The hallucinogenic renaissance: screening for drug abuse potential

A growing body of evidence suggests that hallucinogenic compounds may provide significant therapeutic value in treating traumatic brain injuries (TBIs) and psychiatric disorders. However, to realize this value, researchers need to contend not only with the pharmacology, but also the fears associated with psychedelics: risks of abuse and historical stigma, which links psychedelics to the risk of self-harm and insanity.

Drug abuse is the potential for repeated, non-medical uses of a compound, often recreationally. “Abuse may cause chemical changes in the brain that lead to addiction,” explains Mateusz Dudek, a Senior Client Manager at Charles River Laboratories, Finland.

Despite these risks, the growing need for effective mental health care has propelled research into psychedelics towards the mainstream. “We’ve conducted many studies into how compounds like psilocybin or N,N-Dimethyltryptamine (DMT) — two of the most common psychedelics — help with conditions like depression, anxiety, post-traumatic stress disorder, TBI, and stroke,” reports Dudek. “Activation of some of the 5-HT receptors and induction of neuronal plasticity are reported to be primary drivers.”

But because of the potential drawbacks, psychedelic-drug development necessarily includes screening prospective compounds for drug abuse liability, which is not a trivial task.

Psychedelic screening and neuroplasticity

“Rodents can't tell us what they're feeling, so we’ve had to develop tests where their behaviour can demonstrate how they feel about the drug,” explains Michael Gill, director of in vivo operations at Charles River’s South San Francisco laboratory.

One such test is the head-twitch response. Drug-treated rodents are monitored for head movements – more head movement correlates to higher hallucinogenic and abuse potential. However, this test alone is not adequate. Researchers like Gill will often use a combination of involuntary administration, conditioned place preference, and self-administration tests. Here, rodents are given the psychedelic through various means, and then presented the opportunity to seek out, or avoid the drug.

“Self-administration is usually the gold standard,” says Gill. “If an animal's willing to self-administer the drug peripherally, that's a strong indicator of abuse potential.”

With these tests, researchers are better able to study and develop psychedelics for therapeutic applications. Of particular interest is the use of psychedelics to induce neuroplasticity: the brain’s ability to adapt and remodel over time.

Psychedelics can promote growth of dendritic spines on cortical neurons, which is where 5-HT receptors are concentrated. The growth of new spines may help form new synapses and promote recovery from mechanical brain injuries (Lukasiewicz, Front Mol Neurosci 2021).

“In mechanical injuries, such as in a TBI or stroke, there is damage to the brain tissue,” explains Dudek, “and because of psychedelics’ ability to induce neuroplasticity, they may support long-term recovery.”

Dudek and his colleagues at Charles River support drug developers in early discovery of therapeutic psychedelics – testing a compound’s ability to induce neuronal plasticity, hallucinations, and addictive behaviors. To do this, they usually start with a neurite outgrowth test in which ex vivo cortical neurons are treated with test compounds, and subsequently observed for phenotypic changes in maximum neurite length, number of extremities, formation of new dendritic spines, and more. With automated analytic software, this assay can be a reliable predictor of a compound's neuroplastic potential.

A promising future

Collectively, these tests help researchers screen large libraries of psychedelic compounds for desirable qualities, enabling efficient development of therapeutics. “It’s going in a good direction,” Dudek says, “I'm keeping my fingers crossed that these compounds will succeed and we’ll see more of them in the clinical setting.”