Little-known psychedelic drug reduces motivation to take heroin in rats, study finds

A study on rats found that administering 2,5-dimethoxy-4-iodoamphetamine before giving them an opportunity to take heroin reduced their motivation to do so—that is, it lowered the maximum effort the animals were willing to expend to obtain a single dose of heroin. The study also identified a specific type of receptor on neural cells that is crucial for this effect. The paper was published in Neuropharmacology.

Opioid use disorder is a chronic medical condition characterized by the compulsive use of opioids despite negative consequences to health, relationships, and daily life. It involves physical dependence, tolerance, and withdrawal symptoms when opioid use is reduced or stopped. Common opioids associated with opioid use disorder include prescription painkillers like oxycodone and fentanyl, as well as illicit drugs such as heroin.

Mainstream treatments for opioid use disorder involve giving the patient a substitute drug, a substance that activates the same receptors in the brain that opioids attach to when exerting their effects. However, many of these substitute drugs come with the same disadvantages as opioids themselves, such as the risk of overdose and abnormally slow or shallow breathing, which can sometimes be life-threatening (respiratory depression). That is why scientists are still searching for an alternative that does not produce these effects.

Study author Joel Bonilla and his colleagues wanted to explore whether the psychedelic drug 2,5-dimethoxy-4-iodoamphetamine, or DOI, has the potential to be used as a substitute drug in opioid use disorder treatment. Previous studies showed that its use might reduce the motivation to consume fentanyl and alcohol, so they wanted to determine whether it could have similar effects in rats accustomed to consuming heroin and alcohol.

DOI strongly activates certain receptors in the brain called 5-HT2A and 5-HT2C, which normally respond to the neurotransmitter serotonin, leading to altered perceptions, mood changes, enhanced sensory experiences, and changes in thought patterns.

The researchers conducted a study on Wistar rats of both sexes. Wistar rats are a widely used albino strain of laboratory rats known for their docile nature, rapid growth, and genetic consistency. The rats were 50–60 days old at the start of the study and were kept in a temperature- and humidity-controlled environment with free access to food and water.

Using an intricate apparatus, the rats were trained to self-administer substances. One group of rats was trained to self-administer alcohol and heroin, while the other group self-administered heroin and saccharin. The rats self-administered heroin directly into their jugular veins by pressing a lever. Similarly, they received access to alcohol or saccharin solutions. One dose of heroin amounted to 40 μg/50 μl.

After the rats learned the self-administration procedure, the researchers gradually increased the number of lever presses needed to obtain the desired substance. At one point, the rats were given the opportunity to press the lever but did not receive the substance regardless of the number of presses. These trials are called progressive ratio tests. They were conducted to assess the rats’ breakpoints—that is, the highest effort (number of lever presses) a rat was willing to exert before stopping—indicating how motivated the rat was to receive a dose of the substance in question.

The first series of progressive ratio tests was conducted without administering any substances. Subsequent tests were conducted after administering DOI, after administering substances meant to block the receptors in the brain that DOI activates, and after administering both DOI and these blockers (receptor antagonists).

Results showed that the rats’ motivation to obtain heroin (i.e., breakpoint) was higher than their motivation to obtain alcohol. However, their motivation to obtain heroin was reduced after receiving a shot of DOI. This effect was observed 30 minutes after DOI administration. When the researchers also gave the rats a substance that blocks the 5-HT2A receptors, the effect of DOI on heroin motivation disappeared. However, it did not disappear when the 5-HT2C receptors were blocked. This indicated that the effects of DOI are achieved through the 5-HT2A receptors. DOI had no effect on the rats’ motivation to obtain alcohol.

“These data support the view that psychedelic drugs like DOI may have therapeutic effects on opioid use in individuals with OUD [opioid use disorder] and comorbid alcohol use, by acting as a 5-HT2A receptor agonist,” the study authors concluded.

The study sheds light on the potential therapeutic effects of 2,5-dimethoxy-4-iodoamphetamine in opioid use disorder. However, it should be emphasized that this study was conducted on rats, not humans. While humans and rodents share many physiological similarities, they are still very different species, and the effects in humans may not be identical.

The paper, “The psychedelic drug DOI reduces heroin motivation by targeting 5-HT2A receptors in a heroin and alcohol co-use model,” was authored by Joel Bonilla, Giuseppe Giannotti, Nathaniel P. Kregar, Jasper A. Heinsbroek, David E. Olson, and Jamie Peter.