The study was published in Nature Communications and led by researchers at the National Institute on Drug Abuse (NIDA) and the National Institute on Alcohol Abuse and Alcoholism (NIAAA), parts of the National Institutes of Health, at the NIH Clinical Center.
“We’ve known for a long time that the faster a drug enters the brain, the more addictive it is – but we haven’t known exactly why. Now, using one of the newest and most sophisticated imaging technologies, we have some insight,” said Nora Volkow, MD, NIDA Director, chief of the NIAAA Laboratory of Neuroimaging, and senior author on the study. “Understanding the brain mechanisms that underlie addiction is crucial for informing prevention interventions, developing new therapies for substance use disorders, and addressing the overdose crisis.”
People who smoke or inject drugs—two methods that deliver drugs to the brain quickly—often report doing so to get faster relief from withdrawal or to experience euphoria more quickly. However, drug smoking and injection are associated with developing a substance use disorder more quickly than taking drugs orally or by insufflation (e.g., snorting). In addition, injecting drugs is also associated with higher rates of infectious diseases and overdose. To better understand how route of drug administration impacts the brain’s response to the drug, researchers conducted a double-blind, randomized, counterbalanced clinical trial using simultaneous PET/fMRI imaging.
Twenty healthy adults participated in the trial. Over three separate sessions, participants received either a small dose of a placebo or of the stimulant drug methylphenidate, commonly known as Ritalin, orally or intravenously. Methylphenidate is a safe and effective prescription medication used for the treatment of attention deficit hyperactivity disorder (ADHD). For research purposes, methylphenidate can be a useful model drug to safely study the relationship between how drugs affect the brain and the subjective experience of drug reward.
After participants received the study drug or placebo, researchers then simultaneously looked at differences in dopamine levels (through PET imaging) and brain activity (through fMRI imaging) while people reported their subjective experience of euphoria in response to the drug.
The PET scan gave an estimate of how fast dopamine increased in the brain in response to the different drug administrations. Consistent with previous research, this study showed that when participants received methylphenidate orally, the rate of dopamine increases peaked more than an hour after administration. Comparatively, when participants received an intravenous injection of methylphenidate, the rate of dopamine increases peaked much faster – within 5 to 10 minutes of the administration.
Through the fMRI, researchers observed that one brain region, the ventromedial prefrontal cortex, was less active after both oral and intravenous administration of the study drug. However, two brain regions, the dorsal anterior cingulate cortex and the insula, which are part of the brain’s salience network, were activated only after receiving the injection of methylphenidate, the more addictive route of drug administration. These same areas of the brain were not activated after taking methylphenidate orally, the route with lower addiction potential. This finding was consistent among all 20 research participants.
The salience network attributes value to things in our environment and is important for recognizing and translating internal sensations—including the subjective effects of drugs. This research adds to a growing body of evidence documenting the important role that the salience network appears to play in substance use and addiction. For instance, studies have shown that people who experience damage to the insula, part of the brain’s salience network, can have a complete remission of their addiction.
In this study, researchers also asked patients to track the real-time, conscious experience of drug reward or euphoria in response to both the oral and intravenous dose of the medication. After receiving the drug intravenously, researchers noticed that the activity and connectivity of the salience network, observed via fMRI imaging, very closely paralleled almost every participant’s subjective experience of feeling high. When the imaging showed increased activity in this part of the brain, participants’ reports of feeling high increased. When the imaging showed decreasing activity in the salience network, participants’ reports of feeling high decreased. Researchers theorize that the network identified in this study is relevant not just for the chemical action of the drug, but also the conscious experience of drug reward.
The authors note that a key next step for this research will be to study whether inhibiting the salience network when someone takes a drug effectively blocks the feeling of being high, which could further support the salience network as an appropriate target to treat substance use disorders.
“I’ve been doing imaging research for over a decade now, and I have never seen such consistent and clear fMRI results across all participants in one of our studies. These results add to the evidence that the brain’s salience network is a target worthy of investigation for potential new therapies for addiction,” said Peter Manza, PhD, research fellow at NIAAA and lead author on the study.
This press release describes basic research findings. Basic research increases our understanding of human behavior and biology, which is foundational to advancing new and better ways to prevent, diagnose, and treat disease. Science is an unpredictable and incremental process—each research advance builds on past discoveries, often in unexpected ways. Most clinical advances would not be possible without the knowledge of fundamental basic research. To learn more about basic research, visit Basic Research – Digital Media Kit (NIH).
For more information on substance and mental health treatment programs in your area, call the free and confidential National Helpline 1-800-662-HELP (4357) or visit www.FindTreatment.gov.
Reference: P Manza, et al. Neural circuit selective for fast but not slow dopamine increases in drug reward. Nature Communications. DOI: 10.1038/s41467-023-41972-6 (2023).
###
About the National Institute on Drug Abuse (NIDA): NIDA is a component of the National Institutes of Health, U.S. Department of Health and Human Services. NIDA supports most of the world’s research on the health aspects of drug use and addiction. The Institute carries out a large variety of programs to inform policy, improve practice, and advance addiction science. For more information about NIDA and its programs, visit www.nida.nih.gov.
About the National Institutes of Health (NIH): NIH, the nation’s medical research agency, includes 27 Institutes and Centers and is a component of the U.S. Department of Health and Human Services. NIH is the primary federal agency conducting and supporting basic, clinical, and translational medical research, and is investigating the causes, treatments, and cures for both common and rare diseases. For more information about NIH and its programs, visit www.nih.gov.
About substance use disorders: Substance use disorders are chronic, treatable conditions from which people can recover. In 2021, over 46 million people in the United States had at least one substance use disorder. Substance use disorders are defined in part by continued use of substances despite negative consequences. They are also relapsing conditions, in which periods of abstinence (not using substances) can be followed by a return to use. Stigma can make individuals with substance use disorders less likely to seek treatment. Using preferred language can help accurately report on substance use and addiction. View NIDA’s online guide.
NIH…Turning Discovery Into Health®
END
