The psychedelic drug DOI reduces heroin motivation by targeting 5-HT2A receptors in a heroin and alcohol co-use model
J. Alfred Bonilla, Giuseppe Giannotti, Nathaniel P. Kregar, Jasper A Heinsbroek, David E. Olson, Jamie Peters
Neuropharmacology September 26, 2024 DOI: 10.1016/j.neuropharm.2024.110163 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Preclinical experimental study Peer reviewed |
|---|---|
| Population | Male and female rats |
| Interventions | DOI MDL 100 907 SB-242084 |
| Dose | 0.4 mg/kg DOI, 0.3 mg/kg MDL 100,907, 0.5 mg/kg SB-242084 |
| Duration | Weeks of behavioral training |
| Topics | Serotonin |
| Keywords | Heroin Drug Pharmacology Alcohol |
| Citations | 12 |
| Key findings | DOI reduced heroin motivation in rats via 5-HT2A receptor agonism, with no effect on alcohol motivation. |
Abstract
There has been a recent renewed interest in the potential use of psychedelic drugs as therapeutics for certain neuropsychiatric disorders, including substance use disorders. The psychedelic drug 2,5-dimethoxy-4-iodoamphetamine (DOI) has demonstrated therapeutic efficacy in preclinical models of opioid use disorder (OUD). Alcohol is commonly co-used in individuals with OUD, but preclinical models that recapitulate this comorbidity are lacking. We developed a polydrug model wherein male and female rats were allowed to self-administer intravenous heroin and oral alcohol (or saccharin control solution) over weeks of behavioral training, and then we conducted a series of progressive ratio tests to assess the animals' motivational state for heroin and alcohol. In this model, motivation for heroin is higher than alcohol, and DOI (0.4 mg/kg) administered prior to testing significantly reduced heroin motivation measured as the animals' break point, or maximum effort the animal is willing to expend to obtain a single infusion of heroin. The 5-HT2A receptor antagonist MDL 100,907 (0.3 mg/kg), but not the 5-HT2C receptor antagonist SB-242084 (0.5 mg/kg), blocked the therapeutic effect of DOI on heroin motivation. No significant effects on alcohol break points were observed, nor did MDL 100,907 or SB-242084 have any effect on break points on their own. These data support the view that psychedelic drugs like DOI may have therapeutic effects on opioid use in individuals with OUD and comorbid alcohol use, by acting as a 5-HT2A receptor agonist.
Comparable studies
Other preclinical and animal studies on serotonin, most cited first.
| Study | Year | Design | Participants |
|---|---|---|---|
| Psilocybin induces rapid and persistent growth of dendritic spines in frontal cortex in vivo Mice | 2021 | Observational cohort | |
| Neurotoxicity of the psychedelic amphetamine, methylenedioxymethamphetamine. Rats (implied by typical neurochemical study context) | 1987 | Experimental study | |
| Psychedelics promote neuroplasticity through the activation of intracellular 5-HT2A receptors In vitro and in vivo (rodent) models | 2023 | Experimental study | |
| 3,4-Methylenedioxymethamphetamine and 3,4-methylenedioxyamphetamine destroy serotonin terminals in rat brain: quantification of neurodegeneration by measurement of [3H]paroxetine-labeled serotonin uptake sites. Rat brain | 1987 | Animal experiment | |
| Comparison of the monoamine transporters from human and mouse in their sensitivities to psychostimulant drugs Human and mouse dopamine, norepinephrine, and serotonin transporters expressed in cells | 2006 | In vitro laboratory study |
Citations in the library
Cited by 8
- The psychedelic (-)-2,5-dimethoxy-4-iodoamphetamine [(-)-DOI] demonstrates efficacy in reducing cocaine reward and motivation in male rats. Psychopharmacology August 1, 2025
- Emerging medications and pharmacological treatment approaches for substance use disorders. Pharmacology, Biochemistry, and Behavior March 1, 2025
- Psychedelics as pharmacotherapeutics for substance use disorders: A scoping review on clinical trials and perspectives on underlying neurobiology British Journal of Pharmacology September 2, 2025
- Short- and Long-Acting Psychedelics: Structure-Activity Relationships, Pharmacology, and Implications for Neuropsychiatric Therapeutics. ACS Chemical Neuroscience June 17, 2026
- Effects of Psychedelics Lysergic Acid Diethylamide and R (–)-2,5-Dimethoxy-4-Iodoamphetamine on Oral Opioid Consumption and Naloxone-Precipitated Withdrawal in Male C57Bl/6J Mice Psychedelic Medicine March 28, 2026
and 3 more in the library
Cites 22
- A non-hallucinogenic psychedelic analogue with therapeutic potential. Nature 2021
- The abuse potential of medical psilocybin according to the 8 factors of the Controlled Substances Act Neuropharmacology June 5, 2018
- Effects and aftereffects of ibogaine on morphine self-administration in rats. European Journal of Pharmacology April 3, 1991
- Psilocybin targets a common molecular mechanism for cognitive impairment and increased craving in alcoholism Science Advances November 17, 2021
- An analog of psychedelics restores functional neural circuits disrupted by unpredictable stress Molecular Psychiatry May 25, 2021
and 17 more in the library