New research published in the journal Neuropharmacology has found that low doses of a psychedelic drug called DOPR significantly increased motivation in mice with low baseline motivation—without triggering signs of hallucinogenic activity. The findings suggest that microdoses of psychedelic compounds may enhance goal-directed behavior in states of low motivation, potentially offering a new avenue for treating symptoms such as amotivation in depression, while avoiding the intense subjective effects typically associated with psychedelics.
Amotivation—defined as a lack of drive to pursue rewards or goals—is a common and debilitating symptom in many psychiatric disorders, including major depressive disorder and schizophrenia. Existing treatments like selective serotonin reuptake inhibitors often fail to address motivational deficits and take weeks or months to show therapeutic effects. Alternative treatments such as ketamine offer faster symptom relief, but they are not without side effects or limitations.
There has been growing interest in the idea that psychedelics such as psilocybin and LSD could offer rapid-acting relief from depression. However, these drugs typically induce strong hallucinogenic effects, which limits their widespread use and necessitates supervision by trained clinicians. This has led researchers to explore the potential of “microdosing”—the administration of psychedelic drugs at doses too low to produce noticeable psychedelic experiences—as a possible workaround.
In this study, the researchers investigated whether sub-hallucinogenic doses of a synthetic psychedelic called 2,5-Dimethoxy-4-propylamphetamine (DOPR) could enhance motivation in mice. DOPR is structurally related to other psychedelic compounds in the phenethylamine class and is known to activate the 5-HT2A serotonin receptor, which is implicated in the effects of classical psychedelics. The goal was to determine whether DOPR could increase effort-based behavior at doses that do not produce psychedelic-like activity.
To assess motivation, the team used a task called the progressive ratio breakpoint task (PRBT), a behavioral test that measures how much effort an animal is willing to exert to obtain a reward. Mice were trained to nosepoke for drops of a sweet liquid. The number of nosepokes required increased after every few rewards, and the highest number of responses completed before the mouse stopped trying was recorded as the “breakpoint.” This task is used in both animal and human research as a proxy for motivational drive.
The researchers tested 80 mice (half female) using a within-subject design. Each mouse received several different doses of DOPR (ranging from 0.0106 to 0.32 mg/kg) across multiple test sessions. For comparison, the researchers also administered amphetamine, a well-known stimulant that increases motivation. A separate group of mice was tested using the head twitch response (HTR), a behavior in rodents used to gauge whether a compound produces hallucinogenic-like effects.
The results were striking. Low-performing mice—those with the lowest baseline motivation—showed significantly increased breakpoint scores after receiving low doses of DOPR. The effect was most robust at doses of 0.0106, 0.106, and 0.32 mg/kg. Notably, high-performing mice did not show any change, indicating that the drug’s effects were specific to those starting in a low motivational state. This pattern mirrored the effects of amphetamine, which also increased motivation only in low-performing mice.
To assess whether these same doses of DOPR produced psychedelic-like activity, the team measured head twitch responses in a separate experiment. This behavior, commonly used in rodent studies, is highly predictive of whether a drug will produce hallucinogenic effects in humans. The researchers found that DOPR only induced significant HTR at doses of 0.1 mg/kg and above. The lowest dose tested, 0.01 mg/kg—one of the doses that enhanced motivation—did not produce a detectable increase in HTR. This suggests that the motivational benefits seen at low doses occurred without activating the full range of psychedelic effects.
To better understand how DOPR works at a molecular level, the researchers conducted additional pharmacological tests. These showed that DOPR acts as a potent agonist at the 5-HT2A receptor, similar to other psychedelic drugs, but with limited activity at other serotonin receptor subtypes such as 5-HT1A. This receptor selectivity may make DOPR particularly useful for isolating the therapeutic aspects of psychedelics from their more disruptive hallucinogenic effects.
Importantly, this study offers preclinical evidence that microdoses of psychedelics can produce targeted behavioral benefits—specifically in subjects experiencing a low motivational state—without the side effects typically associated with higher doses. This supports the possibility that psychedelics might be able to treat depression-related amotivation through mechanisms that are separate from the altered states of consciousness they usually induce.
But the researchers note several limitations. While the progressive ratio breakpoint task is widely used to measure motivation, the study did not use a full model of depression, such as social defeat stress or chronic inflammation. The division of animals into high- and low-performing groups based on a median split is also not a perfect stand-in for clinical populations. Future work will need to confirm these effects in more robust models of psychiatric illness and explore whether DOPR or related compounds can also affect other depression-related symptoms such as cognitive dysfunction or reward sensitivity.
Additionally, while the study found that DOPR increases motivation at low doses, the precise contribution of different serotonin receptors remains uncertain. DOPR also activates the 5-HT2C receptor, which has been implicated in appetite and motivation. However, previous studies suggest that selective activation of 5-HT2C actually reduces motivation, making it unlikely that this receptor is responsible for the observed effects.
The study, “Low (micro)doses of 2,5-dimethoxy-4-propylamphetamine (DOPR) increase effortful motivation in low-performing mice,” was authored by Michael Noback, Johnny A. Kenton, Adam K. Klein, Zoe A. Hughes, Andrew C. Kruegel, Yasmin Schmid, Adam L. Halberstadt, and Jared W. Young.
