Nabilone is associated with TNF-α reduction and consecutive agitation decrease, however no significant effects are shown for the oxidative stress marker 4-HNE.
Summary
RCT substudy (n=38 Alzheimer's patients with agitation, 14 weeks cross-over, nabilone vs. placebo); OS marker 4-HNE associated with agitation severity (F=6,41, p=0,016); in the nabilone phase: lower baseline TNF-α predictive of agitation decrease (b=1,14, p=0,045), TNF-α decrease correlates with agitation decrease (b=1,12, p=0,006); indication of anti-inflammatory mechanism of action.
P
PopulationAdults with Alzheimer's dementia and agitation, n=38, substudy of a cross-over RCT
I
InterventionNabilone (oral, 6 weeks) with biomarker analysis (4-HNE, TNF-α)
C
ControlPlacebo (6 weeks, cross-over with 1 week washout phase)
O
OutcomeLower baseline TNF-α associated with agitation reduction under nabilone (b=1,14; p=0,045); TNF-α decrease correlated with agitation decrease under nabilone (b=1,12; p=0,006); 4-HNE changes not associated with agitation change
Confidence in the evidence
Very lowLowModerateHigh
Moderate
The third of four GRADE levels, the effect estimate is probably reliable.
The endocannabinoid system has been a target of interest for agitation in Alzheimer disease (AD) because of potential behavioral effects and its potential impact on mechanisms implicated in AD such as oxidative stress (OS) and neuroinflammation. We explored whether serum markers of OS and neuroinflammation were associated with response to the cannabinoid nabilone in agitated patients with AD (N = 38). All participants were enrolled in a 14-week, double-blind, cross-over trial comparing nabilone to placebo (6 weeks each) with a 1-week washout between phases. Samples were collected at the start and end of each phase. The cross-sectional relationship agitation (Cohen Mansfield Agitation Inventory) and OS and inflammatory markers were investigated to select markers of interest. Significant markers were then explored for their relationship with response. The OS marker, 4-hydroxynonenal (4-HNE; <i>F</i><sub>1, 35</sub> = 6.41, <i>P</i> = .016), and the proinflammatory cytokine, tumor necrosis factor-α (TNF-α; <i>F</i><sub>1, 29</sub> = 3.97, <i>P</i> = .06), were associated with agitation severity, and TNF-α remained significantly associated (<i>F</i><sub>2, 25</sub> = 3.69, <i>P</i> = .04) after adjustment for cognition. In the placebo phase, lower baseline 4-HNE was associated with decreases in agitation severity only (b = 0.01, <i>P</i> = .01), while lower baseline TNF-α was associated with decreases in agitation severity in the nabilone phase only (b = 1.14, <i>P</i> = .045). Changes in 4-HNE were not associated with changes in agitation severity in either phase. In the nabilone phase, lower baseline TNF-α was associated with decreases in agitation severity (b = 1.14, <i>P</i> = .045), and decreases in TNF-α were associated with decreases in agitation severity (b = 1.12, <i>P</i> = .006). These findings suggest that OS and neuroinflammation may be associated with agitation severity, while nabilone may have anti-inflammatory effects.