Medical Cannabis Research
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Destabilization of the Alzheimer’s amyloid-β protofibrils by THC: A molecular dynamics simulation study
CBD reduces plaque, improves cognition in model of familial Alzheimer’s
- Date: March 9, 2021
- Source: Medical College of Georgia at Augusta University
- A two-week course of high doses of CBD helps restore the function of two proteins key to reducing the accumulation of beta-amyloid plaque, a hallmark of Alzheimer’s disease, and improves cognition in an experimental model of early onset familial Alzheimer’s, investigators report.
A two-week course of high doses of CBD helps restore the function of two proteins key to reducing the accumulation of beta-amyloid plaque, a hallmark of Alzheimer’s disease, and improves cognition in an experimental model of early onset familial Alzheimer’s, investigators report.
The proteins TREM2 and IL-33 are important to the ability of the brain’s immune cells to literally consume dead cells and other debris like the beta-amyloid plaque that piles up in patients’ brains, and levels of both are decreased in Alzheimer’s.
The investigators report for the first time that CBD normalizes levels and function, improving cognition as it also reduces levels of the immune protein IL-6, which is associated with the high inflammation levels found in Alzheimer’s, says Dr. Babak Baban, immunologist and associate dean for research in the Dental College of Georgia and the study’s corresponding author.
There is a dire need for novel therapies to improve outcomes for patients with this condition, which is considered one of the fastest-growing health threats in the United States, DCG and Medical College of Georgia investigators write in the Journal of Alzheimer’s Disease.
“Right now we have two classes of drugs to treat Alzheimer’s,” says Dr. John Morgan, neurologist and director of the Movement and Memory Disorder Programs in the MCG Department of Neurology. One class increases levels of the neurotransmitter acetylcholine, which also are decreased in Alzheimer’s, and another works through the NMDA receptors involved in communication between neurons and important to memory. “But we have nothing that gets to the pathophysiology of the disease,” says Morgan, a study coauthor.
The DCG and MCG investigators decided to look at CBD’s ability to address some of the key brain systems that go awry in Alzheimer’s.
They found CBD appears to normalize levels of IL-33, a protein whose highest expression in humans is normally in the brain, where it helps sound the alarm that there is an invader like the beta-amyloid accumulation. There is emerging evidence of its role as a regulatory protein as well, whose function of either turning up or down the immune response depends on the environment, Baban says. In Alzheimer’s, that includes turning down inflammation and trying to restore balance to the immune system, he says.
That up and down expression in health and disease could make IL-33 both a good biomarker and treatment target for disease, the investigators say.
CBD also improved expression of triggering receptor expressed on myeloid cells 2, or TREM2, which is found on the cell surface where it combines with another protein to transmit signals that activate cells, including immune cells. In the brain, its expression is on the microglial cells, a special population of immune cells found only in the brain where they are key to eliminating invaders like a virus and irrevocably damaged neurons.
Low levels of TREM2 and rare variations in TREM2 are associated with Alzheimer’s, and in their mouse model TREM2 and IL-33 were both low.
Both are essential to a natural, ongoing housekeeping process in the brain called phagocytosis, in which microglial cells regularly consume beta amyloid, which is regularly produced in the brain, the result of the breakdown of amyloid-beta precursor protein, which is important to the synapses, or connection points, between neurons, and which the plaque interrupts.
They found CBD treatment increased levels of IL-33 and TREM2 — sevenfold and tenfold respectively.
CBD’s impact on brain function in the mouse model of early onset Alzheimer’s was assessed by methods like the ability to differentiate between a familiar item and a new one, as well as observing the rodents’ movement.
People with Alzheimer’s may experience movement problems like stiffness and an impaired gait, says Dr. Hesam Khodadadi, a graduate student working in Baban’s lab. Mice with the disease run in an endless tight circle, behavior which stopped with CBD treatment, says Khodadadi, the study’s first author.
Next steps include determining optimal doses and giving CBD earlier in the disease process. The compound was given in the late stages for the published study, and now the investigators are using it at the first signs of cognitive decline, Khodadadi says. They also are exploring delivery systems including the use of an inhaler that should help deliver the CBD more directly to the brain. For the published studies, CBD was put into the belly of the mice every other day for two weeks.
A company has developed both animal and human inhalers for the investigators who also have been exploring CBD’s effect on adult respiratory distress syndrome, or ARDS, a buildup of fluid in the lungs that is a major and deadly complication of COVID-19, as well as other serious illnesses like sepsis and major trauma. The CBD doses used for the Alzheimer’s study were the same the investigators successfully used to reduce the “cytokine storm” of ARDS, which can irrevocably damage the lungs.
There is a dire need for due innovative therapeutic modalities to improve outcomes of AD patients. In this study, we tested whether cannabidiol (CBD) improves outcomes in a translational model of familial AD and to investigate if CBD regulates interleukin (IL)-33 and triggering receptor expressed on myeloid cells 2 (TREM2), which are associated with improved cognitive function. CBD was administered to 5xFAD mice, which recapitulate early onset, familial AD. Behavioral tests and immunoassays were used to evaluate cognitive and motor outcomes. Our findings suggest that CBD treatment enhanced IL-33 and TREM2 expression, ameliorated the symptoms of AD, and retarded cognitive decline.
Keywords: Alzheimer’s disease; CBD; ILC2; cannabidiol; dementia; innate lymphoid cells.
Nov. 2020: Medical Cannabis Use: Exploring the Perceptions and Experiences of Older Adults with Chronic Conditions
- PMID: 33250007
- DOI: 10.1080/07317115.2020.1853299
Objectives: Although the rate of cannabis use by older adults is increasing more quickly than all other age groups, little is known about the reasons older adults use cannabis and the outcomes they experience. With this research, we investigated older adults’ perceptions and experiences of medical cannabis use to treat and/or manage chronic conditions, specifically as a substitute for prescription drugs.
Methods: Researchers relied on qualitative inquiry in the form of semi-structured, one-on-one interviewing to investigate the phenomenon of medical cannabis use for the management of chronic conditions.
Results: Our findings suggest that older adults are open to medical cannabis as an alternative to pharmaceutical drugs, hopeful with regard to the management of symptoms and pain, and aware of and astute at managing issues related to stigma both from their physicians and family and friends. Furthermore, older adults describe the frustrations with education, awareness, and lack of support with dosing.
Conclusions: Participations found medical cannabis use to be beneficial in managing chronic conditions and alleviating symptoms such as chronic pain. Findings are presented as an interpretation of the participants’ perceptions of their medical cannabis use. Implications for putting medical cannabis use into everyday practice as well as policy implications are considered.
Clinical Implications: This information will help clinicians better support older adults desiring to use medical cannabis. This research will help clinicians learn more about factors impacting medical cannabis use, and the types of information and assistance that may aid older adults in their health and well-being with the use of medical cannabis to treat chronic conditions.
“Cannabis Use among Persons with Dementia and Their Caregivers: Lighting up an Emerging Issue for Clinical Gerontologists”
Objectives: Our goal is to illuminate cannabis use among persons with dementia (PwD) and their informal caregivers relative to the use of evidence-based as well as other complementary and alternative care practices.
Methods: We analyzed focus group (FG) narratives provided by 26 caregivers of PwD and identified five themes concerning the provision of cannabis to PwD and caregivers’ self-use.
Results: Three of the 26 caregivers provided PwD cannabis and also used themselves, another 3 of the 26 used themselves only, and all but two of the remaining FG participants indicated they would consider providing cannabis to PwD or using for themselves. These caregivers expressed a desire to obtain more empirically-based information about cannabis and to discuss options with their clinical care providers.
Conclusions: A small but significant proportion of caregivers are providing cannabis to PwD as a possible treatment for agitation, sleep disturbances and other problematic secondary symptoms and using for themselves as way to relieve stress. Many other caregivers may start using cannabis upon receiving information and guidance from a credible source.
Clinical Implications: Notwithstanding the need for more research, clinical gerontologists and other dementia care specialists are being looked upon to provide information and guidance about the benefits and harms of cannabis use among PwD and their caregivers.
Implications for clinicians
● Clinicians need to acquire more knowledge about frequency, motives and methods of cannabis use among older adults in general, and among PwD and their caregivers in particular.
● Clinicians may wish to become familiar with the range of undesirable and beneficial outcomes experienced by persons who use cannabis.
● Clinicians may wish to consider including questions about cannabis use as part of formal evaluations of dementia and being open to conversations with PwDs and their caregivers about the potential harms and benefits cannabis use.
● Clinicians need to be become familiar with their clinic or health system’s positions on discussing cannabis with patients and with referral mechanisms to state medical cannabis programs.
● Clinicians should consider calling upon their professional provider organizations to offer cannabis education and training, and developing standards for incorporating cannabis into patient care.
Oct 2020: “Docs Develop Clinical Guides for Medical Cannabis”
— Physicians strive to provide guidance as patients increasingly ask about treatment
“As medical cannabis gains more mainstream acceptance, and as physicians increasingly encounter patient questions about its use, doctors are developing more clinical resources to guide those who decide to prescribe it.
At this year’s PAINWeek in September, Alan Bell, MD, of the University of Toronto, and colleagues presented recommendations for using medical cannabis to treat chronic pain. The same month, two physicians published a book aimed at helping colleagues treat patients, and the previous month a pain medicine specialist published a similar book.
Though evidence from gold-standard randomized controlled trials has been severely limited, authors of the publications told MedPage Today that it’s important to start somewhere.
“We are trying to advocate for more physicians to provide better care,” said Kevin Hill, MD, of Beth Israel Deaconess Medical Center in Boston, a co-author of one of the new clinical textbooks. “We wanted to present exactly where things stand now — understanding we have a long way to go in some areas.”
The “consensus recommendations” presented at PAINWeek were supported by Canopy Growth, described on its website as the “first cannabis company in North America to be publicly traded.”
The group met via video calls to develop the guidelines, setting the bar at 75% agreement to include any recommendations, and touting the use of a modified Delphi process.
Ultimately their recommendations included: stratifying patients into conservative, routine, or rapid treatment protocols based on level of need; following a regimen heavy on cannabidiol (CBD), introducing tetrahydrocannabinol (THC) in small doses only when CBD alone cannot yield desired patient outcomes; and starting with 2.5-mg doses of THC and 5-mg CBD doses and increasing dosages by 1-5 mg.
“Our main focus was to provide directions to clinicians to surmount the huge barrier that may exist because of the knowledge gap” about medical cannabis overall, Bell told MedPage Today. “There’s a huge knowledge gap and no way clinicians can fall back on a specified dosing regimen.”
Hill and Samoon Ahmad, MD, of New York University, authored Medical Marijuana: A Clinical Handbook, published by Wolters Kluwer Health in September. The 500-plus-page book features chapters on the endocannabinoid system, adverse effects, pharmacology, among other topics. It also contains 11 chapters on using cannabis within individual medical specialties.
In August, Springer published a similar book edited by Kenneth Finn, MD, a longtime Colorado pain medicine specialist who has written about medical cannabis for KevinMD and MedPage Today. Finn’s 585-page book includes chapters on cannabinoids and pain, dermatology, and public health. Chapters are co-written by clinicians and professors, as well as advocates including Kevin Sabet and David Evans.
Also this summer, Matthew Mintz, MD, who uses medical cannabis in his primary care practice in the suburbs of Washington, D.C., self-published a book for providers and patients based largely on his clinical experience. Bonni Goldstein, MD, a Los Angeles medical cannabis specialist, authored a similar book aimed at both audiences.
“There’s a strong need for good education,” said Leslie Mendoza Temple, MD, director of NorthShore Medical Group’s Integrative Medicine program in Chicago and a board member of the advocacy group Doctors for Cannabis Regulation. “The more we add to the knowledge base, the better it is for everyone.”
The resources seek to provide guidance in a field that lacks a substantial evidence base, in large part because research has been limited by federal regulations and the Drug Enforcement Administration’s Schedule 1 designation. Few randomized controlled trials have been completed, and the aging studies cited in a 2017 National Academies report still serve as prominent sources.
Hill and Ahmad said they aimed to incorporate all the credible research they could find into their book, including new evidence beyond the NAS report, and at a more detailed level. A website affiliated with the book will continuously update as new evidence emerges.
Medical and scientific groups have called for better research into medical cannabis. In May, the Parkinson’s Foundation issued a consensus statement calling for “well-designed studies that will address the question of whether cannabis-based medicines offer therapeutic benefit in the treatment of motor and non-motor symptoms of [Parkinson’s disease].”
The American Heart Association published a scientific statement on medical cannabis in September, highlighting a “pressing need for refined policy, education of clinicians and the public, and new research.” All practitioners “need greater exposure to and education on the various cannabis products and their health implications during their initial training and continuing education,” the statement said.
Just this week, the American Society of Addiction Medicine published a policy statement calling for medical cannabis to be rescheduled “to promote more clinical research and FDA oversight typical of other medications…. Federal legislation and regulation should encourage scientific and clinical research on cannabis and its compounds, expand sources of research-grade cannabis, and facilitate the development of FDA-approved medications derived from cannabis such as CBD or other cannabis compounds.”
On the other hand, some experts have argued existing evidence is enough to work with. Writing in BMJ Open, David Nutt, DM, of Imperial College London, and colleagues criticized British physicians for using the lack of RCTs as a crutch, saying “it is utterly deceitful for people who need it not to be offered medical cannabis.”
Clinicians should evaluate other published evidence, including observational studies and patient-focused trials, he wrote.
Yet the lack of randomized controlled trials has largely prevented British physicians from prescribing medical cannabis since it was legalized in 2018, the paper noted.
Additional Resources Needed
The field still lacks other key resources, such as consensus medical guidelines from a leading medical association, Hill said.
Physicians should scrutinize current resources, experts said. In the consensus guidelines, for example, the 2.5-mg doses and CBD-only treatments lack much evidence to support their use in chronic pain, and using the Delphi process does not make their recommendations science-based, Mintz said.
Mintz took umbrage with extracting guidelines from a poster presentation “not based on true data.” (The guideline task force plans to include more information when they submit for publication, Bell said.)
“It’s an interesting, good start, but calling these guidelines is an overshoot,” Mintz said. “At least there is a consensus group of clinicians. … A lot of what we are using [now] is based on clinical experience.”
The next step would be for the group to develop guidelines based on data, said Jordan Tishler, MD, president of the Association of Cannabis Specialists.
Mintz credited the other resources’ authors for striving to add to the field’s knowledge, regardless of how complete and controversial they may be.
“All physicians should be aware there is some evidence for cannabis and should be aware because it is a good option for some patients,” he said. “The more we can get clinicians, physicians out there saying, ‘yes this is something we can use and here’s a couple ideas how to use it,’ while waiting on federal regulations, that will help.”
“And hopefully we will see the laws change so we can get the data we need.”
Oct 2020: Journal of American Geriatrics Society
“Cannabis: An Emerging Treatment for Common Symptoms in Older Adults”
Use of cannabis is increasing in a variety of populations in the United States; however, few investigations about how and for what reasons cannabis is used in older populations exist.
A total of 568 adults 65 years and older.
Survey assessing characteristics of cannabis use.
Approximately 15% (N = 83) of survey responders reported using cannabis within the past 3 years. Half (53%) reported using cannabis regularly on a daily or weekly basis, and reported using cannabidiol‐only products (46%). The majority (78%) used cannabis for medical purposes only, with the most common targeted conditions/symptoms being pain/arthritis (73%), sleep disturbance (29%), anxiety (24%), and depression (17%). Just over three‐quarters reported cannabis “somewhat” or “extremely” helpful in managing one of these conditions, with few adverse effects. Just over half obtained cannabis via a dispensary, and lotions (35%), tinctures (35%), and smoking (30%) were the most common administration forms. Most indicated family members (94%) knew about their cannabis use, about half reported their friends knew, and 41% reported their healthcare provider knowing. Sixty‐one percent used cannabis for the first time as older adults (aged ≥61 years), and these users overall engaged in less risky use patterns (e.g., more likely to use for medical purposes, less likely to consume via smoking).
Most older adults in the sample initiated cannabis use after the age of 60 years and used it primarily for medical purposes to treat pain, sleep disturbance, anxiety, and/or depression. Cannabis use by older adults is likely to increase due to medical need, favorable legalization, and attitudes.
Sept 2020: Medical cannabis and cognitive performance in middle to old adults treated for chronic pain
First published: 22 September 2020 https://doi.org/10.1111/dar.13171
Sharon R. Sznitman PhD, Senior Lecturer, Simon Vulfsons MD, Director, David Meiri PhD, Lecturer, Galit Weinstein PhD, Senior Lecturer.
Introduction and Aims
Cannabis exposure is becoming more common in older age but little is known about how it is associated with brain health in this population. This study assesses the relationship between long‐term medical cannabis (MC) use and cognitive function in a sample of middle‐aged and old chronic pain patients.
Design and Methods
A cross‐sectional study was conducted among chronic pain patients aged 50+ years who had MC licenses (n = 63) and a comparison group who did not have MC licenses (n = 62). CogState computerised brief battery was used to assess cognitive performance of psychomotor reaction, attention, working memory and new learning. Regression models and Bayesian t‐tests examined differences in cognitive performance in the two groups. Furthermore, the associations between MC use patterns (dosage, cannabinoid concentrations, length and frequency of use and hours since last use) with cognition were assessed among MC licensed patients.
Mean age was 63 ± 6 and 60 ± 5 years in the non‐exposed and MC patients, respectively. Groups did not significantly differ in terms of cognitive performance measures. Furthermore, none of the MC use patterns were associated with cognitive performance.
Discussion and Conclusions
These results suggest that use of whole plant MC does not have a widespread impact on cognition in older chronic pain patients. Considering the increasing use of MC in older populations, this study could be a first step towards a better risk–benefit assessment of MC treatment in this population. Future studies are urgently needed to further clarify the implications of late‐life cannabis use for brain health.
Objectives: In Canada, cannabis prohibition ended in October 2018. Older adults are the fastest growing group of cannabis users and are out-pacing other groups as new users. Clinical evidence indicates that cannabis may be helpful for select medicinal purposes in this population. Yet there is limited research about older adults experiences of starting to use cannabis in later life. The purpose of this study was to begin to address this gap.
Methods: This study employed qualitative description. A convenience sample of Canadian community-dwelling older adults who were new users of cannabis were recruited. Data were collected using semi-structured interviews. Data analysis was inductive and thematic.
Results: Twelve older adults between the ages of 71 and 85 participated. All of the participants used cannabis for medicinal reasons, however, only one had a prescription. The main reasons for using were: pain management, alternative to prescription or over-the-counter medication, and sleep aide. Most participants obtained cannabis from non-licensed stores. Eleven discussed cannabis use with their family physicians, however, none received prescriptions from them. The main sources of information were friends, cannabis store staff, and the media.
Conclusions: Older adults who begin using cannabis are likely using for what they perceive to be medicinal purposes for a range of issues. However, they receive minimal guidance from their family physicians and instead obtain information from non-clinician sources.
Clinical implications: Cannabis screening should be included in geriatric assessments and medicine reconciliation. Continuing education for clinicians needs to address knowledge gaps about cannabis use among older adults.
The Health Effects of Cannabis and Cannabinoids: The Current State of Evidence and Recommendations for Research.National Academies of Sciences, Engineering, and Medicine; Health and Medicine Division; Board on Population Health and Public Health Practice; Committee on the Health Effects of Marijuana: An Evidence Review and Research Agenda.Washington (DC): National Academies Press (US); 2017 Jan 12.
Chapter 4 Therapeutic Effects of Cannabis and Cannabinoids