Synthetic THC Improves Agitation in Patients With Alzheimer Disease

In this video, Paul B. Rosenberg, MD, discusses his team’s research on using dronabinol, a legal form of synthetic THC, to treat agitation in patients with Alzheimer disease. The study found that dronabinol significantly reduced agitation with a favorable safety profile over a short 3-week period. Dr. Rosenberg emphasizes the need for longer studies and further research on cannabis products.

Additional Resources:

• Clinical trial shows synthetic cannabis reduces agitation in alzheimer’s disease. News release. Johns Hopkins Medicine; Oct 2, 2024. Accessed Oct 7, 2024. https://www.hopkinsmedicine.org/news/newsroom/news-releases/2024/10/clinical-trial-shows-synthetic-cannabis-reduces-agitation-in-alzheimers-disease

• Drye LT, Ismail Z, Porsteinsson AP, et al. Citalopram for agitation in Alzheimer's disease. Alzheimer's Dement. 2012;8(2):121-30. doi:10.1016/j.jalz.2011.01.007.

• Woodward MR, Harper DG, Stolyar A, et al. Dronabinol for the treatment of agitation and aggressive behavior in acutely hospitalized severely demented patients with noncognitive behavioral symptoms. Am J Geriatr Psychiatry.2014;22(4):415-9. doi:10.1016/j.jagp.2012.11.022.

• Herrmann N, Ruthirakuhan M, Gallagher D, et al. Randomized placebo-controlled trial of nabilone for agitation in alzheimer's disease. Am J Geriatr Psychiatry. 2019;27(11):1161-1173. doi:10.1016/j.jagp.2019.05.002.

TRANSCRIPTION

Consultant360: What was the impetus of this research?

Paul B. Rosenberg, MD: So I'm a psychiatrist working in Alzheimer's disease, and we've been working on finding better treatments for the psychological symptoms of Alzheimer's for many years. One of the most important of those symptoms, behavioral symptoms, is agitation. Agitation can be a lot of things. Agitation can be excessive motor activity like pacing. It can be verbal aggression like yelling or cursing. It can be physical aggression like being combative or hitting. Obviously the hitting is the worst of it. Fairly common in Alzheimer's disease and a major source of burden for caregivers and a major source of distress for patients. And agitation is associated with people going in a nursing home sooner, declining sooner, even dying sooner.

We've been trying to find both behavioral treatments, non -pharmacologic treatments, and medications for a long, long time. We've had some success. We've done a study of Cetalopram, which is an SSRI and antidepressant, which was quite good for reducing agitation. There's an FDA -approved drug, Brexpripazol, which is an anti -psychotic, but these also have some side effects. So we thought we needed to add another arrow to the quiver, another weapon in the armamentarium. And we noticed that people have been using THC off-label for a number of years. THC is the main active ingredient of marijuana, and it is actually a legal drug called dronabinol. It's been on the market for many years for loss of appetite at the end of life. But in recent years, people have been using this legal form of THC. This is legal at all levels, federal and so forth. It's a Schedule III controlled substance, but it is perfectly legal to prescribe. People have been trying dronabinol off-label for agitation with some success. My colleague Brent Forester at McLean Hospital, he was at McLean Hospital at Harvard at the time, had a case series of 40 patients on their inpatient unit with agitation, most of whom improved with dronabinol. And the THC dose was about seven milligrams a day.

There've been a variety of other studies. Our colleagues in Canada, Krista Lanctôt and Nathan Herrmann, did a nursing home study. In Canada it's a different drug called nabilone, same idea but it's a different chemical actually, and they've had quite a bit of success in treating agitation in nursing home patients but had a fair amount of sedation. They had to cut back the dose in a number of people. So we sought to test dronabinol in a variety of patients with Alzheimer's and agitation.

C360: How does your study fill a current gap in our knowledge?

Dr Rosenberg: People are prescribing this drug quite a bit for agitation without any rigorous knowledge on whether it works. So the thing in science is you really need to do a rigorous study, that means a placebo-controlled study. If you want enough of drug work, you really have to do that. And so that's what this study is, was, to fill that gap in our knowledge.

C360: What surprised you about the results of this study? What are the takeaways?

Dr Rosenberg: Well, you don't do a study if you don't think it's going to work. So I don’t think we were truly surprised. But we had quite a positive result. We had two primary outcomes, one of which is called the Pittsburgh Agitation Scale, one of which is called the Neuropsychiatric Inventory Aggression Agitation Scale. Think of it as similar scales. They were both statistically significant and positive. Patients on drug improved.It was a short study. It was a 3-week study. That's because it started as an inpatient study on a dementia unit at Hopkins and a psych unit at McLean.It's since morphed into an outpatient study, but we kept the same 3 weeks so as to be consistent.

I think the thing that pleasantly surprised me was the safety profile. I mean, 3 weeks is a short time, but we found really no safety signal to worry about. And many of the things that you would worry about with giving see to frail elderly adults, like do they get more confused? That would be delirium. Or do they get stoned? Do they get intoxicated? We actually did a scale. There's a scale called the drug effectiveness questionnaire, which was designed to measure THC intoxication in younger people. We adapted it to this study by having the families or the caregivers do it because the patients were too advanced to really answer questions. And we did not find evidence of intoxication. That was certainly a pleasant surprise.

C360: What gaps in our knowledge still remain? What kind of research is needed to fill those gaps?

Dr Rosenberg: I think there's a couple of things to do right now. One of them is it would behoove us to do a longer study. We chose a 3-week study for a variety of practical reasons having to do with the fact that we started on inpatient units. Without patients you can do much longer studies and in general in this field you try to do a 12-week study. 12 weeks is a lot longer than 3 and it's a reasonable period of time to see if the benefits are longer lasting. It's also a much more reasonable amount of time to assess safety.

The other place the research needs to go, but it's really quite challenging would be to study cannabis products that you can get at a dispensary. We used a drug, a chemical made in a factory purified according to FDA standards. It's called actually good manufacturing practice, GMP. And so that drug has the quality control that you'd expect from a prescription drug. Cannabis is legal in, I think it's 23 states right now. It's illegal at a federal level. It's still a Schedule I drug. So it's in a bit of a legal limbo. But in the meantime, in these 23 states, most people can obtain cannabis products. They're not the same thing we tested. They're not the same thing we tested. They have a cocktail of chemicals called cannabinoids. and we really are not sure whether the cocktail is going to work as well or be as safe as the individual drug.

Personally, I'd like to try to test a dispensary product, but there are some real scientific challenges. One of them is quality control. Can you make sure that each batch you get is similar? The second one is choice of product. As I said before, most of these products contain THC plus a lot of other cannabinoids. We really, I do not know whether we would want to test CBD as well. CBD is also a cannabinoid. It doesn't have any intoxicating effect pretty much. And some people are using it for anxiety and other problems. I am not at all convinced it works for anything. The question is whether we would want to test it. So those are the two areas to go. I want us to do a longer, more definitive study with the drug dronabinol, and the other is to find a way to do a rigorous study of dispensary products. There is a chance that the DEA may reclassify cannabis products instead of Schedule 1, which is essentially illegal, to Schedule 3, which is something you can prescribe. And if they do that, that would actually make the research a lot easier. So those are two ways I think we can go.

C360: What was the main takeaway from your study that other experts in your field should know?

Dr Rosenberg: Dronabinol worked quite well and appeared quite safe for agitation and Alzheimer disease. It's well worth adding to your armamentarium of medication treatments.