THC-CBD Combination Reduces Agitation in Advanced Dementia

LONDON — A purified oral combination of tetrahydrocannabinol (THC) and cannabidiol (CBD) may offer a new treatment option for agitation in patients with advanced dementia who are eligible for or receiving hospice care.In a randomized, placebo-controlled study of 120 patients with Alzheimer’s disease (AD) and other dementias, the THC/CBD combination reduced severe agitation within 2 weeks, with a 6.27-point greater reduction in Cohen-Mansfield Agitation Inventory (CMAI) scores than placebo. Benefits were sustained through 12 weeks, with higher rates of clinician-rated global improvement (87.2% vs 23.6%) and a similar overall adverse event (AE) profile.“The difference was six points in the Cohen-Mansfield Agitation Inventory, which is larger than any other study in agitation ever done — almost two to three times larger,” lead investigator Jacobo Mintzer, MD, professor at the Medical University of South Carolina in Charleston, South Carolina, told Medscape Medical News.Mintzer emphasized that the significance of the study extends beyond the treatment itself.“The most important message is that patients suffering from agitation in the late stages of their life deserve appropriate research to find ways to alleviate their symptoms. We have now developed the methodology to do it. We opened the door,” he said.The findings were presented on July 14 at the Alzheimer’s Association International Conference (AAIC) 2026.An Understudied PopulationAgitation is one of the most challenging neuropsychiatric symptoms in advanced dementia. Current pharmacologic treatment options are limited, and evidence supporting cannabinoids has remained inconclusive because previous studies have been small.Mintzer said he and his colleagues were encouraged by earlier research, including a 2019 study published in The American Journal of Geriatric Psychiatry that evaluated nabilone, a synthetic THC analogue, and demonstrated improvements in agitation but did not show improvements in other clinical measures.The current study was also designed to address whether patients with advanced dementia receiving end-of-life care could successfully participate in rigorous randomized clinical trials.The phase 2 Life’s End Benefits of Cannabidiol and Tetrahydrocannabinol (LiBBY) trial was a multicenter, randomized, double-blind, placebo-controlled study conducted at nine US sites.The study included 120 hospice-eligible patients with AD or other dementias (mean age, 80.5 years; 55% women) who had clinically significant agitation. Of the participants, 58% were from historically underrepresented ethno-racial groups (Asian, Black, or African American, and Hispanic individuals), and 75% lived in community settings.Participants were randomly assigned to receive either placebo or an oral formulation containing THC and CBD dissolved in digestible oil. The formulation was designed to be swallowed or administered through a feeding tube. Participants received 2 mg THC and 100 mg CBD twice during week 1, followed by the full treatment dose of 4 mg THC and 200 mg CBD twice daily through week 12.Study visits were conducted in participants’ homes rather than research clinics, and individuals continued to receive routine care from their own physicians throughout the study.The primary endpoint was change in agitation at 2 weeks, measured with CMAI. Secondary endpoints included sustained improvement through week 12 and clinician-rated global improvement using the Clinical Global Impression of Change in Behavior scale.Improvement in AgitationAt week 2, participants receiving THC/CBD experienced a greater reduction in CMAI scores compared with those receiving placebo (between-group difference, -6.27 points; 95% CI, -9.66 to -2.87; P = .0004).Treatment benefits persisted through week 12, with a between-group area-under-the-curve difference of -8.23 points (95% CI, -11.60 to -4.86; P < .0001).Clinician-rated global improvement was also higher with THC/CBD treatment. At week 2, 83.9% of patients receiving THC/CBD were rated as improved compared with 30.5% of those receiving placebo (P < .0001). By week 12, improvement rates increased to 87.2% and 23.6%, respectively (P < .0001).AE rates were similar between groups (46.7% vs 42.4%). Serious AEs occurred more frequently in the treatment group than in the placebo group (23.3% vs 11.9%), and more deaths occurred among patients receiving THC/CBD during the 12-week study.The investigators determined that none of the serious AEs, including deaths, were related to the study medication.Moving Toward Phase 3An open-label extension of the LiBBY trial has since been completed and was also presented at the conference.Participants who began active treatment continued to improve during the extension, suggesting that the response may be durable, Mintzer noted.The investigators are now seeking funding for a phase 3 trial that would expand the study population beyond hospice-eligible patients to determine whether similar benefits can be observed in a broader group of individuals with agitation.“The logical next step would be to broaden the population,” Mintzer said. “Phase 3 will obviously include those people in the dying process, but also a wider range of individuals suffering from agitation across neuropsychiatric symptoms, because we need to show whether we can see similar effects in the population that really needs it.”Questions RemainThe results provide important evidence for an intervention that some clinicians have already used despite limited randomized data, Nathan Herrmann, MD, professor emeritus of psychiatry at the University of Toronto in Toronto, Ontario, Canada, who was not involved in the study, told Medscape Medical News.“It is extremely fortunate to have results from a high-quality randomized clinical trial for an intervention that, I believe, has been adopted prematurely by clinicians without appropriate understanding of the risks and benefits of using cannabinoids to treat agitation and aggression in Alzheimer’s disease and other dementias,” said Herrmann, who is also the director of Psychopharmacology Services at the Merchavim Center for Brain and Mental Health in Be’er Yaacov, Israel.Herrmann, who was also the lead investigator of the 2019 The American Journal of Geriatric Psychiatry study, said the findings appear clinically meaningful, and the safety profile is reassuring. He said this suggests the formulation may eventually become an alternative to atypical antipsychotics after nonpharmacologic interventions have been attempted.However, “the devil is in the details,” he cautioned. Larger studies will be needed to better define safety, assess outcomes such as falls and cognition, and determine the optimal THC/CBD formulation. “I believe the true risks and benefits of cannabinoids in patients with dementia still require clarification and further studies,” Hermann concluded.The LiBBY trial was funded by the National Institute on Aging, with support from the Alzheimer’s Association for the open-label extension. Herrmann reported having no relevant financial disclosures.