The unmet need for improved treatments is huge. Published evidence indicates that between 30% and 40% of cancer patients experience depression, the caveat being that it is likely underreported since individuals aren’t consistently screened for it, Jones says. Multiple studies suggest conventional antidepressants don’t work as well or at least don’t have as good of an established evidence base for treating cancer-related depression, though they certainly work well for some patients. The clinical gap has a parallel among people with treatment-resistant depression without cancer, he adds.
Cancer patients with depression and people with treatment-resistant depression without cancer have similar phenotypes in that they share an upregulated inflammatory state, says Jones. His interest in finding rapid-acting treatments stems from his firsthand view of the added burden of depression on top of an already life-altering cancer diagnosis.
While every patient is different, Jones says he has repeatedly seen patients beset by depression almost immediately able to experience authentic joy and spontaneity after taking ketamine and, more recently, psilocybin. “The most rewarding part of my job here is being an assistant therapist on our clinical trials and seeing some of these patients who have cancer and are under immense distress turn around very rapidly and feel like they can handle all that burden in a much better way,” Jones says. “It is unlike anything I have seen as a psychiatrist except maybe ECT, and that’s very invasive and requires an anesthesiologist.”
Thus far, researchers have not encountered any significant issues using cancer treatments and psychedelics at the same time, he reports, which is something they have been actively monitoring. No sort of interaction has been seen in the phase 1 and phase 2 trials for patients with cancer or in tumor models in the lab, although Jones underscores that “cancer-specific safety monitoring is an ongoing process and available data with psilocybin comes from a very small population, so this far from a settled topic.”
In fact, a new clinical trial is soon to open based on findings of a preclinical study conducted by Jones and Moran Amit, M.D., Ph.D., an immunotherapy expert in the department of head and neck surgery at MD Anderson. In mice, psilocybin prevents chemotherapy-induced peripheral neuropathy, which has been a major, dose-limiting toxicity in patients. The psychedelic has not interfered with immunotherapies in earlier trials, he points out.
The latest study was a complex undertaking that integrated CSF proteomics from healthy volunteers who received intravenous ketamine with transcriptomic analyses from induced pluripotent stem cells (iPSCs) derived from participants with treatment-resistant depression and the healthy volunteers. The iPSCs were treated with ketamine, (2 R,6 R)-hydroxynorketamine (HNK, one of ketamine’s major metabolites), LSD, or psilocybin.
As is well known, animal-based models for psychiatric conditions like refractory depression don’t seem to translate well to humans, says Jones. “So, we need to come up with better, more creative ways to validate things in the lab that’ll at least reflect some important part of human physiology to give us confidence to go forward.”
At MD Anderson, in collaboration with the National Institutes of Health (NIH), research now underway uses iPSCs and organoids in addition to other models as a testing vehicle for drugs, he shares. This ensures “getting a real genetic component of real patients who have depression, even if you don’t get the behavioral readout.”
Work on the published paper was facilitated by a collaboration between the NIH and the MD Anderson Cancer Neuroscience Program, a highly collaborative, cross-disciplinary initiative that unites neurobehavioral health, neurotoxicity mitigation, primary brain tumors, and the neurobiology of cancer, Jones says. Those collaborators include Moran Amit, M.D., Ph.D., assistant professor in the department of head and neck surgery who co-founded cancer neuroscience as a discipline, and renowned immunologist Katy Rezvani, M.D., Ph.D., vice president and head of the Institute for Cell Therapy Discovery and Innovation, whose specialty is adoptive cell therapy using engineered natural killer cells.
Of the four drugs recently tested, psilocybin and ketamine have proven to be highly effective in early studies and the other two are currently undergoing clinical evaluation, continues Jones. HNK is in a phase 2 study at NIH and LSD in a phase 3 study, both for treating depression.
Researchers found slightly more than 100 genes that were “convergently upregulated” across the four psychedelic drugs to produce their stunningly rapid antidepressive effects, he says. Among the core regulators of that signature were IL-15, monocyte chemoattractant protein-1, and some cellular adhesion molecules that dictate how immune cells get in and out of blood vessels and neurons connect with each other.
The study used iPSC neurons to show that this reflects what’s happening in human biology, emphasizes Jones. A post-hoc analysis was performed on data (whole blood RNA sequencing, plasma cytokines, clinical outcomes, and MEG) drawn from a previous randomized, placebo-controlled ketamine clinical trial conducted at an NIH research site.
Measuring gamma power with MEG was a costly but necessary undertaking, given the limitations of using a normal EEG cap for the task, says Jones. MEG, being magnetic based, doesn’t encounter issues picking up signals in the brain due to skull thickness.
When all the markers found in the blood of those trial participants were treated with ketamine, an increase in IL-15 levels at the RNA level was found to correlate with those who felt relief from their depression, he says. At the same time, the research team observed a “massive drop in virtually all the B cell signals.”
The next logical question was what happened to IL-7, the canonical cytokine for overall early B cell development, continues Jones, and it was found to correlate both with patients feeling better and MEG gamma power—the leading biomarker of ketamine response. “Whereas higher IL-7 correlated with higher MEG gamma power at baseline, ketamine seemed to reduce [it] in ... the default mode network,” describing a connected system of brain regions that drives self-referential thinking when a person is not engaged in a task.
The default mode network is typically overactive and hyper-connected in depression, he says. Patients get a lot of ruminative thoughts, making a key goal of treatment “getting them out of their own head.” Psilocybin has had the most repeated success in doing this, based on neuroimaging findings and default mode activity.
All this presents researchers with more questions than answers, says Jones. But they are excited by the fact that a core set of signaling regulators were found in iPSC neurons and that in the blood, reflective of what is happening inside the brain, they saw a convergent immune signature that’s more immunoregulatory than anti-inflammatory correlating with positive clinical outcomes.
The next step is to look at psilocybin clinically to search for the same signature, as well as a lot of validation work in animals and neurons to see if this repeats itself, he adds. The goal is to come up with immunoregulatory targets for depression treatments.
In the NeuroGuard clinical trial of psilocybin that is expected to start in the next few months, with Amit serving as principal investigator and Jones as co-investigator, patients with three different types of cancer (breast, colorectal, and head and neck) receiving highly neurotoxic chemotherapies will for the first time ever be treated with four doses of psilocybin. “Most studies use one to two doses, but what we found in our preclinical models is if you dose it before each chemo cycle you can protect very durably,” says Jones.
In one of the experimental arms, patients will receive two oral doses of psilocybin one week apart prior to chemotherapy cycle 1 (days 7 and 14), followed by two monthly doses prior to chemotherapy cycles 2 and 3 (days 42 and 70). The hope is that the psychedelic will lessen neuropathy so that patients can complete their full treatment regimen, Jones says.
“We think that psychedelics, particularly psilocybin, are highly amenable to cancer patients because conventional SSRIs [selective serotonin reuptake inhibitors], while they certainly work for a lot of patients with cancer ... come with bleeding risks and take a long time to work,” he says. “Rapid-acting treatments are a much better model [from a safety perspective] because you don’t have to dose all the time.”
Two different doses of psilocybin (25 mg and 10 mg) will be tried in the upcoming trial, and various biomarkers will be developed to guide its use in treating a wide range of indications in the future, he says. “The longest-term goal would be to use biomarkers in order to do patient selection [and] predict who is going to respond, because these are resource-intensive treatments” requiring a lot of psychotherapy and monitoring.
Another objective is to look more at resilience, “before patients get to the need of psilocybin,” and after, to determine what psilocybin or another psychedelic is imparting to make people feel better, says Jones, highlighting his personal long-term interest. The ideal scenario would be to intervene before patients fall into depression and end the trial-and-error cycle that too often ends in treatment-refractory mental illness.