pattern of repeated use of drugs or alcohol, it can pose serious social and health risks, including school failure, problems with family and other relationships, loss of interest in normal healthy activities, impaired memory, increased risk of contracting an infectious disease (like HIV or hepatitis C) via risky sexual behavior or sharing contaminated needles, mental health problems, and the the real risk of suffering a fatal overdose.

Unfortunately, teenagers who lack confidence report that they’ll do things under the influence of drugs or alcohol that they might not do otherwise. This is actually part of the appeal of drugs and alcohol; it gives the user courage to dance, or to kiss a girl they’re attracted to. Alcohol and other drugs tend not only to loosen inhibitions, they also alleviate social anxiety. Getting drunk or high with other teens makes you feel you have something in common with them. There is the mentality that if you do or say anything stupid, everyone will just think you had too many drinks or smoked too much weed.

The high produced by drugs represents a flooding of the brain’s reward circuits with much more dopamine than natural rewards generate. In fact, oxycodone is 20 to 30 times more potent than dopamine. This creates an especially strong drive to repeat the experience. The adolescent, already struggling with balancing impulse and self-control, is more likely to take drugs again without adequately considering the consequences. If the experience is repeated, the brain will reinforce neural links between pleasure and drug-taking, making the association stronger and stronger. Chronic drug use not only realigns the user’s priorities, but also may alter key brain areas necessary for judgment and self-control, thereby reducing the ability to control or stop getting high. This is why, despite popular belief, willpower alone is typically insufficient to overcome addiction. Drug use compromises the very part of the brain that make it possible to say no.

When substance use disorder occurs in adolescence, it affects key developmental and social transitions, and can interfere with normal brain maturation. These potentially lifelong consequences make addressing adolescent drug use an urgent matter. Chronic marijuana use in adolescence, for example, has been shown to lead to a loss of IQ that is not recovered even if the individual quits using in adulthood. Impaired memory or thinking ability and other problems caused by drug use can derail a young person’s social and educational development and hold him or her back in life. Persistent cannabis users show neuropsychological decline from childhood to midlife. Proceedings of the National Academy of Sciences of the United States of America Oct 2;109(40):E2657–E2664 (2012).

Adolescents are less likely than adults to feel they need help, and usually won’t seek treatment on their own. Given their shorter history of using drugs (as well as parental protection), adolescents may have experienced relatively few adverse consequences from their drug use; their incentive to change or engage in treatment may correspond to the number of such consequences they have experienced. Also, adolescents may have more difficulty than adults seeing their own behavior patterns (including causes and consequences of their actions) with enough detachment to tell they need help. Only 10 percent of 12- to 17-year-olds needing substance abuse treatment actually receive any services. When they do get treatment, it is often for different reasons than adults. By far, the largest proportion of adolescents who receive treatment are referred by the juvenile justice system. Given that adolescents with substance use problems often feel they do not need help, engaging young patients in treatment often requires special skills and patience.

When substance use disorders are identified and treated in adolescence, especially if they are mild or moderate, they frequently give way to abstinence from drugs with no further problems. Relapse is a possibility, and should not be seen as a sign that treatment failed. Rather, it should be seen as an occasion to engage in additional or different treatment modalities. Averting and detecting relapse involves cooperation by the adolescent, monitoring by parents and teachers, and follow-up through outpatient treatment providers. Although recovery programs are not a substitute for formal evidence-based treatment, they may help some adolescents maintain a positive and productive drug-free lifestyle that promotes meaningful and beneficial relationships and connections to family, peers, and the community both during and after treatment. Whatever services or programs are used, an adolescent’s path to recovery will be strengthened by support from family members, non-drug-using peers, the school, and others in his or her life.

This is truly a battle we must win. The future of our children depend on it. I feel both honored and challenged by the calling God has placed on my life to counsel teens and young adults who are struggling with addiction and mental illness. Rather than cry about how my life has turned out to this point as a result of nearly four decades of drug and alcohol abuse, I plan on focusing my attention and energy on helping teenagers avoid  a lifetime of substance abuse and the literally hundreds of complications that usually result. Please join me in praying for the young adults and their families being decimated by addiction.