Non-intoxicating cannabis compound may reverse opioid-induced brain changes

A new study has revealed that cannabidiol, a non-intoxicating compound found in the cannabis plant, may help prevent opioid relapse by repairing specific cellular damage in the brain. Researchers found that the compound reduced heroin-seeking behavior in rats by reversing genetic disruptions caused by drug use. The treatment appeared to target the brain’s structural support system and immune responses. These findings were published recently in the journal Biological Psychiatry.

Opioid use disorder is a chronic condition defined by a cycle of use, abstinence, and relapse. Even after a person stops using the drug, the risk of returning to it remains high. Relapse is often triggered by environmental cues. These cues can be anything associated with past drug use, such as specific people, places, or paraphernalia.

Current treatments for opioid addiction often involve substituting one opioid for another, less harmful one. While effective, these treatments have limitations and regulatory hurdles. There is a pressing need for non-opioid medications that can reduce cravings without addictive side effects.

Cannabidiol, commonly known as CBD, has emerged as a potential candidate for this role. Previous research has indicated that CBD can reduce cravings and anxiety in humans with a history of heroin use. However, scientists did not fully understand the biological mechanisms behind this effect.

To address this gap, a team of researchers led by Alexandra Chisholm and Yasmin L. Hurd investigated the molecular changes in the brain associated with CBD treatment. Yasmin Hurd is a prominent researcher in the field of addiction neurobiology at the Icahn School of Medicine at Mount Sinai. Alexandra Chisholm is the study’s first author.

The team focused their investigation on the nucleus accumbens. This brain region serves as a central hub for processing rewards and motivation. It plays a primary role in addiction and the response to drug-related cues. The nucleus accumbens is divided into two subregions: the core and the shell.

The researchers began the study by training male rats to self-administer heroin. The rats learned to press a lever to receive a dose of the drug. Each time the rats received the drug, a specific light turned on. This light served as a cue, creating a mental association between the visual signal and the drug’s effect.

After the training period, the rats went through a phase of abstinence. They were kept away from the drug for two weeks to simulate a person in recovery. This period allows the brain to transition from a state of intoxication to a drug-free state.

At the end of the abstinence period, the researchers administered either CBD or a placebo vehicle to the rats. They tested two different doses of CBD to see if the amount of medication influenced the outcome. The researchers then returned the rats to the environment where they had previously used heroin.

During this test, the cue light was turned on, but pressing the lever did not deliver any heroin. This setup is designed to measure “drug-seeking behavior.” The researchers counted how many times the rats pressed the lever in response to the light. This action serves as a proxy for craving and relapse vulnerability.

The behavioral results showed a clear effect. Rats that had been treated with heroin but received only the placebo pressed the lever frequently. They demonstrated a strong drive to seek the drug when presented with the cue.

In contrast, rats treated with CBD pressed the lever far fewer times. This reduction in drug seeking was most evident in the group that received the higher dose of 10 milligrams per kilogram. The treatment effectively dampened the urge to respond to the trigger.

Following the behavioral tests, the researchers analyzed the brain tissue of the rats. They used a technique called RNA sequencing to examine gene activity. They looked specifically at the nucleus accumbens core and the nucleus accumbens shell. This allowed them to see which genes were turned on or off by heroin exposure and how CBD affected them.

The analysis revealed that heroin use left a lasting genetic imprint on the brain. However, the impact was not uniform across the nucleus accumbens. The shell region showed a much more extensive disturbance than the core. Heroin exposure altered the expression of over 4,000 genes in the shell, compared to roughly 400 in the core.

The researchers then looked at how CBD influenced these disrupted genes. They found that CBD acted as a normalizing agent. In the rats treated with CBD, the expression levels of many genes that heroin had disturbed returned to levels similar to those seen in drug-naive animals.

This normalization was particularly strong in the nucleus accumbens shell. The study identified that CBD specifically restored genes related to two key biological systems. These were the extracellular matrix and the function of astrocytes.

The extracellular matrix is a complex mesh of proteins and carbohydrates that surrounds brain cells. It provides structural support and helps regulate communication between neurons. Heroin exposure appeared to degrade this structure. The data suggested that CBD helped rebuild or stabilize this critical scaffolding.

Astrocytes are star-shaped glial cells that support neurons. They manage the chemical environment of the brain and control inflammation. The study found that heroin caused an upregulation of a gene called Gfap, which is a marker for astrocyte activation and potential inflammation.

High levels of Gfap often indicate that the brain is reacting to injury or stress. In the rats treated with CBD, levels of Gfap were reduced. This suggests that CBD may lower neuroinflammation caused by opioid history.

Another critical finding involved a gene known as Slc1a2. This gene produces a protein responsible for clearing glutamate from the spaces between neurons. Glutamate is the brain’s main excitatory chemical messenger.

In the heroin-exposed rats, Slc1a2 expression was lower than normal. This reduction would likely lead to excess glutamate building up around neurons. Such a buildup can cause over-excitement in the brain circuits that drive craving.

CBD treatment restored Slc1a2 expression to near-normal levels. By doing so, CBD likely helps astrocytes clear glutamate more efficiently. This would restore chemical balance and reduce the overactive signaling that contributes to relapse.

The researchers also noted a connection between these cellular changes and the immune system. Upstream regulators, which are molecules that control gene expression, were identified in the analysis. Many of these regulators are involved in immune responses.

This connection implies that the brain’s immune system interacts with the structural matrix and support cells to drive addiction behavior. By modulating these immune-related pathways, CBD appears to interrupt the cycle of damage and repair that fuels drug seeking.

The study provides a detailed map of the molecular “signatures” associated with heroin relapse. It highlights the nucleus accumbens shell as a particularly sensitive region. The ability of CBD to reverse these specific signatures offers a biological explanation for its therapeutic potential.

However, there are limitations to this research. The study utilized only male rats. Biological sex can influence addiction and the response to treatments. It is not yet known if female rats would show the exact same molecular changes or respond to CBD in an identical manner.

Additionally, the study focused on gene expression. While gene activity is a strong indicator of cellular function, it does not always correspond perfectly to protein levels. Proteins are the functional molecules that carry out cellular tasks. Future research will need to confirm that these genetic changes result in corresponding changes in protein levels.

The researchers also noted that they did not include a group of drug-naive rats treated with CBD. This control would help determine if CBD affects these genes in a healthy brain or only in a brain altered by opioids. However, the primary goal was to see if CBD could reverse heroin-induced damage.

Future studies will likely investigate the functional consequences of these molecular changes. Scientists will want to prove that fixing the extracellular matrix or calming astrocytes directly causes the reduction in drug seeking. This would strengthen the case for targeting these specific systems in addiction treatment.

This research represents a step forward in understanding the biology of addiction recovery. It moves beyond observing behavior to identifying the cellular repair mechanisms that may enable recovery. By stabilizing the brain’s environment, CBD may offer a physiological shield against the cues that trigger relapse.

The study, “Cannabidiol Attenuates Heroin Seeking in Male Rats Associated With Normalization of Discrete Neurobiological Signatures Within the Nucleus Accumbens With Subregional Specificity,” was authored by Alexandra Chisholm, Jacqueline-Marie N. Ferland, Randall J. Ellis, and Yasmin L. Hurd.