Medical Cannabis Research

Medical Cannabis Research

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Destabilization of the Alzheimer’s amyloid-β protofibrils by THC: A molecular dynamics simulation study

Highlights

The destabilization of Aβ17-42 by THC was studied by MD simulations.
Hydrophobic interactions were the driving force for binding.
Native interactions in the hydrophobic core of Aβ17-42 were disrupted.
Disruption of important hydrogen bonds and salt bridges was observed.
Reduction in overall β-sheet content of the fibrils was observed.

Abstract

Alzheimer’s disease is a leading cause of dementia in the elderly population for which there is no cure at present. Deposits of neurotoxic plaques are found in the brains of patients which are composed of fibrils of the amyloid-β peptide. Molecules which can disrupt these fibrils have gained attention as potential therapeutic agents. Δ-tetrahydrocannabidiol (THC) is a cannabinoid, which can bind to the receptors in the brain, and has shown promise in reducing the fibril content in many experimental studies. In our present study, by employing all atom molecular dynamics simulations, we have investigated the mechanism of the interaction of the THC molecules with the amyloid-β protofibrils. Our results show that the THC molecules disrupt the protofibril structure by binding strongly to them. The driving force for the binding was the hydrophobic interactions with the hydrophobic residues in the fibrils. As a result of these interactions, the tight packing of the hydrophobic core of the protofibrils was made loose, and salt bridges, which were important for stability were disrupted. Hydrogen bonds between the chains of the protofibrils which are important for stability were disrupted, as a result of which the β-sheet content was reduced. The destabilization of the protofibrils by the THC molecules leads to the conclusion that THC molecules may be considered for the therapy in treating Alzheimer’s disease


CBD reduces plaque, improves cognition in model of familial Alzheimer’s

Date: March 9, 2021
Source: Medical College of Georgia at Augusta University
Summary:
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.


Abstract

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

Abstract

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.


“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.”

Latest Resources

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.”

Evidence Challenges

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

Clinical InvestigationFirst published: 07 October 2020

“Cannabis: An Emerging Treatment for Common Symptoms in Older Adults”

Abstract

BACKGROUND/OBJECTIVES

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.

DESIGN

Anonymous survey.

SETTING

Geriatrics clinic.

PARTICIPANTS

A total of 568 adults 65 years and older.

INTERVENTION

Not applicable.

MEASUREMENTS

Survey assessing characteristics of cannabis use.

RESULTS

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).

CONCLUSION

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.


Original Paper

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.

Abstract

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.

Results

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.


Abstract

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.

 

FTA:

Chapter 4 Therapeutic Effects of Cannabis and Cannabinoids

Chapter Highlights

    • In adults with chemotherapy-induced nausea and vomiting, oral cannabinoids are effective antiemetics.
    • In adults with chronic pain, patients who were treated with cannabis or cannabinoids are more likely to experience a clinically significant reduction in pain symptoms.
    • In adults with multiple sclerosis (MS)-related spasticity, short-term use of oral cannabinoids improves patient-reported spasticity symptoms.
    • For these conditions the effects of cannabinoids are modest; for all other conditions evaluated there is inadequate information to assess their effects.

CHRONIC PAIN

Relief from chronic pain is by far the most common condition cited by patients for the medical use of cannabis. For example,  reported that 94 percent of Colorado medical marijuana ID cardholders indicated “severe pain” as a medical condition. Likewise,  reported that 87 percent of participants in their study were seeking medical marijuana for pain relief. In addition, there is evidence that some individuals are replacing the use of conventional pain medications (e.g., opiates) with cannabis. For example, one recent study reported survey data from patrons of a Michigan medical marijuana dispensary suggesting that medical cannabis use in pain patients was associated with a 64 percent reduction in opioid use (). Similarly, recent analyses of prescription data from Medicare Part D enrollees in states with medical access to cannabis suggest a significant reduction in the prescription of conventional pain medications (). Combined with the survey data suggesting that pain is one of the primary reasons for the use of medical cannabis, these recent reports suggest that a number of pain patients are replacing the use of opioids with cannabis, despite the fact that cannabis has not been approved by the U.S. Food and Drug Administration (FDA) for chronic pain.


The Endocannabinoid System – An Overview

October 1, 2019 By: Jeffrey Stamberger, MEDICAL MARIJUANA, INC.

Have you ever wondered how cannabinoids interact with your body? The answer is through the endocannabinoid system and natural cannabinoid receptors in the human body. Keep reading for more about the role of the endocannabinoid system.

The endocannabinoid system (EC system) is responsible for regulating balance in our body’s communication between cells, appetite and metabolism, memory, and more. In spite of the balancing role the EC system takes on, until the recent endocannabinoid system discovery, it remained an unknown part of the human body’s functions.

Named for the plant that inspired its discovery, the endocannabinoid system is a key to promoting overall health and equilibrium, but its role in regulating the body is only just becoming understood.

It is through the endocannabinoid system that the naturally occurring cannabinoids interact with our bodies and trigger their beneficial effects. With the potential to greatly affect the way our bodies work, a healthy endocannabinoid system is essential and it’s key that we recognize how to maintain it.

The History of the Endocannabinoid System

Across cultures and building through the 19th century, extractions of the cannabis plant were widely used for a number of natural purposes. However, following practical prohibition of the cannabis plant in 1937 by the U.S. government for fear of abuse of its psychoactive properties, the study of cannabis was eliminated, stalling the progress of our understanding of the endocannabinoid system and its role in the body. For nearly 50 years, marijuana was labeled as illicit in the minds of Americans, which directly affected our relationship with hemp as well.

Scientists were able to define endocannabinoids in the early 1990’s when Lisa Matsuda announced that her team at the National Institute of Mental Health had first identified a THC sensitive receptor in the brains of lab rats.

The path to the discovery of the endocannabinoid system and cannabinoid receptors in the human body, however, started more than a century earlier.

In 1895, researchers T. Barlow Wood, W.T. Newton Spivey, and Thomas Hill Easterfield became the first to isolate and identify a cannabis-derived cannabinoid, cannabinol (CBN) (Wood, Spivey & Easterfield, 1896).

Over the next 70 years, researchers identified more cannabinoids, including R. Adams and others who identified and isolated CBD in 1940, and in 1964, Ralph Mechoulam and colleagues isolated and identified tetrahydrocannabinol (THC) (Pertwee, 2006) (Gaoni & Mechoulam, 1964).

Following those monumental breakthroughs, researchers spent decades exploring those cannabinoids and their properties.

Before Matsuda’s discovery of the cannabinoid receptor in the animal’s brain, it was often speculated that cannabinoids produced their balancing effects via nonspecific interactions.

It was in the early and mid-1990s when Mechoulam and colleagues officially discovered the endocannabinoid system. It happened after he and his team were able to locate and identify two of the body’s naturally produced major endocannabinoids: anandamide and 2-arachidonoylglycerol, or 2-AG (Mechoulam & Hanus, 2000).

Since then, scientists have labored to learn as much as they can about the endocannabinoid system, our naturally occurring cannabinoids, and the ways cannabis alters this balance, publishing over 20,000 scientific studies referencing cannabinoids in just the last two decades.

What Is the Endocannabinoid System?

The endocannabinoid system is made up of several integrated mechanisms:

      • Enzymes responsible for creating and destroying cannabinoids
      • Receptor sites on cells to receive cannabinoids
      • Endocannabinoids themselves (cannabinoid like compounds that are naturally produced by the human body)

These mechanisms are predominantly responsible for communication within the body to best regulate various biological responses to keep the body in homeostasis.

One of the prime questions raised in these early studies was whether or not the body produces its own natural equivalents to the previously discovered compounds called phytocannabinoids, like THC and CBD, found in the cannabis plant (Mandal, 2014). The answer turned out to be “yes” – in the form of the endocannabinoids anandamide and 2-AG, which are the two prominent analogs to THC and CBD, (Pacher et al, 2006). With the understanding that the cannabinoid system allows humans to create our own cannabinoids, the door to deconstructing the purpose of the endocannabinoid system was opened.

Endocannabinoids As a Response

Endocannabinoids are created in response to needs within the larger physiological system and are largely understood to be used for the body’s regulatory functions. Acting backwards on presynaptic cells, they control the volume at which communicating signals are sent. It is in this way that endocannabinoids affect duration and intensity of the wide range of physiological processes under their control.

How Does the Endocannabinoid System Work?

Whenever there are deviations from homeostasis (balance) in the body’s functions, the endocannabinoid system is activated and begins to respond accordingly by synthesizing endocannabinoids, which act as neurotransmitters.

When the body creates endocannabinoid neurotransmitters, they are picked up by specialized cannabinoid receptors, which sit on the surface of cells. These receptors are found in a wide range of physiological regions.

Like a key fits into a lock, endocannabinoids interact with these receptors and transmit information about changing conditions to kick-start a response, with the goal of helping the body achieve homeostasis, or equilibrium, within the body, despite outside influences (Alger, 2013).

The endocannabinoid system’s receptor sites include CB1 and CB2 receptor variants, which respond differently to various cannabinoids (Pacher et al, 2006). Some cells can even contain both types of receptors, each responsible for a different function.

where are cannabinoid receptors

There are two major endocannabinoids produced by the body – 2-arachidonoylglycerol (2-AG) and Anandamide (AEA).

2-AG is considered a full agonist of both CB1 and CB2 receptors. This means that it binds with, and fits well inside, both receptors to activate them to stimulate a physiological response.

Anandamide is considered a partial agonist of both receptors, because, while it binds with and activates the receptors, it doesn’t fit as well inside them and subsequently doesn’t trigger such a powerful physiological response (Parcher, Batkai & Kunos, 2006).

Once the function that had deviated from homeostasis returns to equilibrium and the endocannabinoids are no longer needed, the third piece of the system – the metabolic enzymes – breaks down and degrades these endocannabinoids to shut off their signal.

Cannabis Endocannabinoid System - Agonist vs Antagonist

Fatty acid amide hydrolase (FAAH) degrades Anandamide, and monoacylglycerol lipase (MAGL) breaks down 2-AG. By eliminating the endocannabinoids, the endocannabinoid system “turns off” the molecular signals and ends whatever physiological activity it had stimulated.

How Do Cannabis Derived Cannabinoids Work with the Endocannabinoid System?

As scientists learn more about the endocannabinoid system, they also explore the potential role the cannabis derived cannabinoids like THC, cannabidiol (CBD), cannabinol (CBN), and more could play in supporting the system.

Science evidences a strong relationship between the endocannabinoid system and CBD. Cannabinoids, like those found in CBD isolates and CBD oils, mimic the behavior of endocannabinoids and interact with the cannabinoid receptors to augment the endocannabinoid system. As the cannabinoids interact with the cannabinoid receptors, they stimulate various physiological responses.

THC, the well recognized psychoactive compound found in marijuana, activates receptors to elicit a chemical response. It is considered an agonist of both CB1 and CB2 receptors because it directly binds to the receptors and activates them. THC tends to favor CB1 receptors because it fits very well inside them and therefore is able to stimulate a strong physiological reaction.

When THC reacts with CB1 receptors, this is what causes the well known “high” feeling from marijuana. THC also directly activates CB2 receptors, but is considered a partial agonist and therefore doesn’t elicit such a strong physiological response.

CBD causes chemical changes by blocking receptors. It tends to have low affinity for both CB1 and CB2 receptors, and instead acts as an indirect antagonist of agonists. This means that CBD sits imperfectly inside the receptors, not activating them but preventing other chemical messengers like THC from binding to them (Pacher, Batkai & Kunos, 2006).

Cannabis and the Human CB Receptors

As we continue to learn more about the endocannabinoid system, we will also learn about the potential for the scope of active compounds from cannabis (like THC, CBD, and CBN).

Should I Add Cannabinoids to My Body?

One theory about the endocannabinoid system is the proposed endocannabinoid deficiency syndrome, or CECD, which speculates that, for some people, the body does not generate enough endocannabinoids due to under stimulation of the system (Smith and Wagner, 2014). This concept, originally proposed by researcher E.B. Russo in 2004, further speculates that the endocannabinoid system deficiency could negatively affect your quality of life.

Phytocannabinoids, like the THC from cannabis or the concentrated CBD in hemp, obviously affect the endocannabinoid system. However, it has also been shown that non-intoxicating phytocannabinoids from other plants, and even other compounds like terpenes and flavonoids, are picked up by receptors in our endocannabinoid systems (Gertsch et al, 2010).

Because small doses of phytocannabinoids can encourage the body to create more naturally occurring endocannabinoids and their receptors, it may be possible to bolster the sensitivity of our native systems with regular cannabinoid servings (Pacher et al, 2006).

Overall, significant research must still be done to better understand the impact of the endocannabinoid system on our overall health and how supporting our natural endocannabinoid production with plant based cannabinoids may play a significant therapeutic role in our health. However, extensive early studies show great potential for using this vital system to the benefit of patient health.

To learn more about how individual cannabinoids can be used to promote overall well-being, read our informational articles on CBDTHCCBN, and CBC.

References:

Alger, B. E. (2013). Getting High on the Endocannabinoid System. Cerebrum: The Dana Forum on Brain Science2013, 14. Retrieved from https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3997295

Gaoni, Y., and Mechoulam, R. (1964). Isolation, Structure, and Partial Synthesis of an Active Constituent of Hashish. Journal of the American Chemical Society, 86(8), 1646-47. Retrieved from http://pubs.acs.org/doi/abs/10.1021/ja01062a046.

Gertsch, J., Pertwee, R. G., & Di Marzo, V. (2010). Phytocannabinoids beyond the Cannabis plant – do they exist? British Journal of Pharmacology160(3), 523–529. Retrieved from http://doi.org/10.1111/j.1476-5381.2010.00745.x

Kaur, R., Ambwani, S.R., Singh, S. (2016). Endocannabinoid system: A multi-facet therapeutic target. Current Clinical Pharmacology, 11(2), 110-7. Retrieved from http://www.eurekaselect.com/141330/article.

Kogan, N. M., & Mechoulam, R. (2007). Cannabinoids in health and disease. Dialogues in Clinical Neuroscience9(4), 413–430. Retrieved from https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3202504.

Lee, M. (2012). The Discovery of the endocannabinoid system. Retrieved from http://www.beyondthc.com/wp-content/uploads/2012/07/eCBSystemLee.pdf

Mandal, A. (2014, June 14). Phytocannabinoids. News Medical. Retrieved from http://www.news-medical.net/health/Phytocannabinoids.aspx.

Mechoulam, R., and Hanus, L (2000, November). A historical overview of chemical research on cannabinoids. Chemistry and Physics of Lipids, 108(1-2), 1-13. Retrieved from http://www.sciencedirect.com/science/article/pii/S0009308400001845.

National Cancer Institute. (2016). Cannabis and cannabinoids. Retrieved from http://www.cancer.gov/about-cancer/treatment/cam/hp/cannabis-pdq#section/_11

Pacher, P., Batkai, S., & Kunos, G. (2006). The Endocannabinoid System as an Emerging Target of Pharmacotherapy. Pharmacological Reviews58(3), 389–462. http://doi.org/10.1124/pr.58.3.2. Retrieved from https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2241751.

Pacher, P., & Kunos, G. (2013). Modulating the endocannabinoid system in human health and disease: successes and failures. The FEBS Journal280(9), 1918–1943. Retrieved from http://doi.org/10.1111/febs.12260.

Pandey, R., Mousawy, K., Nagarkatti, M., & Nagarkatti, P. (2009). Endocannabinoids and immune regulation. Pharmacological Research : The  Official Journal of the Italian Pharmacological Society60(2), 85–92. Retrieved from http://doi.org/10.1016/j.phrs.2009.03.019.

Pertwee, R.G. (2006). Cannabinoid pharmacology: the first 66 years. British Journal of Pharmacology, 147(Suppl 1), S163-S171. Retrieved from https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1760722.

Smith, S. & Wagner, M. (2014) Clinical endocannabinoid deficiency (CECD) revisited: can this concept explain the therapeutic benefits of cannabis in migraine, fibromyalgia, irritable bowel syndrome and other treatment-resistant conditions. Neuro Endocrinol Letters. 35(3):198-201. Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/24977967.

Wood, T.B., Spivey, W.T.N., and Easterfield, T.H. (1896). XL. – Charas. The resin of Indian hemp. Journal of the Chemical Society, Transactions, 69, 539-546. Retrieved from http://pubs.rsc.org/en/content/articlelanding/1896/ct/ct8966900539#!divAbstract.


Studies: How Cannabis Helps Dementia

Links to studies using cannabis for dementia

Cannabis Therapeutics and the Future of Neurology 

10/2018 [FTA] “…No current pharmacotherapy is approved for agitation in AD. Commonly used anti-psychotics, antidepressants, anxiolytics and hypnotics are often associated with increased mortality in demented patients (Kales et al., 2007), with an FDA “Black Box Warning.” Four acetylcholinesterase inhibitors are approved in the USA to improve memory: galantamine, donepezil, tacrine and rivastigmine. None show strong evidence of efficacy and are of limited benefit on a temporary basis. Various NMDA receptor antagonists in development have proven largely ineffective on disease progression or have proven toxic. In contrast, treatment with cannabinoids appears both more promising and benign. As demonstrated in 1998 (Hampson et al., 1998), and the subject of USA patent US09674028, CBD is a neuroprotective antioxidant, more potent than ascorbate or tocopherol, that works on the same NMDA target without attendant toxicity…

…In addition to its neuroprotective antioxidant effects (Iuvone et al., 2004), THC competitively inhibited acetylcholinesterase, increasing levels, and prevented Aβ aggregation via binding to the enzyme in a critical region affecting amyloid production (Eubanks et al., 2006)…

…Initial trials of herbal cannabis for AD have begun sporadically, with a more focused effort in a California nursing home [assisted living] (Hergenrather, 2017). Patients were treated with a variety of preparations: THC-predominant (2.5–30 mg/dose), CBD predominant, and THCA, mainly in tinctures and confections. Marked benefit was reported on neuroleptic drug sparing, decreased agitation, increased appetite, aggression, sleep quality, objective mood, nursing care demands, self-mutilation and pain control.

… Based on its pharmacology (Russo and Marcu, 2017), cannabis components may provide myriad benefits on target symptoms in this complex disorder:

    • Agitation: THC, CBD, linalool
    • Anxiety: CBD, THC (low dose), linalool
    • Psychosis: CBD
    • Insomnia/Restlessness: THC, linalool
    • Anorexia: THC
    • Aggression: THC, CBD, linalool
    • Depression: THC, limonene, CBD
    • Pain: THC, CBD
    • Memory: alpha-pinene (Russo, 2011; Russo and Marcu, 2017) + THC
    • Neuroprotection: CBD, THC
    • Reduced Aβ plaque formation: THC, CBD, THCA

Thus, an extract of a Type II chemovar of cannabis (THC/CBD) with a sufficient pinene fraction would seem to be an excellent candidate for clinical trials (Lewis et al., 2018). ” 

Cannabinoids in late-onset Alzheimer’s disease

06/2015 [FTA] “…Several in vitro and in vivo studies have demonstrated that cannabinoids can reduce oxidative stress, neuroinflammation, and the formation of amyloid plaques and neurofibrillary tangles, the key hallmarks of LOAD. In addition, in population-based studies, cannabinoids reduced dementia-related symptoms (e.g., behavioral disturbances)…”

Cannabinoids for treatment of Alzheimer’s disease: moving toward the clinic

03/2014 [FTA] “…Several findings indicate that the activation of both CB1 and CB2 receptors by natural or synthetic agonists, at non-psychoactive doses, have beneficial effects in Alzheimer experimental models by reducing the harmful β-amyloid peptide action and tau phosphorylation, as well as by promoting the brain’s intrinsic repair mechanisms. Moreover, endocannabinoid signaling has been demonstrated to modulate numerous concomitant pathological processes, including neuroinflammation, excitotoxicity, mitochondrial dysfunction, and oxidative stress…” 

Cannabis, Cannabinoids, and Sleep: a Review of the Literature

04/2017 [FTA] “…Preliminary research into cannabis and insomnia suggests that cannabidiol (CBD) may have therapeutic potential for the treatment of insomnia…”

Mortality risk in patients with dementia treated with antipsychotics versus other psychiatric medications

10/2007 [FTA] “…Antipsychotic medications taken by patients with dementia were associated with higher mortality rates than were most other medications used for neuropsychiatric symptoms…”

Cannabidiol and (-)Delta9-tetrahydrocannabinol are neuroprotective antioxidants 

07/1998 [FTA] “…Cannabidiol and THC also were shown to prevent hydroperoxide-induced oxidative damage as well as or better than other antioxidants in a chemical (Fenton reaction) system and neuronal cultures. Cannabidiol was more protective against glutamate neurotoxicity than either ascorbate or alpha-tocopherol, indicating it to be a potent antioxidant. These data also suggest that the naturally occurring, nonpsychotropic cannabinoid, cannabidiol, may be a potentially useful therapeutic agent for the treatment of oxidative neurological disorders such as cerebral ischemia…”

US Department of Health patent on Cannabinoids as Neuroprotectant 6630507B1

04/1998 [FTA] “…The cannabinoids are found to have particular application as neuroprotectants, for example in limiting neurological damage following ischemic insults, such as stroke and trauma, or in the treatment of neurodegenerative diseases, such as Alzheimer’s disease, Parkinson’s disease and HIV dementia…”

Neuroprotective effect of cannabidiol, a non-psychoactive component from Cannabis sativa, on beta-amyloid-induced toxicity in PC12 cells

04/2004 [FTA] “…Our results indicate that cannabidiol exerts a combination of neuroprotective, anti-oxidative and anti-apoptotic effects against beta-amyloid peptide toxicity…”

Cannabis Pharmacology: The Usual Suspects and a Few Promising Leads

06/2017 [FTA] Investigation reveals these aromatic compounds to contribute modulatory and therapeutic roles in the cannabis entourage far beyond expectations considering their modest concentrations in the plant. Synergistic relationships of the terpenoids to cannabinoids will be highlighted and include many complementary roles to boost therapeutic efficacy in treatment of pain, psychiatric disorders, cancer, and numerous other areas.

Taming THC: potential cannabis synergy and phytocannabinoid-terpenoid entourage effects

08/2011 [FTA] “…Terpenoids are quite potent, and affect animal and even human behaviour when inhaled from ambient air at serum levels in the single digits ng·mL(-1) . They display unique therapeutic effects that may contribute meaningfully to the entourage effects of cannabis-based medicinal extracts. Particular focus will be placed on phytocannabinoid-terpenoid interactions that could produce synergy with respect to treatment of pain, inflammation, depression, anxiety, addiction, epilepsy, cancer, fungal and bacterial infections (including methicillin-resistant Staphylococcus aureus). Scientific evidence is presented for non-cannabinoid plant components as putative antidotes to intoxicating effects of THC that could increase its therapeutic index. Methods for investigating entourage effects in future experiments will be proposed. Phytocannabinoid-terpenoid synergy, if proven, increases the likelihood that an extensive pipeline of new therapeutic products is possible from this venerable plant.”

Pharmacological Foundations of Cannabis Chemovars

03/2018 [FTA] “…Specific chemovars may produce enhanced analgesia, anti-inflammatory, anticonvulsant, antidepressant, and anti-anxiety effects, while simultaneously reducing sequelae of Δ9-tetrahydrocannabinol such as panic, toxic psychosis, and short-term memory impairment.”

Cannabinoids for the Treatment of Agitation and Aggression in Alzheimer’s Disease

08/2015 [FTA] “…The behavioural effects of ECS medications, as well as their ability to modulate neuroinflammation and oxidative stress, make targeting this system potentially relevant in AD. This article summarizes the literature to date supporting this rationale and evaluates clinical studies investigating cannabinoids for agitation and aggression in AD. Letters, case studies, and controlled trials from four electronic databases were included. While findings from six studies showed significant benefits from synthetic cannabinoids—dronabinol or nabilone—on agitation and aggression, definitive conclusions were limited by small sample sizes, short trial duration, and lack of placebo control in some of these studies. Given the relevance and findings to date, methodologically rigorous prospective clinical trials are recommended to determine the safety and efficacy of cannabinoids for the treatment of agitation and aggression in dementia and AD.”

The therapeutic potential of the endocannabinoid system for Alzheimer’s disease

04/2012 [FTA] “…Importantly, cannabinoids show anti-inflammatory, neuroprotective and antioxidant properties and have immunosuppressive effects. Thus, the cannabinoid system should be a prime target for AD therapy…”

Endocannabinoid signalling in Alzheimer’s disease

12/2013 [FTA] “…The ECs, OEA and PEA have multiple physiological roles including involvement in learning and memory, neuroinflammation, oxidative stress, neuroprotection and neurogenesis. They have also been implicated in the pathology of, or perhaps protective responses to, neurodegenerative diseases. This is particularly the case with Alzheimer’s disease, the most common age-related dementia associated with impairments in learning and memory accompanied by neuroinflammation, oxidative stress and neurodegeneration…”

A molecular link between the active component of marijuana and Alzheimer’s disease pathology

10/2008 [FTA] “…Compared to currently approved drugs prescribed for the treatment of Alzheimer’s disease, THC is a considerably superior inhibitor of Aβ aggregation, and this study provides a previously unrecognized molecular mechanism through which cannabinoid molecules may directly impact the progression of this debilitating disease…”

Neuroprotective effect of CBD… on beta-amyloid-induced toxicity in PC12 cells

04/2004 [FTA] “…Our results indicate that cannabidiol exerts a combination of neuroprotective, anti-oxidative and anti-apoptotic effects against beta-amyloid peptide toxicity, and that inhibition of caspase 3 appearance from its inactive precursor, pro-caspase 3, by cannabidiol is involved in the signalling pathway for this neuroprotection.”

The Potential Therapeutic Effects of THC on Alzheimer’s Disease

[FTA] “…From the results, we have discovered THC to be effective at lowering Aβ levels in N2a/AβPPswe cells at extremely low concentrations in a dose-dependent manner…We did discover that THC directly interacts with Aβ peptide, thereby inhibiting aggregation. Furthermore, THC was effective at lowering both total GSK-3β levels and phosphorylated GSK-3β in a dose-dependent manner at low concentrations. At the treatment concentrations, no toxicity was observed and the CB1 receptor was not significantly upregulated. Additionally, low doses of THC can enhance mitochondria function and does not inhibit melatonin’s enhancement of mitochondria function. These sets of data strongly suggest that THC could be a potential therapeutic treatment option for Alzheimer’s disease through multiple functions and pathways.”

The Role of Endocannabinoid Signaling in the Molecular Mechanisms of Neurodegeneration in Alzheimer’s Disease 

2015 [FTA] “…AD is multifaceted in nature and is linked to different multiple mechanisms in the brain…The ideal treatment for AD should be able to modulate the disease through multiple mechanisms rather than targeting a single dysregulated pathway…In this review, we recapitulate the role of endocannabinoid signaling in AD and the probable mechanisms through which modulators of the endocannabinoid system provide their effects, thus highlighting how this target might provide more advantages over other therapeutic targets.”

CBD in vivo blunts beta-amyloid induced neuroinflammation by suppressing IL-1beta and iNOS expression 

08/2007 [FTA] “…The results of the present study confirm in vivo anti-inflammatory actions of CBD, emphasizing the importance of this compound as a novel promising pharmacological tool capable of attenuating Abeta evoked neuroinflammatory responses.”

CBD: A promising drug for neurodegenerative disorders?

2009 [FTA] “…cannabidiol (CBD), which lacks any unwanted psychotropic effect, may represent a very promising agent with the highest prospect for therapeutic use.”

Cannabinoid receptor 1 deficiency in a mouse model of Alzheimer’s disease leads to enhanced cognitive 

11/2013 [FTA] “Alzheimer’s disease (AD) is characterized by amyloid-β deposition in amyloid plaques, neurofibrillary tangles, inflammation, neuronal loss, and cognitive deficits. Cannabinoids display neuromodulatory and neuroprotective effects and affect memory acquisition…the findings indicate that CB1 deficiency can worsen AD-related cognitive deficits and support a potential role of CB1 as a pharmacologic target.”

The role of the endocannabinoid system in Alzheimer’s disease 

2008 [FTA] “…There is evidence, from in vivo studies on beta-amyloid-induced neurotoxicity, also for a possible causative role of endocannabinoids in the impairment in memory retention, which is typical of AD. This might open the way to the use of cannabinoid receptorantagonists as therapeutic drugs for the treatment of cognitive deficits in the more advanced phases of this disorder. The scant, but nevertheless important literature on the regulation and role of the endocannabinoid system in AD, and on the potential treatment of this disorder with cannabinoids and endocannabinoid-based drugs, are discussed in this mini-review.”

The role of phytochemicals in the treatment and prevention of dementia 

06/2011 [FTA] “This review presents the potential and actual therapeutic strategies for dementia in relation to the known mechanisms of dementia pathology. Phytochemicals that have shown mechanistic effects relevant to the pathological targets in dementia are discussed, with an emphasis on those showing positive clinical trial evidence… phytochemicals discussed include cannabinoids (e.g. cannabidiol) from Cannabis sativa, which are emerging as potential therapeutic agents for BPSD, and resveratrol (occurs in various plants) and curcumin (from turmeric [Curcuma longa]), which have been investigated for their pharmacological activities relevant to dementia and their potential effects on delaying dementia progression….Other plants and their extracts that have produced promising clinical data in dementia patients, with respect to cognition, include saffron (Crocus sativus), ginseng (Panax species), sage (Salvia species) and lemon balm (Melissa officinalis), although more extensive and reliable clinical data are required…most studies focused on ChEIs, nicotine (from Nicotiana species), curcumin, wine polyphenols such as resveratrol and G. biloba…”

Cannabidiol Promotes Amyloid Precursor Protein Ubiquitination and Reduction of Beta Amyloid Expression 

in SHSY5YAPP+ Cells Through PPARγ Involvement

07/2014 [FTA] “…Results indicated the CBD capability to induce the ubiquitination of APP protein which led to a substantial decrease in APP full length protein levels in SHSY5Y(APP+) with the consequent decrease in Aβ production. Moreover, CBD promoted an increased survival of SHSY5Y(APP+) neurons, by reducing their long-term apoptotic rate…”

Cannabinoids for treatment of Alzheimer’s disease: moving toward the clinic  

03/2014 [FTA] “…Several findings indicate that the activation of both CB1 and CB2 receptors by natural or synthetic agonists, at non-psychoactive doses, have beneficial effects in Alzheimer experimental models by reducing the harmful β-amyloid peptide action and tau phosphorylation, as well as by promoting the brain’s intrinsic repair mechanisms. Moreover, endocannabinoid signaling has been demonstrated to modulate numerous concomitant pathological processes, including neuroinflammation, excitotoxicity, mitochondrial dysfunction, and oxidative stress…”

Can Marijuana Prevent Alzheimer’s?  

10/2012 [FTA] “Cognitive decline is the No. 1 fear among Americans older than 50, but while we know that exercise, proper diet and social and educational engagement can help maintain brain health, there is as yet no intervention that can fully prevent the onset of dementia or Alzheimer’s disease.If no such development occurs, the number of Americans with Alzheimer’s disease is expected to triple in the next 50 years…new treatments that can reproduce, through natural or synthetic means, some of the beneficial effects of cannabinoids could hold promise. In 2007, Ohio State University researchers published a paper stating that medications which can stimulate cannabinoid receptors in the brain “may provide clinical benefits in age-related diseases that are associated with brain inflammation, such as Alzheimer’s disease.” In 2009, Italian and Israeli researchers found that cannabidiol (CBD), marijuana’s primary non-psychoactive cannabinoid, may also block the formation of the plaques in the brain believed to bring on Alzheimer’s…

Safety and Efficacy of Medical Cannabis Oil for Behavioral and Psychological Symptoms of Dementia

2016 [FTA] “…NPI domains of significant decrease were: Delusions, agitation/aggression, irritability, apathy, sleep and caregiver distress…Adding MCO to AD patients’ pharmacotherapy is safe and a promising treatment option.”

Cannabinoids for the Treatment of Agitation and Aggression in Alzheimer’s Disease

08/2015 [FTA] “…Letters, case studies, and controlled trials from four electronic databases were included. While findings from six studies showed significant benefits from synthetic cannabinoids—dronabinol or nabilone—on agitation and aggression, definitive conclusions were limited by small sample sizes, short trial duration, and lack of placebo control in some of these studies. Given the relevance and findings to date, methodologically rigorous prospective clinical trials are recommended to determine the safety and efficacy of cannabinoids for the treatment of agitation and aggression in dementia and AD.”

Natural Phytochemicals in the Treatment and Prevention of Dementia: An Overview

04/2016 [FTA] “…In this review, we summarize the neuroprotective effects of the main phytochemicals belonging to the polyphenol, isothiocyanate, alkaloid and cannabinoid families in the prevention and treatment of the most common kinds of dementia. We believe that natural phytochemicals may represent a promising sources of alternative medicine, at least in association with therapies approved to date for dementia.”

Delineating the Efficacy of a Cannabis-Based Medicine at Advanced Stages of Dementia in a Murine Model

10/2016 [FTA] “Previous reports have demonstrated that the combination of Δ9-tetrahydrocannabinol (Δ9-THC) and cannabidiol (CBD) botanical extracts, which are the components of an already approved cannabis-based medicine, reduce the Alzheimer-like phenotype of AβPP/PS1 transgenic mice when chronically administered during the early symptomatic stage. Here, we provide evidence that such natural cannabinoids are still effective in reducing memory impairment in AβPP/PS1 mice at advanced stages of the disease but are not effective in modifying the Aβ processing or in reducing the glial reactivity associated with aberrant Aβ deposition as occurs when administered at early stages of the disease. The present study also demonstrates that natural cannabinoids do not affect cognitive impairment associated with healthy aging in wild-type mice. The positive effects induced by Δ9-THC and CBD in aged AβPP/PS1 mice are associated with reduced GluR2/3 and increased levels of GABA-A Rα1 in cannabinoid-treated animals when compared with animals treated with vehicle alone.”

CBD Modulates the Expression of Alzheimer’s Disease-Related Genes in Mesenchymal Stem Cells

12/2016 [FTA] “…we found that CBD led to the downregulation of genes linked to AD, including genes coding for the kinases responsible of tau phosphorylation and for the secretases involved in Aβ generation. In parallel, immunocytochemistry analysis has shown that CBD inhibited the expression of GSK3β, a central player in AD pathogenesis, by promoting PI3K/Akt signalling…In conclusion, we have found that pre-treatment with CBD prevented the expression of proteins potentially involved in tau phosphorylation and Aβ production in GMSCs. Therefore, we suggested that GMSCs preconditioned with CBD possess a molecular profile that might be more beneficial for the treatment of AD…”

In vivo Evidence for Therapeutic Properties of CBD for Alzheimer’s Disease

02/2017 [FTA] “… The studies demonstrate the ability of CBD to reduce reactive gliosis and the neuroinflammatory response as well as to promote neurogenesis. Importantly, CBD also reverses and prevents the development of cognitive deficits in AD rodent models. Interestingly, combination therapies of CBD and Δ9-tetrahydrocannabinol (THC), the main active ingredient of cannabis sativa, show that CBD can antagonize the psychoactive effects associated with THC and possibly mediate greater therapeutic benefits than either phytocannabinoid alone. The studies provide “proof of principle” that CBD and possibly CBD-THC combinations are valid candidates for novel AD therapies…”

Neurological aspects of medical use of CBD

2017 [FTA] “..Pre-clinical evidence largely shows that CBD can produce beneficial effects in AD, PD and MS patients, but its employment for these disorders needs further confirmation from well designed clinical studies. CBD pre-clinical demonstration of antiepileptic activity is supported by recent clinical studies in human epileptic subjects resistant to standard antiepileptic drugs showing its potential use in children and young adults affected by refractory epilepsy…”

The influence of cannabinoids on generic traits of neurodegeneration

[FTA] “…Neurodegenerative diseases are a heterogeneous group of age-related disorders. While AD, PD and HD have a variety of different genetic and environmental causes, the principal factor involved is the progressive and severe loss of neurons. It is widely accepted that neuroinflammation, excitotoxicity and oxidative stress are key mediators of neurodegeneration, and impaired neurogenesis as well as reduced trophic support leave neuronal systems unable to cope. The eCB system is emerging as a key regulator of many neuronal systems that are relevant to neurodegenerative disorders. Activation of CB1 receptors regulates many neuronal functions such as Ca2+ homeostasis and metabolic activity while the CB2 receptor is mainly involved in regulating the inflammatory response.

Here, we have put forward the mechanisms of neurodegeneration in the three most prevalent neurodegenerative disorders, AD, PD and HD, as well as showing the vulnerability of the brain as a result of age. We have summarized evidence of the beneficial role of modulating the cannabinoid system to reduce the burden of neurodegeneration. Pharmacological modulation of the eCB system ( Figure 3) has been shown to reduce chronic activation of the neuroinflammatory response, aid in Ca2+ homeostasis, reduce oxidative stress, mitochondrial dysfunction and the resulting proapoptotic cascade, while promoting neurotrophic support…”

Effects of Dronabinol on anorexia and disturbed behavior in patients with Alzheimer’s disease

[FTA] “…These results indicate that dronabinol is a promising novel therapeutic agent which may be useful not only for treatment of anorexia but also to improve disturbed behavior in patients with Alzheimer’s disease…”

https://www.ncbi.nlm.nih.gov/pubmed?Db=pubmed&Cmd=ShowDetailView&TermToSearch=9309469

These results indicate that dronabinol is a promising novel therapeutic agent which may be useful not only for treatment of anorexia but also to improve disturbed behavior in patients with Alzheimer’s disease.

Delta-9-tetrahydrocannabinol for nighttime agitation in severe dementia. 

2006 [FTA] “…The study suggests that dronabinol was able to reduce nocturnal motor activity and agitation in severely demented patients. Thus, it appears that dronabinol may be a safe new treatment option for behavioral and circadian disturbances in dementia…”

Cannabis and the Brain: Neuroprotection vs Toxicity Gregory Gerdeman, PhD – 6/2016

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