MGC Pharmaceuticals | 22 October 2018
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Preclinical studies show potential efficacy of cannabinoids in AD
Several studies in cell culture and animal models have shown that cannabinoids can reduce
oxidative stress, neural inflammation, and the formation of amyloid plaques and neurofibrillary
tangles, the key hallmarks of AD.
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Some studies have shown that cannabinoids appear to remove
the amyloid plaques that are a hallmark of AD from nerve cells grown in the lab.
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A study in an
animal model of AD found that a combination of THC and CBD preserved memory, reduced
learning impairment and decreased levels of soluble beta amyloid1-42, a key component of amyloid
plaques found in the brains of patients with AD.
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Some researchers believe that targeting the CB2
receptor (eg with CBD) could control the activity of microglia cells, preventing the potentially harmful
overactivation of the immune system in the brain seen in AD.
Clinical studies in dementia have focused on THC monotherapy, with mixed
results
Most clinical studies of cannabinoids in dementia have focused on THC monotherapy, rather than
THC/CBD combinations like CogniCann. A scientific review published in 2015 identified four small
studies, all using THC monotherapy, in a total of 60 dementia patients suffering from behavioural
disturbances. While the studies were either not randomised or included a limited number of
participants, they observed reduced levels of disturbed behaviour and agitation in THC-treated
patients (Ahmed et al 2015). However, a subsequent 60-patient randomised study (van den Elsen
et al 2015, clinicaltrials.gov identifier NCT01608217) found that there was no benefit of low-dose
oral THC in dementia-related neuropsychiatric symptoms such as agitation and aggression, or in
quality of life.
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In contrast to the negative findings from the van den Elsen study, in July 2018 the synthetic
cannabinoid nabilone (Cesamet, Mylan/Meda Pharmaceuticals) successfully met its primary
endpoint of reducing agitation and aggression in a randomised 39-patient Phase II/III study in AD
patients (NCT02351882).
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Nabilone is a synthetic cannabinoid analogue of THC that causes
minimal euphoria. In addition to meeting the primary endpoint of improving agitation as measured
by the Cohen-Mansfield Agitation Inventory, nabilone also improved quality of life, cognition and
overall neuropsychiatric symptoms. Although the treatment was well tolerated, there was an
increase in sedation (drowsiness/sleepiness, 45% on nabilone vs 16% on placebo).
Despite the fact that the results of the investigator-sponsored Phase II/III study of nabilone are
positive, larger trials and replication would be needed to make recommendations that would change
clinical practice.
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Nabilone is currently approved in the US and certain European countries for the
treatment of chemotherapy-related nausea and vomiting. The study was sponsored by the
Sunnybrook Research Institute in Canada, and we could not find any evidence that Mylan plans to
conduct a confirmatory study of nabilone in dementia.
In addition to the completed trials above, our search of clinicaltrials.gov identified two ongoing
studies of cannabis or cannabinoids in dementia. The first was a 60-patient randomised Phase II
study in dementia-related agitation and aggression (NCT03328676). This study, which is being
conducted by TO Pharmaceuticals, a subsidiary of Tikun Olam, is investigating the effect of
Avidekel, a low THC cannabis oil (THC:CBD 1:20). The study commenced in December 2017 and
is expected to complete in November 2019.
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Ahmed et al 2015. Clinical Pharmacology & Therapeutics 96 (6):597-606
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Currais et al 2016. npj Aging and Mechanisms of Disease. 2, Article number: 16012
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Aso et al 2015. J. Alzheimers Dis. 43, 977–991.
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van den Elsen et al 2015. Neurology;84:2338–2346
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Lanctot et al 2018. Alzheimer’s Association International Conference; Abstract F4-02-04
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https://www.medpagetoday.com/meetingcoverage/aaic/74214