Non-Hallucinogenic Psychedelic Analogs Could Be Game Changers for Neuropsychiatry

Neuroplasticity plays an important role in a patient’s recovery from mental health conditions such as depression. However, traditional plasticity-inducing antidepressants can take a long time to provide relief, while currently available faster-acting psychoplastogens may cause undesirable effects such as addiction or hallucinations, meaning their use is restricted to a controlled clinical setting. Non-hallucinogenic psychedelic analogs could address some of these issues and provide patients with a treatment option that is both accessible and effective.

In a study recently published in Cell, a novel cellular imaging platform that predicts hallucinogenic potential was used to identify DLX-1, a non-hallucinogenic psychedelic analog with neural plasticity-promoting and antidepressant properties. To learn more about DLX-1 and its discovery, Technology Networks spoke with David E. Olson, co-author of the study and co-founder and chief scientific officer of Delix Therapeutics. In this interview, David also discusses the potential commercial, clinical and scientific implications of non-hallucinogenic psychedelic compounds.

Anna MacDonald (AM): What role does neuroplasticity play in a patient’s recovery from mental health conditions such as depression and PTSD?

David E. Olson (DO): In healthy individuals, neurons in the prefrontal cortex communicate with other brain regions to regulate motivation, fear, and reward.  However, in depression, PTSD, and related disorders, these critical neurons atrophy—their dendritic branches retract and many of their synapses are eliminated. Antidepressants fix these broken circuits by promoting neuroplasticity and re-establishing synaptic connectivity in the prefrontal cortex. However, traditional antidepressants, like SSRIs, take weeks to months to regrow these lost connections, which might explain why they need to be administered chronically before patients will start feeling better. Psychoplastogens like ketamine, psychedelics, and the non-hallucinogenic compounds we are developing, rapidly promote neuroplasticity to fix the damaged circuits in depression and related disorders.

AM: Can you give us an overview of psychoplastogens and their mechanisms of action? Are there any downsides associated with their use?

DO: Psychoplastogens are compounds that rapidly and robustly promote structural and functional neuroplasticity in cortical neurons by ultimately turning on TrkB and mTOR signalling in the brain. These are key kinases responsible for producing the ion channels and structural proteins necessary for neuronal growth and plasticity. Several well-known psychoplastogens, such as ketamine and serotonergic psychedelics, have several downsides associated with them such as abuse liability, potential cardiotoxicity, and hallucinogenic effects. Delix is focused on developing the next generation of psychoplastogens capable of re-wiring pathological neural circuitry without these undesirable properties. 

AM: You recently published a study in Cell demonstrating the therapeutic potential of a psychoplastogen without hallucinogenic effects. Can you tell us more about the study and its findings?

DO: My colleague Lin Tian and I engineered the 5-HT2A receptor—the receptor responsible for the hallucinogenic properties of psychedelics—to light up when it binds to hallucinogenic compounds only. We then used that sensor to identify DLX-1 (also known as AAZ) as a non-hallucinogenic ligand and verified that result using an in vivo model of hallucinations. Next, we tested the ability of DLX-1 to promote neuroplasticity in neurons grown in a dish and found that it was as potent as ketamine. Finally, we tested DLX-1 in two different behavioral tests related to motivation and anhedonia—important aspects of depression. We found that despite lacking hallucinogenic effects in rodents, DLX-1 was still capable of producing robust, long-lasting antidepressant effects after a single dose.

AM: What scientific, clinical and commercial implications do non-hallucinogenic versions of psychedelic compounds, such as DLX-1, present?

DO: Scientifically, it is important to determine whether or not the molecular and circuit-level mechanisms mediating the hallucinogenic and antidepressant effects of psychedelics are distinct so that we can better understand the neurobiology of mental illnesses and how best to treat them. From a clinical perspective, the implications are huge. While I am very hopeful that compounds like psilocybin will one day be approved for treating depression or perhaps other brain disorders, I suspect that these hallucinogenic molecules will only be used as a last resort for a variety of reasons. First, the cost associated with psychedelic-assisted therapy is likely to be extremely high given that multiple sessions with healthcare professionals are required to ensure safety. Second, psychedelic-assisted therapy is contraindicated for patients with certain comorbidities or a family history of psychotic illness. Given the overlapping genetics of neuropsychiatric diseases, this means that a large portion of the patient population will not be allowed to participate in psychedelic-assisted therapy. Finally, many patients won't want to take hallucinogenic drugs given their intense, and sometimes anxiety-inducing effects. When you consider that nearly 20% of people will suffer from a brain disorder at some point in their lifetime, it becomes clear that ketamine and psychedelics simply can't meet that demand, and thus, are perhaps best suited for patients who have tried everything else. What we really need are scalable solutions, new first-line treatments that people can take home and put in their medicine cabinets. The only way we can get there is with non-hallucinogenic compounds that lack abuse liability, and that is why I co-founded Delix Therapeutics. The Delix platform leverages non-hallucinogenic psychoplastogens to re-wire pathological neural circuitry, and we think that these compounds will really be game changers for neuropsychiatry.

AM: Can you tell us more about the discovery of DLX-1 and how Delix is working to discover additional non-hallucinatory psychedelic analogs? How is the hallucinogenic potential of compounds predicted?

DO: DLX-1 was discovered through rational chemical design. It's important to remember that the structure of a compound dictates its function. Our medicinal chemists have deep expertise in neuropharmacology and understand what structural features are important for producing psychoplastogenic effects and what features lead to hallucinations. This has allowed us to take every major psychedelic scaffold—tryptamines, ergolines, amphetamines, iboga, etc.—and tweak these molecules just enough to eliminate the undesired properties while retaining their beneficial psychoplastogenic effects. Our library has grown substantially, and now contains over 500 novel compounds from multiple, distinct chemical scaffolds. Each scaffold has unique properties that make it better suited for certain indications. We are also investigating advanced machine learning approaches that use our in-house dataset to computationally predict the structures of novel psychoplastogens. Once we have designed and synthesized the compounds, we test them in a battery of assays to demonstrate that they are efficacious while lacking hallucinogenic effects. To measure the hallucinogenic potential of compounds, we rely on a combination of psychLight, more traditional GPCR assays, and in vivo models.

AM: What further steps are needed before non-hallucinogenic psychoplastogens could become widely available to patients?

DO: Like all drugs, non-hallucinogenic psychoplastogens need to undergo rigorous testing to ensure both safety and efficacy. Those studies are ongoing at Delix, and we hope to have two molecules ready for clinical trials by 2022, with several additional molecules following close behind.

David E. Olson was speaking to Anna MacDonald, Science Writer for Technology Networks.