Alzheimer’s Disease and Cannabis (April 2017)
The following information has been curated and distilled from Watt and Karl’s 2017 review on cannabis and Alzheimer’s Disease. 1
Terms to familiarize yourself with
- In vitro: (Latin for “within the glass”) refers to the technique of performing a given procedure in a controlled environment outside of a living organism.
- In vivo: (Latin for “within the living”) refers to experimentation using a whole, living organism as opposed to a partial or dead organism. Animal studies and clinical trials are two forms of in vivo research.
- Amyloid-β (Aβ): crucially involved inAlzheimer’s diseaseas the main component of the amyloid plaques found in the brains of Alzheimer patients.
- Tau: Pathologies and dementiasof the nervous systemsuch as Alzheimer’s disease and Parkinson’s disease are associated with tau proteins that have become defective and no longer stabilize microtubules properly.
CBD has demonstrated neuroprotective, anti-inflammatory and antioxidant properties in vitro, and has thus been investigated as a potential multifunctional treatment option for Alzheimer’s Disease (AD). AD is characterized by the accumulation of amyloid-β and tau hyperphosphorylation, as well as neuroinflammation and oxidative stress.
CBD reverses and prevents the development of cognitive deficits in AD rodent models. Interestingly, combination therapies of CBD and ∆9-tetrahydrocannabinol (THC), the main active ingredient of cannabis sativa, show that CBD can stop the psychoactive (i.e. high-inducing) effects associated with THC and possibly contribute greater therapeutic benefits than either phytocannabinoid alone.
AD exhibits a neurodegenerative cascade that appears to be instigated by the accumulation of Aβ (forming senile plaques) and hyperphosphorylated tau [forming neurofibrillary tangles (NFTs)] 2. The cascade induces neuroinflammation and oxidative stress, which creates a neurotoxic environment that potentiates neurodegeneration and eventually leads to cognitive decline 3.
Also, Aβ-induced neurodegeneration elevates glutamate levels in the cerebral spinal fluid of AD patients and cholinergic neurons are lost in brain areas relevant for memory processing (and accompanied by a decrease in acetylcholine) 4. There are four approved drugs available, three are acetylcholinesterase inhibitors (rivistagmine, donepezil and galantamine) and one is a N-methyl-D-aspartate (NMDA) receptor antagonist (memantine). Unfortunately, most of these have severe adverse side effects and are not well tolerated by patients.
Epidemiological data have shown that non-steroidal anti- inflammatory drugs (NSAIDs) are associated with a reduced risk of AD 5. Furthermore, animal studies indicated that NSAID treatment could attenuate AD pathogenesis, proposing that inhibiting neuroinflammation may slow the progression of AD 6. NSAIDs have also been associated with severe long-term adverse effects (e.g., gastrointestinal problems) and have only shown limited efficacy in reducing or preventing clinical symptoms 5.
It is unlikely that any drug acting on a single pathway or target will mitigate the complex pathoetiological cascade leading to AD. Therefore, a multifunctional drug approach targeting a number of AD pathologies simultaneously will provide better, wider-ranging benefits than current therapeutic approaches 7. With this in mind, the endocannabinoid system (acting upon a number of different physiological pathways) has recently gained attention in AD research as it is associated with regulating a variety of processes related to AD, including oxidative stress 8, glial cell activation 9, and clearance of macromolecules 10. The phytocannabinoid cannabidiol (CBD) is a prime candidate for this new treatment strategy.
CBD has been found in vitro to be neuroprotective 11, to prevent hippocampal and cortical neurodegeneration 12, to have anti-inflammatory and antioxidant properties 13. CBD reduces tau hyperphosphorylation 11 and regulates microglial cell migration 14. Furthermore, CBD was shown to protect against Aβ mediated neurotoxicity and microglial-activated neurotoxicity to reduce Aβ production, and to improve cell viability 15.
CBD acts as an inverse agonist at the CB2 receptors, which may explain some of its anti-inflammatory properties as inverse agonists at CB2 receptors are able to inhibit the migration of immune cells 16. The wide range of targets of CBD emphasizes its potential as a multimodal drug for AD treatment. The in vivo therapeutic potential of CBD in AD has not been widely documented, however, there are a number of studies that have reported the effect of CBD in pharmacological models of AD (e.g., inoculation with fibrillar Aβ). The in vivo anti-inflammatory effects of CBD were confirmed in a mouse model of AD. Injections of CBD (2.5 or 10 mg/kg) for 7 days dose-dependently inhibited glial fibrillary acidic protein (GFAP) mRNA and protein expression 17. NO is a free radical and important in neuroinflammatory and neurodegenerative conditions, which include accelerating protein nitration and increasing tau hyperphosphorylation. CBD reduced both iNOS and interleukin-1β (IL-1β) protein expression and the related NO and IL-1β release 11,17.
The anti-inflammatory and neuroprotective effects of CBD were further investigated in a rat model of AD-related neuroinflammation. CBD was able to dose-dependently decrease Aβ-induced expression. This study found that CBD-induced anti-inflammatory properties are mediated (at least partially) through the PPAR-γ receptor. Finally, the study found that CBD was able to restore CA1 pyramidal neurons to a similar integrity to that of the control rats. CBD also down-regulated gliosis and repaired neurogenesis in the dentate gyrus 18.
One study to date has investigated the effects of CBD on cognition in a pharmacological model of AD. CBD treatment was able to reverse the cognitive deficits of Aβ-treated mice.
They were then treated with 20 mg/kg CBD using daily i.p. injections for 1 week and then 3 times/week for the following 2 weeks. Interestingly, selective CB2 agonists did not prevent the cognitive deficit, indicating that CBD exerts this therapeutic effect via other mechanisms 19. Behavioral benefits documented may be mediated by glial activation modulation. CBD treatment prevented the ATP-induced intracellular calcium increase and promoted microglial activation. Some effects of CBD could be related to a direct effect of the phytocannabinoid on exogenous Aβ administration rather than the long-term effects of the accumulated Aβ.
To assess the remedial effects of CBD, mice were treated for 3 weeks with CBD (20 mg/kg CBD
post onset of cognitive deficits and AD pathology. CBD treatment was able to reverse cognitive deficits in object recognition memory and social recognition memory without influencing anxiety parameters 19. In the preventative treatment study, mice were treated for 8 months with CBD. This assessed the long-term effect of CBD prior to “AD onset.” Long-term CBD treatment was able to prevent the development of social recognition memory deficits without affecting anxiety domains in AD transgenic mice. There was also a subtle impact of CBD on inflammatory markers of the brain 19.
Recent research has indicated that a combination of CBD and ∆9-tetrahydrocannabinol (THC) can avoid the detrimental effects caused by THC-induced activation of the CB1 receptors (e.g., psychoactivity), and actually provide greater therapeutic benefits than either phytocannabinoid alone 20. Importantly, there is controversy about what the ratios of CBD:THC should be used in order to antagonize detrimental THC effects. It has been reported that 10-fold higher dose of CBD was necessary to prevent the unwanted side effects of THC, however, combination therapy using a 1:1 ratio of CBD and THC is approved as an anti-inflammatory drug treatment against spasms in multiple sclerosis and does not appear to be associated with any adverse THC effects, suggesting that CBD effectively blocks those at the ratio chosen 21.
Three studies to date have evaluated the efficacy of a combination of CBD and THC on AD-related processes in vivo. One study created a mouse model that is foremost a model of frontotemporal dementia, parkinsonism and lower motor neuron disease. The study found that Sativex decreased gliosis, increased the ratio of reduced/oxidized glutathione and reduced the levels of iNOS, thereby showing neuroprotective and anti-oxidant properties 22. Importantly, Sativex reduced Aβ and tau deposition in the hippocampus and cerebral cortex as well as increasing autophagy, thus implying, that although the mouse model is not directly related to AD, the therapeutic benefits are.
The second study compared the effect of CBD, THC and a CBD-THC combination. This study found that all treatments improved memory deficits, but only the CBD-THC combination prevented the learning deficit. CBD-THC combination also decreased soluble Aβ42 levels and changed plaque composition while CBD and THC individually did not. Finally, reduced astrogliosis, microgliosis and inflammatory related molecules were more pronounced after treatment with the CBD-THC combination than either phytocannabinoid individually 23.
This suggests that when CBD and THC are combined there may be either a summative effect or an interaction effect between the compounds, which potentiates their therapeutic-like effects
In this context, it should be mentioned, that although all treatments had cognition- improving characteristics in the object recognition task, THC alone had a detrimental effect on cognition in control mice, highlighting the need to be cautious when considering THC as a therapeutic.
Other research suggests that CBD might modestly potentiate THC’s psychoactive effects 20. Control mice treated with CBD-THC combination did not show any cognitive deficits suggesting that CBD may be able to antagonize the detrimental effects of THC. Aso et al. also investigated the effect of CBD-THC combination treatment on memory and brain pathology in aged male
Mice. Compared to the non-aged controls, vehicle-treated aged mice demonstrated impaired cognition in the two-object recognition task. Interestingly, CBD- THC combination restored the memory deficit.
In comparison to their previous study testing younger APPxPS1 mice, CBD-THC combination did not influence the Aβ load or the related glial reactivity in aged AD transgenic mice. However, the combination treatment normalized synaptosome associated protein 25, glutamate receptors 2 and 3and γ-aminobutyric acid receptor A subunit α1 expression, implying that CBD-THC may exert its beneficial effects on cognition via these mechanisms.
Unfortunately, there is still no effective treatment on the market that stops or reverses the disease progression. The studies reviewed in this mini review provide “proof of principle” for the therapeutic benefits CBD to become a treatment, and possibly CBD-THC combinations pose for AD therapy. Nevertheless, the studies discussed here provide promising preliminary data and the translation of this preclinical work into the clinical setting could be realized relatively quickly: CBD is readily available, appears to only have limited side effects, and is safe for human use.
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