Alzheimer’s disease (AD) is a progressive condition impacting about 6.7 million Americans aged 65 and older. In addition to memory and cognitive decline, neuropsychiatric symptoms (NPS) are extremely common in AD, affecting around 97% of patients and significantly increasing the burden on caregivers. Anxiety is a prevalent NPS in AD, with its occurrence estimated between 25% and 70%. It often accompanies agitation, leading to difficult behaviors such as combativeness and resistance to care, which further strain caregivers and can necessitate higher levels of care, including hospitalization. Despite the high incidence of anxiety and agitation in AD patients, only one FDA-approved medication exists for agitation, with none specifically targeting other behavioral or psychological symptoms of dementia, highlighting the urgent need for safe and effective treatments.
Cannabidiol (CBD), a non-psychoactive compound in cannabis, is gaining attention for its potential therapeutic benefits and minimal side effects. It shows promise as a treatment for anxiety and agitation in older adults with AD. Studies in animals and humans suggest that CBD can reduce stress and anxiety with few adverse effects. Preliminary research also hints at CBD’s potential neuroprotective effects by inhibiting tau hyperphosphorylation, a key aspect of AD pathology. However, human studies on the effects of CBD on anxiety or agitation in AD patients are lacking.
To address this gap, an 8-week open-label clinical trial is being conducted to evaluate the safety and efficacy of a specially formulated high-CBD/low-THC sublingual solution in 12 older adults (ages 55-90) with mild to moderate dementia due to Alzheimer’s disease. Primary outcome measures for anxiety include various scales such as the anxiety domain of the Neuropsychiatric Inventory – Clinician Version (NPI-C), Generalized Anxiety Disorder-7 Item Scale (GAD-7), and the Beck Anxiety Index (BAI). Safety outcomes include assessments of potential side effects, adverse events, and cognition. Exploratory measures cover agitation and aggression domains on the NPI-C, scores on the Cohen-Mansfield Agitation Inventory (CMAI), and caregiver burden using the Zarit Caregiver Burden Interview.
Preliminary results from five patients who completed the trial show a reduction in anxiety symptoms compared to baseline, with some patients also exhibiting cognitive improvements. Informant and clinician-rated measures indicate significant improvement in anxiety over the trial period. Study partners reported a decrease in anxiety symptoms ranging from 29% to 100% on the BAI, and reductions ranging from 60% to 88% on the NPI-C. Patients’ self-report scales showed more variable results, with four out of five patients reporting a decrease in anxiety symptoms on the BAI. Data on agitation symptoms were consistent with primary outcomes, as all patients showed reductions in agitation symptoms as measured by the CMAI. No serious adverse events were reported by patients or study partners.
While data collection is ongoing, initial findings suggest promising reductions in anxiety symptoms among patients. These results highlight the importance of using multiple-reporter systems in studies involving patients with mild to moderate AD. These findings will inform a planned randomized, placebo-controlled trial aimed at further assessing the clinical efficacy and safety of high-CBD products in older adults with AD.
Under the current scheduling regime, research obstacles are significant. Pharmacologist and professor Ziva Cooper, director of UCLA’s Center for Cannabis and Cannabinoids, describes the stringent security measures required by the DEA for storing cannabis used in her studies: a 750-pound safe bolted to the floor with specific locks and near-constant security provisions. Under a Schedule III designation, these requirements would be much less stringent. Gruber noted that even non-intoxicating cannabis products used in her lab are stored in a massive safe. Igor Grant, a neuropsychiatrist at the University of California, San Diego, School of Medicine, recalled that at one point, he and his colleagues planned to use a “permanent trailer” with cannabis stored in a safe. However, because the trailer wasn’t bolted to the cement, the DEA deemed it inadequate protection against diversion. Meanwhile, Margaret Haney, neurobiologist and professor at Columbia University Medical Center, keeps her cannabis in a gun safe in a locked room that she opens with her fingerprint. These extensive security measures are costly and burdensome for clinical researchers.
Researchers seeking to study cannabis must obtain a DEA Schedule I research license, source their products from DEA-approved manufacturers, keep detailed records of cannabis usage, and report on how it is disposed of. Haney explains that if she gives a study subject an 800-milligram cannabis cigarette, she must collect the butt to report to the DEA exactly how much was used. “You treat it like heroin,” she says.
In most cases, study participants can’t take cannabis home. But large-scale, randomized controlled trials require multiple doses per day. Haney tried importing cannabis products from Canada, where it is legal, but this required permits. The process is lengthy and complex. She hopes that a change to Schedule III will ease the burden on researchers. Grant notes that if researchers want to shift their focus from one condition to another, they must obtain a new DEA license for each study. With a Schedule III drug, this wouldn’t be necessary.
State-level hurdles also exist. In states like California, studies involving Schedule I substances require approval from a state review board, which can extend study timelines. “Having this body review our protocols,” says UCLA’s Cooper, “automatically adds six months to any study approval.” Universities can also be slow to approve research. Grant mentioned that one UC campus was initially reluctant to approve human research on marijuana due to concerns about violating federal drug laws and risking university funding.
Fewer hurdles could encourage more researchers to enter the field. “There are many regulatory requirements to study Schedule I drugs,” says Haney. “This leads to very few people doing it.” Grant hopes the scheduling change will enable more scientists to undertake cannabis research and prompt institutions to take the field more seriously.
Given that 38 states and DC have approved marijuana for recreational or medical use, the federal government’s slow response is puzzling. Researchers suggest that the federal designation hasn’t always been based on science. “There’s been a resistance to see the data, due to bias or the belief that it’s dangerous,” Grant says. Haney adds, “Much of the policy around cannabis is political, not science-based. The Schedule I designation was a political decision, not a scientific one.” Consequently, the DEA’s insistence that cannabis has no medicinal benefit has hindered scientific understanding of its potential benefits. Many questions remain, such as the optimal THC to CBD ratio for treatments and the best administration methods.
As science lags, the industry advances. Many claims about cannabis’s medical benefits have been driven by industry, anecdotes, and politicians, often without scientific backing. This new designation could help bridge the gap, enabling a deeper understanding of the plant’s potential benefits.
Haney remains hopeful. “This is a step in the right direction to start getting answers to the many questions we have,” she says.
“Scientists Rejoice! Studying Cannabis Is About to Get a Lot Easier.” Www.Motherjones.Com, 5 Jun. 2024, www.motherjones.com/politics/2024/05/scientists-rejoice-studying-cannabis-is-about-to-get-a-lot-easier/. Accessed 5 Jun. 2024.
