Can cannabis help people with dementia?
Researchers at NICM Health Research Institute are set to examine the effects of a complex cannabis-based medicine on cognitive function in people with early-stage Alzheimer’s disease, the most common cause of dementia.
The project, a collaboration between NICM Health Research Institute and Australian Natural Therapeutics Group (ANTG), will recruit over the next two years 80 volunteers, for the 12-week randomised, double-blind, placebo-controlled Phase II trial.
Project Chief Investigator and Director of Research at NICM Health Research Institute, Associate Professor Genevieve Steiner says the research has the potential to lead to a desperately needed medical breakthrough for Alzheimer’s disease in an area that has seen over 150 failed attempts at developing drugs for this indication over the past 20 years.
“Mild cognitive impairment is a transitional stage between healthy cognitive ageing and dementia. When memory problems are present it significantly increases the risk of Alzheimer’s disease,” said Associate Professor Steiner.
“There are currently no approved treatments for mild cognitive impairment, and anti-Alzheimer’s disease medications have not been shown to improve memory and thinking in mild cognitive impairment over time, nor do they address the underlying causes of the disease.
“We’re really excited to be partnering with ANTG to advance research in Alzheimer’s disease using a complex cannabis-based treatment in what will be a world-first clinical trial in humans.
“Cannabis rich in cannabidiol (CBD) has been shown to offer properties such as neuroprotection, neurogenesis and anti-inflammatory effects which are relevant to the underlying pathology of Alzheimer’s disease, and medium chain triglycerides (MCTs) can help improve neuronal (brain cell) survival and metabolism. Both have demonstrated promising results on cognition in previous research studies.”
The trial will use ANTG’s Eve strain, which is a CBD rich whole plant extract that also contains other cannabinoids and terpenes including delta-9-tetrahydrocannabinol (THC), in addition to MCTs for the compound combination.
The research team are currently finalising the protocols for ethics approval and final trial registration, aiming to start screening people in 2021 to see if they are eligible to take part in the study.
Supplementing the clinical trial, Co-Chief Investigator, Professor Tim Karl, School of Medicine, will also test the therapeutic potential and superiority systematically in an established preclinical research model relevant to dementia.
Alzheimer's disease and cannabinoids
Born in Barcelona, 17 February 1956. Graduated in medicine and surgery from the University of Barcelona in 1979. For 38 years has worked as an emergency physician in the area of occupational medicine. He became interested in cannabis by chance, and for the last 15 years has studied its therapeutic uses. He currently works at Kalapa Clinic, where he advises on treatments with cannabinoids, performs clinical work with patients and collaborates with different organisations and associations such as Catfac. He is a member of the Spanish Observatory for Medicinal Cannabis. He is a regular member of IACM.
Alzheimer’s disease (AD) is now the most common cause of dementia, accounting for 65% of all recorded cases; in general it affects people aged 60 years and over. Alzheimer’s is an irreversible neurodegenerative disease, leading –at a varying rate– to a loss of cognitive capacities.
Clinical characteristics of AD include memory loss –particularly of recent events in the earlier stages of the process– together with alterations in cognitive capacities that interfere with mood, reasoning and verbal expression. The disease develops stealthily and some AD patients can live for up to 20 years after diagnosis, although the average survival time is between 5 and 10 years. Age is the main risk factor; from 60 years on, the probability of suffering the disease doubles every five years. For this reason, AD is seen as one of the greatest health problems of our time, and it will have a growing socio-economic impact in coming decades.
As well as suffering memory loss, people with Alzheimer’s disease often have problems with verbal language and find themselves unable to express themselves properly, suffering a reduction in vocabulary. Other frequent changes include disorientation, behavioural changes, insomnia, nocturnal agitation –i.e. biorhythm alterations– and appetite loss.
These are caused by a gradual destructuring of the brain as the disease spreads. Alzheimer’s disease develops at different rates depending on the individual, although there are quantifiable genetic and hereditary factors that determine its spread.
The causes of the disease are currently unknown, although in recent years our understanding of the molecular mechanisms involved in the development of the disease has improved.
We basically know that a protein called amyloid beta builds up in the brain tissue, forming plaques and neurofibrillary tangles, which lead to neuroinflammation and toxicity in the brain tissue, resulting in a loss in brain volume as a result of neuron death. This evidently leads to a loss in the patient capabilities. Initially, this tends to be manifested in an effect on memory. From a certain age, this is difficult factor to assess, although there are a number of tests and questionnaires that offer acceptable guidance when considering a diagnosis of Alzheimer’s disease.
The therapeutic arsenal available for treating AD continues to be very limited at this time. Among the drugs most commonly used today are acetylcholinesterase inhibitors (donepezil, rivastigmine and tacrine). Acetylcholinesterase is the enzyme responsible for the degradation of the neurotransmitter acetylcholine. Use of these drugs has been justified by the observation that some of the cognitive, functional and behavioural alterations in AD patients may generally be explained by a cholinergic deficit in the brain. However, other lines of therapy need to be considered to address different aspects of the disease. Here the use of agents capable of modulating the endocannabinoid tone may be important. They include antiglutamatergic, antioxidant and anti-inflammatory agents and others used to address certain symptoms of the disease, such as loss of appetite, sleep disorder and behavioural changes.
Although the use of cannabinoids might initially be seen as counterproductive in treating AD, due to their psychoactive effects and their effect on the memory (considering that THC use affects short-term memory), there are other aspects of the disease’s symptomatology for which they can have beneficial effects. These include nocturnal agitation, in which THC and CBD appear to have a beneficial effect. Their effect as appetite stimulants and antiemetics may also be useful in the treatment of such patients.
There are studies indicating that the endocannabinoid system is directly involved in processes that develop in the brain of Alzheimer’s disease patients.
Here we might consider the use of phytocannabinoids for treating these patients’ pathologies.
There are two situations in which cannabinoids have shown to be effective, neuroinflammation and oxidative stress, which lead to neurotoxicity and neuron death in the medium and long term.
It is also important to remember that phytocannabinoids have a low level of toxicity. This means that they are safe to use without risking the appearance of side effects that might endanger the lives of patients or create inconvenient situations. It is worth stressing that acute cannabis intoxication has never been found to be a direct cause of death.
Studies have essentially centred on the application of Cannabidiol (CBD) for medium and long term treatment, since it possesses very interesting properties for treating the symptomatology and counteracting the situation of neuroinflammation presented by the patients.
We have discussed neuroinflammation, and CBD is also an effective anti-inflammatory in the CNS, where inflammatory processes associated with the accumulation of plaques and neurofibrillary tangles generate a great number of molecules that are toxic for neurons. These molecules, free radicals, are toxic for the cells, and constitute what is known as oxidative stress. The ability to eliminate or counteract these radicals is crucial for the equilibrium of cells and tissues, and CBD also offers the antioxidant effect needed in this situation.
Studies are therefore being carried out into the use of CBD in the treatment of Alzheimer’s disease. However, as yet no medium and long term results are available that might determine the effectiveness of their use, which is also determined by the phase of the disease in which treatment begins.
Many patients present symptoms of anxiety and here the anxiolytic effect of CBD is useful. It can also be used in nocturnal doses to induce sleep among patients with mild sleep disorder. It is often necessary to associate treatment with THC, in order to treat the insomnia or nocturnal agitation found in some patients.
In many cases, CBD also helps improve cognitive aspects, which are quantifiable and have been confirmed by family and carers. Some patients experience an improvement in verbal language, better orientation, better communication with their surroundings and greater emotional stability – all within reasonable expectations and in relationship to the specific phase of the disease and the circumstances of each patient.
We may therefore expect short-term effects from treatment with cannabinoids, since they act on the symptomatology that patients present, but it would also be possible to act in the medium and long term, to slow or halt development of the disease. Current studies and any clinical trials performed in the future will determine whether cannabinoids come to form part of the therapeutic arsenal used for patients with Alzheimer’s disease.
Synonyms: CBD, Epidiolex
Therapy Type: Small Molecule (timeline)
Target Type: Other Neurotransmitters (timeline)
Condition(s): Alzheimer’s Disease
U.S. FDA Status: Alzheimer’s Disease (Phase 2)
Approved for: Seizures in Dravet syndrome, Lennox-Gastaut syndrome or tuberous sclerosis complex
Cannabidiol is a major active compound of the cannabis plant. It is structurally related to tetrahydrocannabinol (THC), but does not produce a high. CBD is also abundant in hemp plants, which have little to no THC, making industrial hemp the usual source of THC-free CBD oil. In many locales, hemp-derived CBD is not subject to cannabis laws, and is freely available as capsules, drops or oil suspensions, or in transdermal patches, topical lotions, or salves. CBD has been studied in clinical trials for anxiety, addiction, cognition, movement disorders, pain, and other conditions, with no strong evidence yet for its effectiveness. Nonetheless, it is widely promoted and used for these and other maladies.
In 2018, an oral solution of CBD was approved in the U.S. to treat rare forms of severe childhood epilepsy. Common side effects include sleepiness, poor sleep, decreased appetite, diarrhea, and fatigue. This formulation can also cause an increase in liver enzymes, and interferes with metabolism of other medications.
Like the THC formulations nabilone and dronabinol, in Alzheimer’s, CBD is mainly being evaluated for treatment of agitation and aggression with this disease.
In preclinical work, extensive studies with CBD in cell and animal models of Aβ-induced neurotoxicity found it had multiple actions on Aβ production, tau phosphorylation and aggregation, oxidative stress, inflammation, and neurogenesis (reviewed by Watt and Karl, 2017; also see Khodadadi et al., 2021). A combination of CBD and THC was reported to preserve memory function and reduced astrogliosis and inflammation in APP/PS1 mice, with the combination more effective than either alone (Aso et al., 2015). CBD is reportedly neuroprotective in models of tauopathy and stroke (e.g. see Kreilaus et al., 2022; Ceprian et al., 2017).
CBD’s mechanism of action is unclear. It has low affinity for the cannabinoid receptors CB1 and CB2; instead, it has been proposed to act through TRPV cation channels, the peroxisome proliferation receptor gamma (PPARγ), novel G protein coupled receptors, and serotonin receptors (reviewed by Vitale et al., 2021).
Previous small trials of CBD in Parkinson’s and Huntington’s diseases found no improvement in symptoms, but the PD patients on treatment reported higher quality of life (Chagas et al., 2014; Consroe et al., 1991).
From 2017-2019, Tikun Olam Pharmaceuticals ran a 64-person Phase 2 trial in Israel testing Avidekel oil, a high CBD/low THC cannabis extract, for the treatment of agitation and aggression in dementia patients. The oil contains 30 percent CBD and 1.5 percent THC. Participants received active or placebo drops under the tongue three times a day for 16 weeks. The primary outcome was a reduction of four points on the Cohen-Mansfield Agitation Inventory; secondary was change on the Neuropsychiatric Inventory-Nursing Home version. According to a published abstract, 72 percent of participants taking CBD oil achieved the primary outcome versus 30 percent on placebo. The average reduction on CBD was 13.3 points versus 2.3 points on placebo. NPI-NH scores were reported to be significantly better with treatment (Hermush et al., 2020; 68, see (Suppl 1):S86 abstract A202 page 86).
In January 2021, an open-label Phase 1 trial began testing an eight-week course of high CBD/low THC oil in 12 people with mild to moderate AD and anxiety and aggression. The custom-formulated hemp extract is given under the tongue twice a day. A target dose of 45 mg CBD per day also delivers approximately 1 mg THC. The primary endpoint is the clinician impression of anxiety from the Neuropsychiatric Inventory-C; other endpoints are additional measures of anxiety, as well as safety and side effects, cognition, and caregiver burden. An optional 12-month extension with similar, commercially available CBD products is offered. According to a presentation at CTAD in November 2021, one person had completed the single-center study at McLean Hospital in Massachusetts. The trial was planned to end in January 2022.
In February 2021, a Phase 2 trial started to assess the effectiveness of a THC-free CBD oil to treat agitation in people with AD dementia or mixed AD dementia. The trial will enroll 40 participants for a six-week regimen of hemp-derived CBD oil capsules or a matching placebo. The dose begins at 30 mg daily, titrating up to 90 mg, or the highest tolerated dose. Primary outcomes are change in Cohen-Mansfield Agitation Inventory, caregiver burden, and quality of life of patient and caregiver. Secondary measures include the Neuropsychiatric Inventory, MMSE, and sleep quality. The single-center study at Eastern Virginia Medical School in Norfolk is expected to finish in June 2022
In April 2021, a study began enrolling older people with mild cognitive impairment who carry the ApoE4 allele, to compare the effects of a CBD or homotaurine on cognition, daily function, and depression. The single-center, Phase 4 study is ongoing in Greece. It will randomize 90 patients to 5 percent CBD oil, homotaurine, or no intervention. Twenty primary outcomes include the MMSE, MoCA, a cognitive battery, dementia ratings, measures of anxiety and depression, and CSF biomarkers of BDNF, tau, inflammation, and oxidative stress. The trial will run through December 2022.
CBD is also being tested for motor symptoms and pain in Parkinson’s disease. Other active studies include amyotrophic lateral sclerosis, psychosis, anxiety, autism, insomnia, pain conditions, and substance use disorders, among others.