Temple research finds that tweaking CBD may help it curb pain and opioid use in mice

The next generation of cannabis-inspired medicine might be grown in test tubes instead of greenhouses.

Researchers at Temple University have partnered with Doylestown-based pharmaceutical company Neuropathix to develop a synthetic molecule based on cannabidiol (CBD) that can provide more potent pain relief than CBD itself. They are currently studying it for a type of chronic pain caused by nerve damage due to chemotherapy. The CBD-based drug could offer an appealing alternative to addictive opioids and milder painkillers to treat chronic pain.

“We see CBD and possibly CBD analogs as giving us a different type of tool that’s not only safer than opioids, but may be more effective because it’s working in a different way,” said Sara Jane Ward, assistant professor of pharmacology at the Lewis Katz School of Medicine at Temple University.

Cannabis contains more than 100 compounds, but tetrahydrocannabinol (THC) — the one that gets users “high” — has long been at the forefront. THC binds to cannabinoid receptors in the brain, immune system, and other cells to control everything from appetite to inflammation. Its wide-ranging effects have made it popular for managing such conditions as pain and anxiety. But because of its mood-altering high, THC also has potential for addiction.

Ward instead focuses on CBD, an enigmatic cannabinoid that doesn’t produce a high or bind to cannabinoid receptors, yet can still relieve pain and anxiety. It is often available in liquid forms such as tinctures, edibles, or vapes. In 2018, Epidiolex — a liquid formulation of CBD — was approved by the Food and Drug Administration to treat certain types of epilepsy.

When Ward tested CBD’s pain-relieving power in mice, she noticed it wasn’t absorbed well by the digestive system, so less than 10% of the amount consumed shows up in the blood. Inhalation, such as smoking or vaping, is more efficient, but has potential health risks compared with more common oral medications.

Low levels of CBD in the blood do not mean it isn’t working, Ward noted. The bigger problem, she said, is how variable CBD blood levels can be.

“If you use one amount and I use the same amount, but your body’s getting a lot more than mine is, that’s really challenging from a patient care and medicine standpoint,” she said. “You want to have an idea of how much to recommend.”

That’s where her path collided with Neuropathix, then called Kannalife. The company wanted to modify CBD to improve absorption, suspecting that the fatty nature of the CBD molecule might be to blame. After making some chemical additions that changed the molecule to be more compatible with the watery environment in the body, researchers found that mice were able to absorb more than eight times more of the new compound — called KLS-13019 — than CBD and needed only 1/200th of the dose to get the same effect.

Ward suggested that they test the compound’s ability to treat chemotherapy-induced peripheral neuropathy (CIPN): a burning pins-and-needles-like sensation in the extremities caused by nerve damage from chemotherapy chemicals. It makes it hard to wear shoes or walk and can ultimately be so unbearable that some patients stop chemo early, said Marisa Weiss, director of breast radiation oncology and breast health outreach at Lankenau Medical Center.

Not all patients receiving chemotherapy experience CIPN, but studies show that Black women with breast cancer are at elevated risk, increasing their chance of not completing chemo and having poorer long-term health outcomes.

“If we had other chemotherapies that didn’t do that, we’d use them, instead,” Weiss said. “But we’re dependent on them to protect people’s lives.”

There are no effective treatments for CIPN, and doctors are wary that using opioids to treat long-term pain could lead to dependence.

In a study published in April, Ward found that KLS-13019 could not only prevent CIPN, but also reverse it in mice receiving paclitaxel — a common CIPN-inducing chemo agent. The study found that CBD could only prevent CIPN, but not reverse it.

That’s not all KLS-13019 could do. When mice were taught to self-administer morphine, they sought out less morphine when they were treated with KLS-13019, hinting that the compound might even interfere with the addictiveness of opioids. Ward acknowledges that mouse models are much simpler than the reality of addiction in humans, which often involves decades of opioid use alongside social and psychological factors. But it’s a starting point for more studies in humans.

“This has tremendous potential therapeutic value,” said Douglas Brenneman, chief pharmacologist at Neuropathix leading the development of KLS-13019. “Can you actually provide a molecule that might decrease the motivation for morphine? Maybe we have one.”

Although KLS-13019 is made in a lab by modifying the structure of CBD, it is nothing like synthetic cannabinoids such as K2, which can lead to erratic behavior and unpredictable side effects, Ward said.

“[K2] has sort of tarnished the term ‘synthetic cannabinoid,’” Ward said.

Neuropathix is running the safety tests required to start Phase 1 clinical trials by mid-2022—provided it has enough juice to get it there. The company with just seven employees has recently listed just over $300,000 in cash with no revenue beyond small research grants. With an accumulated deficit topping $14 million, they’re hoping that issuing additional stock shares will be enough to push KLS-13019 into Phase 1 trials. Meanwhile, Neuropathix is preparing to publish a study showing that the compound also prevents inflammation, which may make it useful in neurodegenerative diseases.

The company’s long-term fortunes rest on the success of KLS-13019 and a second drug—containing CBD—for brain injury. But both are still in preclinical trials and yet to face the hurdles of human trials and regulatory approval, not to mention mixed popular opinion around CBD in the clinic.

Meanwhile the company’s stock closed at 12 cents on Tuesday, down from a high of $5.75 in December 2019.

Still, Weiss, the founder and chief medical officer of Breastcancer.org, knows that the breast cancer community has a growing interest in medical cannabis. In a survey of more than 600 breast cancer patients, she found that 42% had used marijuana to manage symptoms, most commonly pain, insomnia, or anxiety, and 70% had a favorable opinion of cannabis’ benefits. Nearly half were looking for ways to avoid opioids.

In response, Weiss is now running a clinical trial of CBD as a CIPN treatment in patients — one of the first human trials of CBD — and said a synthetic analog — like the one Ward and Neuropathix are developing — should go through the same process. Weiss is sticking with cannabis-derived CBD because more than three-quarters of people she surveyed reported a preference for natural products over pharmaceuticals.

Ward agrees that FDA approval is necessary for CBD-derived drugs to have purity standards, insurance coverage, and doctor supervision of how they may be interacting with other medications. She sees patients’ enthusiasm for CBD as a call for more research.

Ward said patients she has talked to report that CBD “has helped them to get off of opioids or to change their life. So, let’s find out if these people know something that the whole world needs to know.”