THC/CBD Shows Promise for Treating Agitation in Late-Stage Alzheimer’s

As many as half of people who develop Alzheimer’s will experience agitation symptoms like pacing, emotional distress, or verbal and physical aggression, and it becomes more common in later stages. Agitation makes it difficult for caregivers, too, leading to increased rates of anxiety and depression. 

While there are two approved medications for treating Alzheimer’s agitation, their effects are small and may not be clinically meaningful, and aren’t tested for those in the very late stages of the disease.

At the Alzheimer’s Association International Conference in London, researchers presented data Tuesday from the Phase 2 LiBBY trial testing a combination of tetrahydrocannabinol (THC) and cannabidiol (CBD) for treating agitation symptoms at the end-of-life. 

“We made a commitment to try to find a drug or treatment that will alleviate the symptoms and take away the agitation and the despair of these patients,” Dr. Jacobo Mintzer, a psychiatrist at the Ralph H. Johnson VA Healthcare System, who presented the study, told Being Patient.

Compared to those who received the placebo, THC/CBD led to rapid improvement in symptoms at two-weeks, which were sustained at 12 weeks. The results impressed other experts. 

“I think the findings are really intriguing,” Dr. Jerry Gurwitz, a geriatrician at UMass Chan Medical School, who wasn’t involved in the study, told Being Patient. The researchers have not announced a Phase 3 trial yet.

Putting THC/CBD to the test

THC and CBD are two of many active compounds found in cannabis. THC is the compound that often gives people the feeling of a “high,” while CBD may lessen the high and may help with anxiety and some forms of epilepsy — though a lot of the research is preliminary. Both compounds act on the brain’s endogenous cannabinoid receptors and may have synergistic effects in combination. 

The researchers created a novel formula comprising two mg THC and 100mg of CBD dissolved in digestible oil, administered twice daily. The trial recruited 120 participants with dementia and agitation who were eligible for or receiving hospice care. 

Researchers randomly assigned half to receive a placebo while the other half received the THC/CBD. Neither the researchers conducting the study nor the participants knew who received the actual treatment.

After two weeks, those receiving the THC/CBD dropped by 6.27 more points on the Cohen-Mansfield Agitation Inventory (CMAI) — a 203-point scale of agitation symptoms — indicative of a clinically meaningful improvement, with more than 80 percent of participants showing improvement compared to 30 percent in the placebo arm. 

“I haven’t seen one [treatment] study in my life, no matter about what, that has an 80 percent response at two weeks,” said Mintzer.

The improvements grew larger over time: At 12 weeks, the difference was 8.23 points, and a total of 87 percent of the participants experienced improvement. In the 12 week open-label portion of the study where participants are knowingly given the treatment, Mintzer said they continued to improve. 

At 12 weeks, 23.3 percent of participants who received THC/CBD developed severe adverse events compared to 11.9 percent in the placebo group. However, researchers determined that these effects were unrelated to the medication. Mintzer explained that these severe events referred to patient deaths and that the underlying causes were unrelated to the treatment. In the 12-week open label portion of the study, there was no difference in deaths

Mintzer said that researchers often exclude participants from trials if they’re taking many medications because it might drown out any effects of a medication. LiBBY allowed people to stay on, and even change their medications, and still saw an effect. “Over-restrictions of individuals in clinical trials probably makes no sense,” he said. 

Researchers also didn’t require participants to travel to trial sites for assessment, reducing the number of people that dropped out of the study. The study also included a diverse cohort of white, Black, and HIspanic Americans. These factors make the study more generalizable to the real world. 

“The LiBBY findings extend a growing signal that cannabinoid-based treatments may reduce agitation across the dementia spectrum,” Dr. Brent Forester, chair of the Department of Psychiatry at Tufts Medical Center, who wasn’t involved in the research, told Being Patient. Previous studies of other cannabis-related compounds showed potential promising effects, but this study showed sustained benefits in an older population.

He added that the “results are especially striking when viewed alongside the data supporting brexpiprazole and Auvelity, the two FDA-approved treatments for agitation in Alzheimer’s.” The changes at two weeks beat out what either of the approved medications could do at five and 12 weeks. “That said, cross-trial comparisons must be made cautiously,” Forester added, since the population in this study has late-stage dementia. 

While Gurwitz finds the rapid symptom improvements “interesting,” he cautioned that this is still a small study. “Sometimes in the bigger confirmatory Phase 3 trial, things don’t pan out the same way.”

Mintzer explained that a Phase 3 trial is being planned, which will include both those in hospice care as well as individuals in the moderate and severe stages of the disease with agitation.

Caution against over-the-counter cannabis products

While the study showed that THC/CBD may be promising, Gurwitz cautioned against trying to buy similar products over-the-counter. “There’s nothing available from a dispensary or the gas station,“ like the formulation tested in the trial, he said, and that the doses from recreational and medical cannabis are not analogous either.  

“You don’t even know what you’re getting sometimes,” said Gurwitz. Cannabis products and their dosages are routinely contaminated or mislabelled and could lead to severe side effects resulting in emergency room visits for older adults.

“The field now needs larger, longer, carefully monitored trials to clarify which patients benefit most, optimal dosing, comparative safety, and how these treatments should fit alongside FDA-approved therapies and non-pharmacologic care,” said Forester. 

Meanwhile, Mintzer emphasized that researchers must run clinical trials for people in the final stages of  life, when treatments have been based on clinical experience rather than scientific evidence. “We know they are possible and should be done,” he said.