Using multiple types of drugs at once, called polydrug or polysubstance use, is common among opioid users. However, polydrug use is heavily understudied, despite the fact that as many as 80 percent of opioid-related overdose deaths involve alcohol or other drugs.
Research from the Edwards Lab at BYU reveals that co-using morphine, an opioid, and tetrahydrocannabinol (THC), the psychoactive ingredient of marijuana, may expedite the development of addiction. This research may potentially lead to more effective tools for managing and preventing drug dependence and addiction.
Opioids are a class of highly addictive pain-relieving drugs that, from 1999 to 2021, have been responsible for nearly 645,000 overdose-related deaths in the US—approximately 280,000 of which have involved prescription opioids.1 Opioids encompass legal, commonly prescribed pain medications such as oxycodone, hydrocodone, and morphine, as well as illicit drugs such as heroin and fentanyl. Both opioids and cannabis (marijuana) are commonly prescribed to treat chronic pain and are increasingly co-prescribed.
“Being prescribed more than one type of drug is extremely common,” says Dr. Jeffrey Edwards, professor of cell biology and physiology and director of the BYU Neuroscience Center. “And the reality is that most individuals abusing drugs aren’t just abusing one drug—they’re co-abusing.”
Despite the increased mortality rates linked to polysubstance use, the mechanisms of drug interactions and how they affect addiction are less understood.
Addictive drugs act on a region of the brain called the ventral tegmental area (VTA), the brain’s “reward center.” Neurons in the VTA produce dopamine, a chemical responsible for feelings of reward and pleasure. Normally, the amount of dopamine released in the VTA is closely controlled by GABA neurons, which put “brakes” on the dopamine cells to prevent excessive release. But the Edwards Lab has shown that when the GABA neurons are exposed to commonly abused drugs such as opioids and THC, the GABA brakes are released in a process called long-term depression (LTD), a form of synaptic plasticity. Synaptic plasticity is the ability of connections between neurons in the brain to change over time in response to experiences. Releasing the GABA brakes in response to opioids or THC increases dopamine, which modifies plasticity in the VTA. The increase in dopamine levels through drug use changes the brain’s threshold for dopamine, making it more difficult for users to feel pleasure from natural dopamine levels. This is the hallmark of addiction.
So, what happens when both opioids and THC are used at the same time? To explore this question, researchers in the Edwards Lab exposed mice to either morphine, THC, or both drugs combined. When mice were exposed to either drug individually, changes in plasticity that were indicative of addiction took approximately seven days to develop. But when exposed to the combination of morphine and THC, addiction developed within a single day.
“The effect of combining both drugs is much more potent than you’d expect from looking at the effects of each drug individually,” says Michael Von Gunten (NEURO '25) , the PhD candidate spearheading the project. “We saw a rapid acceleration of the onset of addiction, which has serious implications for both prescription and recreational users.”
Based on these results, polysubstance use of morphine and THC appear to have a synergistic effect on the development of drug dependence, which is consistent with population data. This study calls for greater caution when co-prescribing opioids and cannabis for pain management and highlights the need for further research on polysubstance use for other combinations of drugs of abuse.
Currently, the Edwards Lab is exploring unique pharmacological interventions that may mitigate the effects of polydrug use on the VTA and the development of addiction.
“As we take our first steps in exploring the polysubstance effects of drugs like marijuana and opioids,” Edwards explains, “our research underscores the increasing need for the scientific and medical community to understand drugs’ combined effects so that we can make evidence-based decisions on public practices.”