Cannabis Combination Eased End-of-Life Agitation in Dementia Patients

Two active ingredients found in marijuana — tetrahydrocannabinol (THC) and cannabidiol (CBD) — led to significantly less agitation in hospice-eligible patients with Alzheimer’s disease and other dementias, the phase II LiBBY trial showed.

At 2 weeks, Cohen-Mansfield Agitation Inventory (CMAI) scores were better in the THC-CBD group compared with the placebo group, with a mean between-group difference of -6.27 points (95% CI -9.66 to -2.87, P<0.0004), reported Jacobo Mintzer, MD, of the Medical University of South Carolina in Charleston.

CMAI scores were also better in the THC-CBD group at 12 weeks, with a mean area under the curve contrast between groups of -8.23 points (95% CI -11.6 to -4.86, P<0.0001), Mintzer said at the Alzheimer's Association International Conference. The CMAI ranks 29 agitation behaviors on a 7-point scale, with scores ranging from 29 to 203.

The THC-CBD intervention was well tolerated by a majority of participants, Mintzer noted. Adverse event rates were comparable between groups (46.7% vs 42.4%). There were more deaths in the THC-CBD arm, but there was no pattern in the cause of death in either group.

Clinical Global Impression of Change in Behavior scores improved for 83.9% of treated participants compared with 30.5% on placebo at 2 weeks. By week 12, that gap grew to 87.2% versus 23.6%.

“Rarely do we see close to 90% of patients in a trial respond positively to a new medication,” Mintzer stated.

About half of Alzheimer’s disease patients use hospice care in the last days of their life. “Agitation is not trivial in this population,” Mintzer observed.

LiBBY was conducted by the NIH-funded Alzheimer’s Clinical Trials Consortium and is one of the first randomized controlled trials in a hospice-eligible population with Alzheimer’s or other dementias.

“The LiBBY study directly addresses one of the most challenging and under-discussed aspects of Alzheimer’s disease — end-of-life agitation,” noted Elizabeth Edgerly, PhD, of the Alzheimer’s Association, which supported the research. “These results not only highlight a promising therapeutic option, but also underscore the importance of prioritizing attention, care, and research for individuals in mid- and late-stage Alzheimer’s and related dementias.”

The trial tested a combination of purified THC and CBD given orally in a rapid-acting digestible oil suspension each day . “THC is a well-documented psychoactive that exerts a broad effect on the regulation of emotion and activates cannabinoid receptors directly,” Mintzer said.

CBD is a non-psychoactive marijuana component that activates hydroxytryptamine (5-HT1A) serotonin receptors, triggering an inhibitory response that slows 5-HT1A signaling with positive effects on anxiety, appetite, sleep, and pain, he added.

The double-blind LiBBY trial enrolled 120 participants with Alzheimer’s disease or other types of dementia and agitation who were hospice-eligible. Participants were randomized to a THC-CBD formulation (4-mg THC and 200-mg CBD twice daily) or placebo for 12 weeks. The formulation is not publicly available and is not used for any other indication, Mintzer noted.

Ten medical centers nationwide conducted study visits at participants’ homes or place of residence. Participants had a mean age of 80 years, and 55% were women. More than half were from an underrepresented ethnic or racial group, and most participants (75%) lived at home.

Participants who completed the double-blind portion of the study could continue in an extension study to receive treatment for 12 more weeks. Extension study results showed that those who had taken THC-CBD for the first 12 weeks of the study continued to benefit. For those switching to the active drug after week 12, there was a decrease in agitation that persisted through week 24.

LiBBY represents a major step in treating a population that has been overlooked in clinical research, Mintzer noted. It documents three things, he told MedPage Today.

“The first is that a study in this population can be done and should be done,” he said. “The second is that if you’re going to do a study on psychosis or agitation in this population, you need to go to the patient, not expect the patient to come to you.”

The third is that marijuana has more than 60 different cannabinoids and “every plant has a different combination of those,” he pointed out. “Unless we work with purified CBD and THC, we will not know what we’re doing.”

The LiBBY findings apply only to the purified compound tested in the study, not to other forms of cannabis or publicly available marijuana, Mintzer added.