For millennia, humans have been drawn to psychedelic substances because of their profound effects on sensory processing, thought and cognition. For decades, scientists have also been drawn to psychedelics to study and understand their actions in the brain. Today, much of society (including patients, clinicians, and investors) is increasingly drawn to these compounds because they represent a profound opportunity to treat multiple neuropsychiatric diseases and greatly ease the suffering of patients.
New medications for these diseases are desperately needed; it is estimated that over one-quarter of Americans over age 17 experience some form of diagnosable mental disorder in any given year. Indeed, some commonly reported mental health conditions, such as depression, PTSD, and substance use disorders, that have seen little-to-no recent innovation in their treatment, are potential targets for psychedelic-assisted therapy. The uniquely rapid and long-lasting therapeutic effects of psychedelic compounds are not quite a cure, but a definitive step in that direction. I can say without hyperbole, if proven to be as effective as early clinical trials and anecdotal reports show, psychedelics will change the treatment of mental health forever.
However, with the promise of psychedelics also comes serious and significant limitations. One of the important challenges facing psychedelics is the limited patient population that can access them. For various medical reasons, not everyone will be able to take psychedelic-based treatments.
Some Health Conditions Preclude Psychedelics
For example, psychedelics will likely be off-limits for patients with psychotic symptoms, including schizophrenia and bipolar disorder, or who have a family history of psychosis, because their symptoms could be exacerbated. In addition, patients with Alzheimer’s disease or other types of dementia may exhibit strong negative reactions to hallucinations. Indeed, patients with even mild, potentially undiagnosed, dementia may not be able to establish the necessary trust and rapport needed for a therapeutic psychedelic experience.
A recent clinical trial of psilocybin excluded most patients based on criteria that included an immediate family or personal history of psychosis or the suspected or known presence of a preexisting psychiatric condition that could jeopardize rapport between the patient and caregiver. While many patients will be unable to take psychedelic-based medicines, other patients may be unwilling to take them for various reasons, such as on moral, personal, or religious grounds. Layered on top of all these limitations are questions surrounding cost and access. Psychedelic-based treatment is likely to be expensive, potentially requiring numerous therapists and many clinical hours. Unfortunately, restrictions on insurance coverage could ‘price-out’ many of the patients who could experience significant benefit from these compounds.
Fortunately, a new type of medication is emerging that may be able to address these concerns: “psychedelics” that do not produce hallucinations. By modifying the chemical structure of the traditional psychedelics (e.g., psilocybin, DMT), scientists have created compounds that, at least in animals, are just as active in disease models, but do not appear to produce hallucinations. In addition, these compounds also have reduced accessibility-limiting attributes such as abuse potential and cardiovascular risks. These new finely-tuned medicines could significantly increase the number of patients who can benefit from their use.
Can Psychedelics Without the Trip be Therapeutic?
How is it possible for a non-hallucinogenic “psychedelic” compound to maintain the therapeutic benefit, but not produce hallucinations? Scientists at my company, Delix Therapeutics, believe, and have preclinical data to show, that the therapeutic benefit and the hallucinations are likely produced in different brain circuits and can be decoupled. Scientists have discovered that the therapeutic benefit of psychedelics (including the traditional serotonergic psychedelics and the “psychedelic-like” compounds ketamine, ibogaine and MDMA) and their non-hallucinogenic derivatives, have an underlying common effect on structural neuroplasticity in the brain.
These compounds can physically change the shape and connections of specific neurons in the brain, and those changes persist for an extended period. These structural modifications are critical because stress and some pathologies can damage the connections of specific neurons in the brain. By actually “repairing” the connections of the damaged neurons, these compounds can alleviate many disease symptoms. Importantly, while the non-hallucinogenic versions of the psychedelics have the same strong effect on repairing damaged cortical neurons, they do not activate the separate pathways in the brain that cause hallucinations.
Because of the common rapid and enduring “repairing” effects on plasticity and behavior of the psychedelics and their non-hallucinic derivatives, an increasing number of researchers in the neuroscience community are now referring to these compounds as “psychoplastogens”. Since the new generation of non-hallucinogenic psychoplastogens has the potential to treat many types of neuropsychiatric disorders without producing hallucinations, they will be able to reach more patients than the classic psychedelic-assisted therapies. Indeed, non-hallucinogenic psychoplastogens could offer a new common foundation for the future treatment of both neuropsychiatric and neurodegenerative conditions: the resolution of circuit specific cortical damage.
Delix is uniquely focused on developing these non-hallucinogenic psychoplastogens. We have synthesized over 1,500 compounds and our most advanced compounds, DLX-001 and DLX-007, will both start human clinical trials this year.
These new non-hallucinogenic psychoplastogens have deepened the debate around whether the hallucinogenic experience is necessary for the therapeutic effects of psychedelics. One can find proponents on both sides. Some claim that the hallucinogenic experience, and the insights gained, are critical to the therapeutic effect, and for some this may indeed be true. But the need for hallucinations may not be absolute and may vary by disorder.
For example, one study of migraine patients showed that following psilocybin treatment, the hallucinatory intensity did not correlate with the decrease in migraine frequency. The hypothesis that the related non-hallucinogenic psychoplastogens can have the same therapeutic effect as the classic hallucinogenic drugs is an empirical question and Delix will be able to answer it as our compounds progress to and through clinical trials.
All Therapies are Needed
While this non-hallucinogenic hypothesis has ignited fervent debate, it is important to realize that this is not a winner-take-all competition. We are working hard to develop psychoplastogens that do not produce hallucinations, but we simultaneously hope that psychedelic-based therapies succeed. The world needs better treatments for the millions of patients suffering from neuropsychiatric disorders; so, the more treatment options for patients, the better! There is more than enough room for both hallucinogenic and non-hallucinogen approaches in the treatment arsenal.
In fact, I can envision a day when different patients with different disorders (e.g., PTSD or Opiate Use Disorder), or even different symptom clusters within the same disorder (e.g., depression with either prominent anxiety or prominent cognitive symptoms), can be treated with the particular hallucinogenic or non-hallucinogenic psychoplastogen that demonstrates the highest efficacy for that specific patient population.
Further, the same patient potentially could receive different types of compounds at different stages of the illness. Perhaps the same treatment-resistant depressed patient may need a hallucinogenic psychoplastogen, such as psilocybin, administered in a clinic, to “kick-start” their treatment and a non-hallucinogenic psychoplastogen, that can be taken at home, to maintain the response.
However, when it comes to the treatment of disorders like schizophrenia and Alzheimer’s disease, it seems almost certain that a non-hallucinatory approach will be needed. Hopefully, we will eventually have clinically efficacious psychoplastogens with the full spectrum of strong, to moderate, to weak, to no, hallucinogenic activity available for patients. This new paradigm in brain and mental health treatment will focus on reversing the damage of neurons in specific circuits pertinent to each specific disorder or symptom cluster. In that futuristic scenario, a health care provider would have a cornucopia of options to tailor individual treatments for individual patients.
It will take years of careful clinical research to fully understand and correctly integrate hallucinogenic and non-hallucinogenic psychoplastogens into medical practice. But in the end, patients will benefit from more treatment options. Ultimately, isn’t that the future we all want?