View source for Cannabinoids: CBD, CBN, THC. Also HEMP & Marijuana (Cannabis)

== Intro to cannabis and health benefits ==

Products from the cannabis plant offer many health benefits of interest to ApoE4 carriers and can enhance a program addressing lifestyle strategies.   Cannabis products come in many forms with numerous delivery methods: tablets/capsules, edibles, beverages, vaping oil, dermal lotions/patches, sublingual tinctures, suppositories, and more, no need to smoke a joint.  '''THC''' is a cannabinoid that is the psychoactive component of marijuana that produces a high.  '''CBD''', another cannabinoid, modulates several biological functions and, in the right percentages, can counteract the psychoactive effects of THC.  Cannabis products come in various ratios of CBD to THC to best target the effect a person is trying to obtain. Many products with THC produce a high, but some do not, especially those with a high CBD to low THC content. CBD products from hemp do not produce a high.

[[File:Cannabis is hemp & marijuana w cannabinoids 9x5.jpg|framed|right|Cannabis is both hemp and marijuana, each containing a number of cannabinoids]]

The cited medical benefits of cannabinoids are many but it should be noted that legal constraints and the lack of profit incentive for drug companies, have constrained medical studies. Of the studies that exist, many are indicative of medical benefit, but often conclude further study is needed.

Fully exploiting the medical benefits of cannabis products may be long in coming, if ever.  Pharmaceutical companies can’t patent a natural substance unless they turn it into a synthetic chemical first. Doctors in the United States can’t prescribe drugs that aren’t approved by the Food and Drug Administration (FDA) and doctors rarely recommend therapies that fall outside approved protocols and/or are unfamiliar with nontraditional therapies.  

Nevertheless, many studies are encouraging, and there are even more anecdotes citing benefits.  For many of us, there’s no time to wait for FDA approval, thus necessitating self-research for potential beneficial therapies. The deeper dive section below provides papers supporting the claims of some of the health benefits of cannabis products/cannabinoids.

There are no known studies that have singled out the ApoE allele to determine the effects of cannabinoids on the endocannabinoid system within ApoE4 carriers. However, cannabinoids have been cited to aid with numerous health issues for the general population, and these are the '''areas of greatest interest to ApoE4s''':  
* Alzheimer’s Disease
::* Decreases Amyloid-beta plaque
::* Offers neuroprotection and helps generate new neurons
* Inflammation 
* Insulin Resistance
* Stress
* Sleep
* Hormonal balance

There are other health conditions where cannabinoids can be beneficial, such as cancer, Post Traumatic Stress Disorder (PTSD), fibromyalgia, epilepsy, and more, '''<big>but this Wiki article does not attempt to be all encompassing with regard to cannabis, only as it applies to areas of interest to ApoE4 carriers</big>'''.

== A guide to associated terms ==
To better navigate this subject and to make the best decisions, it helps to understand these common terms.

=== Cannabis ===
The plant family that includes both marijuana and hemp.


=== Marijuana ===
A cannabis plant that possesses psychoactive qualities (produces a high).  Used recreationally for the high and for medicinal purposes.

Marijuana is illegal in all 50 states per federal law.  It is recognized as legal for medical purposes (medical marijuana card required) in over half the 50 states.  Marijuana is legal for recreational purposes in some states, per state law. 

Marijuana comes from two '''strains''':  indica and sativa.   Sativa strains produce more of a euphoric high, is a mood elevator, and therapeutically relieves stress. Indica strains relax muscles and work as general analgesics (pain relief), also helps with sleep.

Each state has its own unique list of conditions that qualify a person for a medical marijuana card, but the '''most common medical conditions''' are: 
::*Epilepsy and Seizure disorders -  cannabidiol (CBD) has been found to significantly reduce seizure frequency 
::*Cancer - a balance of THC and CBD helps with pain, nausea, and appetite loss 
::*Multiple Sclerosis – aids with pain, insomnia, inflammation, muscle spasms, abdominal discomfort, and depression,
::*Glaucoma
::*HIV/AIDS – for appetite loss, nausea, and fatigue 
::*Neurodegenerative Diseases (Lou Gehrig’s Disease (ALS), Alzheimer’s, Parkinson’s, and Huntington’s) – improves cognition and mobility, relieving spasticity and rigid muscles, and more
::*Pain - combining both THC and CBD tends to be most effective 
::*Nausea – THC helps, although too much worsens it 
::*Cachexia/Wasting Syndrome – especially for THC rich varieties
::*Post-Traumatic Stress Disorder – high CBD varieties can aid with anxiety and panic episodes 
For more in information, see [https://www.leafly.com/news/cannabis-101/most-common-qualifying-conditions-for-medical-cannabis Most Common Qualifying Conditions for Medical Cannabis]

However, research into marijuana for medical application is restricted.  The US Drug Enforcement Agency (DEA) considers marijuana a Schedule I drug, the same as heroin, LSD, and ecstasy, thus identifying it as likely to be abused and lacking in medical value. Because of that, researchers need a special license to study it.  The US Food and Drug Administration (FDA) has not approved marijuana for medical treatment purposes although it has approved drugs derived from the marijuana plant. '''Marinol''' and '''Casemet''' are man-made versions of THC used to treat nausea and lack of appetite.  '''Epidiolox''' is for treatment of seizures associated with two rare and severe forms of epilepsy.  A 4th drug, '''Sativex''', a cannabis extract containing THC and CBD in a 1-to-1 ratio, is in clinical trials in the U.S. for pain with breast cancer. Sativex is already approved in more than 20 countries to treat muscle spasms from Multiple Sclerosis (MS) and cancer pain.

Even in states where marijuana is legal for '''recreational purposes''', there are laws regarding age of consumption, where it can be consumed, restrictions on driving under the influence, and interstate transport.  Employers and landlords may additionally dictate consumption restrictions regardless of state law.  States that allow medical marijuana do tend to reciprocally respect medical marijuana cards from other states but transport through non-recognizing states or flying with marijuana is illegal. The U.S Transportation Security Administration (TSA) does not allow marijuana or products derived from marijuana on any flights. 

Although legal, '''quality''' can be a concern.  Especially when seeking assistance for medical conditions, it’s important to know that the product being consumed is free of harmful chemicals and toxins.  There are no federal regulatory protections. Marijuana is now being grown using many modern day farming methods which includes growing plants in soils devoid of nutrient content and adding chemicals for rapid growth, pest resistance, and ease of harvest. Marijuana cannot be labeled “organic” by the US Department of Agriculture because it is still illegal at the federal level. Testing regulations vary from state to state, see: [https://www.leafly.com/news/industry/leaflys-state-by-state-guide-to-cannabis-testing-regulations Leafly's state-by-state guide to cannabis testing regulations]

Third parties have taken on the organic certification role for marijuana. Additionally, independent laboratories can test for potency/homogeneity and cannabinoid analysis quantitation. They can also test for potentially harmful contaminants, such as Salmonella, E. coli, as well as total yeast and mold quantification.  There are poor quality products out there, so buyer beware, but a reputable cannabis company will be able to offer information regarding the content of their products.

=== Hemp ===
A variety of the cannabis sativa plant that is grown for various commercial and industrial uses. Although marijuana and industrial hemp are both members of the cannabis family and both contain tetrahydrocannabinol (THC), they are distinct strains. Hemp has a near negligible level of THC.  A person cannot get high from the THC content in hemp nor can drug testing detect THC from hemp products.  Hemp can be grown to make fabrics, construction materials, biofuels, plastic composites and more.  Hemp products for individual consumption include hemp protein powder, hemp seed oil, Hemp extract/CBD oil, hemp lotion, hemp hearts, even hemp beer.  All can be purchased legally, except for the beer if underage.  Just because a product comes from hemp doesn’t mean it has substantive cannabidiol (CBD) or other cannabinoid content.

=== Cannabinoids ===
Or more technically correct, phytocannabinoids are the active ingredients found in cannabis (phyto means from a plant).  The most prevalent and the most well-understood phytocannabinoids are THC and CBD, but there are over 100 other active cannabinoids in cannabis. 

[[File:Cannabinoid table.JPG|framed|right|Some cannabinoids and their benefits.  Source:  https://bengreenfieldfitness.com/article/supplements-articles/how-to-use-cbd-oil/]]

Cannabis is not the only plant to produce phytocannabinoids, an increasing number of plant-derived natural products are being discovered that bind to or interact with the cannabinoid receptors in the body.    For more info:  [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2931553/ Phytocannabinoids beyond the Cannabis plant – do they exist?] (Jürg Gertsch, et al 2010),  [https://herb.co/marijuana/news/non-marijuana-plants-contain-cannabinoids Check Out These Non-Marijuana Plants That Contain Cannabinoids] and [https://www.marijuana.com/news/2017/05/9-plants-that-contain-therapeutic-cannabinoids/ 9 Plants That Contain Therapeutic Cannabinoids]

Cannabinoids are also produced naturally in the body, see endocannabinoids below.  While the functions of these cannabinoids within the body are wide-ranging, it is believed that their primary function is to promote homeostasis (a relatively stable state of equilibrium).

=== THC ===
Delta-9-tetrahydrocannabinol, or Δ9-Tetrahydrocannabinol, or more simply and commonly, tetrahydrocannabinol. THC is a cannabinoid. THC is the principal psychoactive component of cannabis, it’s what produces the high.  Marijuana of the 1960s typically had a THC content of between 3% to 5%, today THC content has been cited to be as much as 35%.


=== CBD ===
Cannabidiol, a cannabinoid. CBD is non-psychoactive, it does not have the intoxicating effects of THC.  CBD can actually counteract the psychoactivity of THC and combat unpleasant effects of THC such as paranoia, anxiety, over-excitability, or memory-loss.  CBD acts on completely different receptors and enzymes than THC.  CBD is associated with a long list of health benefits and is considered the healing component of the cannabis plant. 
 
CBD is found in both marijuana and hemp, although percentages vary widely. 
 
Historically, marijuana was cultivated for THC content, but when CBD was found to have positive benefits, some marijuana strains started being cultivated for CBD content too.  Marijuana products are sold with various CBD to THC ratios but can only be sold in dispensaries in states where marijuana is legal for medical and/or recreational purposes.  However, these marijuana derived products can be freely and legally researched on the internet before entering a dispensary.

In the United States, '''CBD products from hemp''' proliferated after signing the Agricultural Act of 2014 which authorized growing industrial hemp, but the legalities were not crystal clear.  The 2018 Farm Bill eliminated a great deal of this legal confusion by removing hemp from the Controlled Substances Act (CSA).  Hemp is now officially an agricultural commodity, not a controlled substance.  Additionally, hemp was redefined in the bill to include extracts, cannabinoids and derivatives.  As long as the THC level is at or below 0.3% the Drug Enforcement Administration (DEA) can no longer interfere with interstate commerce of hemp products, CBD products derived from hemp can be freely purchased over the internet and consumed.

While hemp derived products such as CBD oil are legal, the FDA's stance remains that it cannot be marketed as a food or dietary supplement.  Businesses offering such products have learned to be very careful with how they label and describe their products on the internet.    However, thoughts at the FDA appear to be changing.  Shortly after the 2018 Farm Bill signing, a letter was released by FDA Commissioner Scott Gottlieb, which for the first time contained a clear new path toward FDA’s permanent and formal acceptance of hemp-derived CBD as a food additive or nutritional supplement. 

[[File:CBD oil vs Hemp oil updated 5x4.jpg|framed|right|Hemp Extract (CBD oil from hemp) is different than Hemp Oil.]]

CBD products typically come as pills/capsules, as oils with droppers for oral ingestion, sprays and tinctures for absorption in the mouth, and as vaping oil. CBD creams, gels, and lotions are also available for external application to address muscle and joint pain.  CBD is non-addictive and can’t be overdosed. It can be ingested safely, although at high doses it can cause gastrointestinal issues and affect certain medications.

When looking to buy CBD oil, pay attention to detail.  Just because something is made from hemp doesn’t mean it contains CBD.  If “CBD oil” is typed into an internet search box, many hemp oil products will show up. Since passage of the 2018 Farm Bill, most products sold as Hemp derived CBD oil are now marketed as '''Hemp Extract'''.  Hemp oil is typically made from hemp seeds, CBD oil from hemp is made from the flowers, leaves, and to a minor extent, the stalk.  Hemp seed oil contains minimally low CBD content.  Pay attention to CBD content per serving and the cost per dose as both can vary widely by product and brand. If the product only lists “cannabinoids” be cautious, the amount of CBD is unknown. 

Also be aware that in 2015 and 2016, the FDA issued warning letters because the products did not have the level of CBD as claimed.  [https://www.fda.gov/NewsEvents/PublicHealthFocus/ucm484109.htm Warning Letters and Test Results for Cannabidiol-Related Products]  Some were higher, but most were lower.  ConsumerLab.com, an independent laboratory which tests numerous products, also tested some of the more popular CBD products.  They also found differences between labels and actual CBD content.  They also tested for lead, cadmium, and arsenic contamination and analyzed for cost.  Some information is available at ConsumerLab.com, but there’s a fee to obtain the actual product test results.  
When researching products look for emphasis on quality control, farming practices, and third party testing for product homogeneity, cannabinoid quantitation, and screening for potential harmful contaminants.  

CBD oil products are sold with recommended dosages or servings, but experimentation is often best to determine the amount required for an individual’s desired effect.  Recommended product dosages are typically low.  The dosages in most clinical trials were high, 200 mg or more a day.  
 
Lastly, just because a product contains CBD doesn’t mean the body can use it.  See discussion on bioavailability below.

=== Endocannabinoids ===
The cannabinoids produced in the body (endo means internal, from within).  This occurs naturally in all mammals, without introduction of phtyocannabinoids from cannabis.  Phytocannabinoids are a similar in chemical structure to our own endocannabinoids.   


=== Endocannabinoid system (ECS) === 
A complex signaling network in the human body that uses cannabinoids to control various bodily processes by interacting with different receptors and regulatory enzymes.   Most of our knowledge of the ECS is fairly recent, starting in the 1980s.  The ECS has two receptors for cannabinoids:  CB1 receptors and CB2 receptors.  

[[File:Endocannabinoid system 6x3.jpg|framed|right|THC and CBD affect the endocannabinoid system in different ways]]

'''CB1 receptors''' are found all around the body in the nervous system and nerves, but '''mostly in the brain'''.  CB1 receptors in the brain deal with coordination and movement, pain, emotions and mood, thinking, appetite, and memories, among others. THC attaches mostly to CB1 receptors

'''CB2 receptors''' are mostly found in the '''immune system''', effecting inflammation and pain.  It used to be thought that CBD acts on these CB2 receptors, but it appears now that CBD does not act on either receptor directly. Instead, it seems to influence the body to use more of its own cannabinoids.  CBD actually has a very low affinity for both CB1 and CB2 receptors but acts as an indirect antagonist of their agonists.  If CBD did attach to CB1 and CB2 receptors it would have the same addictive potential of THC. But since its mechanism of action is not dependent on receptors associated with addiction, CBD is not addictive or habit-forming.

It is theorized that certain health conditions are the result of the body not producing enough endocannabinoids and/or that there are not enough receptors for the endocannabinoid system to function properly. A body that’s unbalanced like this results in functions that aren’t being regulated properly thus manifesting disease.  This is called '''Clinical Endocannabinoid Deficiency (CECD)'''.  CECD has been linked to migraines, fibromyalgia and irritable bowel syndrome.  See [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2931553/ Clinical endocannabinoid deficiency (CECD): can this concept explain therapeutic benefits of cannabis in migraine, fibromyalgia, irritable bowel syndrome and other treatment-resistant conditions?] (Russo EB, 2008)  

The '''endocannabinoid system is responsible for regulating the release of neurotransmitters''', so diseases that are attributed to their dysfunction, such as Alzheimer’s disease and Parkinson’s disease, may also be related to CECD.  According to this article, [https://www.sciencedaily.com/releases/2017/05/170508112400.htm Cannabis reverses aging processes in the brain, study suggests]  scientists discovered that the brain ages much faster when mice do not possess any functional CB1 receptors.  From the article,
::"With increasing age, the quantity of the cannabinoids naturally formed in the brain reduces," says Prof. Zimmer. "When the activity of the cannabinoid system declines, we find rapid ageing in the brain."

=== Bioavailability === 
Bioavailability is the proportion of a drug or substance that enters the circulation when introduced into the body and so it is able to have its intended effect.
CBD is not water soluble, but the body is over 60% water.  It's like trying to wash an oily pot with just water, the oil is hydrophobic, it doesn't want to mix with the water, it wants to repel it.  Getting any oil based substance to pass through a cell wall is challenging, requiring a higher dose for adequate absorption.  

Some products offer “'''liposomal delivery'''.”   According to [https://www.news-medical.net/life-sciences/What-is-a-Liposome.aspx What is a Liposome],  "A liposome is a tiny bubble (vesicle), made out of the same material as a cell membrane. Liposomes can be filled with drugs, and used to deliver drugs for cancer and other diseases." Lipsomes can be absorbed very quickly through a cell wall, so either in a topical or ingested format, they enhance the effects of CBD and other cannabinoids.

According to popular fitness expert and blogger Ben Greenfield in the article [https://bengreenfieldfitness.com/article/supplements-articles/how-to-use-cbd-oil/ Get all the Health Benefits of Smoking Weed without actually Smoking Weed] cannabinoids that are processed into '''nanoparticle size''' (1/100 the width of a human hair) are easier for your body to absorb and transport to where they are needed within your body.

In the same article, Ben Greenfield also cites that '''turmeric (curcumin)''' aids bioavailability, “…when the cannabinoids and terpenoids in CBD are mixed with the isolated curcuminoids of a high-curcumin containing turmeric plant, the bioavailability of the CBD absolutely explodes. This means that if you’ve used CBD oil before in the absence of a curcuminoid blend from turmeric, you probably only felt about 1/5 to 1/10 of the actual effects of the CBD, since CBD by itself is very poorly absorbed.”

Absorption also depends on the method of administration.
 
When consumed '''orally''', a cannabinoid has to be processed by the liver and other digestive organs first. Only a percentage passes through these organs and makes it into the bloodstream so it can be used by the endocannabinoid system.  If there is excess CBD, it is stored in fat cells and can remain there for days, released gradually for use by the endocannabinoid system. So, although oral consumption doesn’t provide the highest availability, if enough is consumed consistently, oral consumption is an effective way to treat certain conditions.

'''Oral mucosal''' administration offers a faster response as it bypasses the digestive system.  With this form, a mouth spray or tincture is held under the tongue for 30-60 seconds before swallowing.  

'''Vaping''' is vapor that is infused with a substance for the purpose of being inhaled to your lungs.  Vaporizing allows CBD to be absorbed by the lungs, into the blood, and across the blood-brain barrier. Compared to oral administration, vaping allows nearly three times as much CBD to enter blood circulation and is best for treating symptoms that need to be addressed quickly.  The effects of vaping wear off after 2-3 hours.


== Before Buying ==

=== Marijuana or products containing THC ===

First, '''know the law''' and any other restrictions (employer, landlord, motor vehicle operation, etc.)  regarding possession, consumption, and transport.  See http://norml.org/legal

'''Research''' before walking into a dispensary.  “Budtenders” are the salespeople who work at dispensaries.  As with any retail environment, these salespeople come with varying degrees of knowledge.  Prior research will make a dispensary visit more productive and it can be done legally over the internet.  There are numerous products out there and a dispensary can only represent so many of them, using the internet to identify promising products and the closest dispensary which sells that product will eliminate wasted time.  

This website https://weedmaps.com/ can help a person find products with reviews by brand, and dispensaries that carry that brand.  The website also provides information on cannabis savvy doctors if assistance is needed there.

Once a potential product has been identified, visit that brand’s website.  If the website doesn’t address certain concerns, such as quality control, there is typically a “contact us” link to ask the manufacturer directly.

Do look for '''quality''', it's important to know that the product being consumed is free of harmful chemicals and toxins. There are poor quality products out there, but a reputable cannabis company will be able to offer information regarding the production and content of their products.  Marijuana cannot be labeled "organic" by the US Department of Agriculture but third parties have taken on the organic certification role.   Testing regulations vary from state to state, see: [https://www.leafly.com/news/industry/leaflys-state-by-state-guide-to-cannabis-testing-regulations Leafly's state-by-state guide to cannabis testing regulations] 

Also recognize that edibles typically come in the form of chocolate, sweet drinks, gummies, and other sugar filled forms, it’s probably best to stay away from them.

'''How much to dose'''.   See [http://herb.co/2017/04/27/dose-medical-cannabis 5 Helpful Tips For Getting The Correct Dose Of Medical Cannabis] for information on medical dosing.

'''For more information'''  This wiki only touches on possible health benefits of marijuana for ApoE4s, many issues have not been addressed and there are many opinions as to efficacy, safety, long-term use consequences, whether or not marijuana is addictive, and on and on.  Additional research is recommended.  Some resources for more information on THC and CBD:

* [https://www.drugabuse.gov/publications/drugfacts/marijuana Drug Facts - Marijuana] -- From the National Institute on Drug Abuse, a federal scientific research institute under the National Institutes of Health, U.S. Department of Health and Human Services.  This write-up addresses short and long-term effects of marijuana on the brain, other health effects both physical and mental, as well as if one can overdose or become addicted. 

* https://www.theroc.us/ -- The Realm of Caring Foundation is dedicated to better treatments and applications for cannabinoid therapies while legitimizing the therapy. 

* https://www.leafly.com  -- Leafly identifies themselves as the World’s Cannabis Information Resource, the website is largely dedicated to making the process of finding the right strains and products easier.

* https://hightimes.com -- High Times says it is the definitive resource for all things cannabis:  from cultivation and legalization, to entertainment and culture.  Of note, they have a major section addressing health:  https://hightimes.com/health/ 

* https://norml.org/aboutmarijuana  -- NORML's mission is to move public opinion sufficiently to legalize the responsible use of marijuana by adults, and to serve as an advocate for consumers to assure they have access to high quality marijuana that is safe, convenient and affordable.

* https://www.marijuana.com/  -- Marijuana.com addresses the cannabis community through coverage of marijuana law + politics, science + medicine, consumer trends, culture and commentary.

=== Cannabidiol (CBD) from Hemp ===
'''Research.'''  The internet contains a wealth of information and is likely the best resource.  A good cannabis-savvy doctor should also know the differences between CBD and THC, when to use each and when to use both in combination.  The places that sell CBD products from hemp typically sell a variety of health related products and likely aren’t that conversant about CBD.  Also, don’t walk into a marijuana dispensary and expect to buy a CBD product from hemp.  

Here’s a list of '''brands that are known and sold over the internet''', there are probably others.  There are certainly many hemp oil products, but they may not contain CBD.  There are also other CBD oil brands that are only sold from certain retail outlets. This is strictly a list, no products are endorsed.

* [https://www.biocbdplus.com/ BioCBD+] 

* [https://bluebirdbotanicals.com/ Bluebird Botanicals]  

* [https://www.cwhemp.com/ CW (Charlotte's Web)] 

* [https://elixinol.com/ Elixinol]  

* [https://www.endoca.com/ Endoca] 

* [https://marysnutritionals.com/ Mary's Nutritionals] 

* [https://www.solcbd.com/ SOL CBD] 

Look for '''quality'''.  Pay attention to detail. Just because something is made from hemp doesn't mean it contains CBD. Look for CBD content per serving for the money and emphasis on quality control to assure consistency of dosing from batch to batch. Also look for  farming practices, third party testing, cannabinoid quantitation, and screening for potential harmful contaminants. If the product only lists "cannabinoids" the amount of CBD is unknown.

'''For more info.'''  Some resources for more information on THC and CBD:

* https://cbdoilreview.org/ -- CBD oil review independently vets CBD vendors to verify the safety and authenticity of their products. They provide ratings of products and after researching for a product that's right for you, you can also buy from this website.

* [https://bengreenfieldfitness.com/article/supplements-articles/how-to-use-cbd-oil/ Get All The Health Benefits Of Smoking Weed Without Actually Smoking Weed ] --  Written by popular fitness expert and health blogger, Ben Greenfield, this is a long and very informative tutorial on CBD.  He used to sell his own brand of CBD, he now endorses the BioCBD+ brand.

* https://www.consumerlab.com/ – ConsumerLab.com is a private lab that tests and post results on a number of health, wellness, and nutrition products.  They have tested some CBD products and have a very thorough write-up on CBD.  Some of their information is free, but there is a fee to obtain the test results.   

* https://www.projectcbd.org/ - Project CBD is a California-based nonprofit dedicated to promoting and publicizing research into the medical uses of cannabidiol (CBD) and other components of the cannabis plant.  They have a beginner's guide:  https://www.projectcbd.org/guidance/beginners-guide

* https://www.theroc.us/ -- The Realm of Caring Foundation is dedicated to better treatments and applications for cannabinoid therapies while legitimizing the therapy.  On their [https://www.theroc.us/quality-matters Quality Matters] they list products they feel can be trusted.

* https://www.leafly.com  -- Leafly identifies themselves as the World’s Cannabis Information Resource, the website is largely dedicated to making the process of finding the right strains and products easier.

* https://hightimes.com -- High Times says it is the definitive resource for all things cannabis: from cultivation and legalization, to entertainment and culture.  Of note, they have a major section addressing health:  https://hightimes.com/health/

* https://norml.org/aboutmarijuana  -- NORML's mission is to move public opinion sufficiently to legalize the responsible use of marijuana by adults, and to serve as an advocate for consumers to assure they have access to high quality marijuana that is safe, convenient and affordable.

* https://www.marijuana.com/  -- Marijuana.com addresses the cannabis community through coverage of marijuana law + politics, science + medicine, consumer trends, culture and commentary.

'''Dosage''' There are many factors involved:  metabolism, body weight, desired effects.  The best advice is to start low and go slow, a process called titrating.  Start with 5 to 10 mg, no more than 15 mg, daily at first.  Go up from there after the body gets accustomed to that dosage.  According to [http://bhangers.com/resources/science/bioavailability-cbd-varies/ Bioavailability of CBD: Comparing Methods of CBD Administration] “Many consumers experience a satisfactory effect by consuming a 15mg capsule twice per day (morning and night).”    Also recognize that most doses of CBD in clinical trials were fairly high, 200 mg or more a day.  Another source of information:  
[https://www.ncbi.nlm.nih.gov/pubmed/24281562 Cannabidiol in humans-the quest for therapeutic targets] (Zhornitsky S and Potvin S. 2012)

== A Deeper dive into areas of interest to ApoE4 carriers ==

=== Cannabinoids and Alzheimer’s Disease, Neuroprotection, Neurogenesis, and Amyloid-Beta clearance ===

Not an all inclusive list.

'''[https://www.neurologyadvisor.com/aaic-2018/alzheimer-disease-agitation-improved-with-cannabinoid/article/783236/ Cannabinoid Shows Promise for Reducing Agitation, Aggression in Alzheimer Disease]'''  Neurology Advisor, 2018
::"Nabilone, a synthetic cannabinoid, significantly improves agitation, cognition, neuropsychiatric symptoms, and nutrition in patients with moderate to severe Alzheimer disease, according to preliminary data presented at the 2018 Alzheimer's Association International Conference, July 22-26, 2018 in Chicago, Illinois"

'''[https://www.sciencedaily.com/releases/2017/05/170508112400.htm Cannabis reverses aging processes in the brain, study suggests ]''' (Science Daily, 2017) 

Israeli researchers reported that administration of THC in a low dose, such that there was no intoxicating effect, reversed age-related memory impairment in mice and may offer a potential treatment option in patients with dementia and other neurodegenerative illnesses. 

::“Memory performance decreases with increasing age. Cannabis can reverse these ageing processes in the brain. This was shown in mice by scientists at the University of Bonn with their colleagues at The Hebrew University of Jerusalem (Israel). Old animals were able to regress to the state of two-month-old mice with a prolonged low-dose treatment with a cannabis active ingredient. This opens up new options, for instance, when it comes to treating dementia.”

::“To discover precisely what effect the THC treatment has in old mice, the researchers examined the brain tissue and gene activity of the treated mice. The findings were surprising: the molecular signature no longer corresponded to that of old animals, but was instead very similar to that of young animals. The number of links between the nerve cells in the brain also increased again, which is an important prerequisite for learning ability. "It looked as though the THC treatment turned back the molecular clock," says Zimmer.”


'''[https://www.ncbi.nlm.nih.gov/pubmed/28217094 In vivo Evidence for Therapeutic Properties of Cannabidiol (CBD) for Alzheimer's Disease]''' (Watt G and Karl T, 2017)

::“Thus, it is investigated as a potential multifunctional treatment option for AD. Here, we summarize the current status quo of in vivo effects of CBD in established pharmacological and transgenic animal models for AD. 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.”


'''[https://www.ncbi.nlm.nih.gov/pubmed/28025562 Cannabidiol Modulates the Expression of Alzheimer's Disease-Related Genes in Mesenchymal Stem Cells. ]''' (Libro R, et al, 2016)

::“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 [gingiva]. Therefore, we suggested that GMSCs preconditioned with CBD possess a molecular profile that might be more beneficial for the treatment of AD.”


'''[https://www.ncbi.nlm.nih.gov/pubmed/27567873 Delineating the Efficacy of a Cannabis-Based Medicine at Advanced Stages of Dementia in a Murine Model]''' (Aso E, et al, 2016)

::“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.


'''[http://www.salk.edu/news-release/cannabinoids-remove-plaque-forming-alzheimers-proteins-from-brain-cells/ Cannabinoids Remove Plaque-Forming Alzheimer's Proteins from Brain Cells]''' (Salk News Release, 2016)
  
::“Although other studies have offered evidence that cannabinoids might be neuroprotective against the symptoms of Alzheimer’s, we believe our study is the first to demonstrate that cannabinoids affect both inflammation and amyloid beta accumulation in nerve cells,”

::“The researchers found that high levels of amyloid beta were associated with cellular inflammation and higher rates of neuron death. They demonstrated that exposing the cells to THC reduced amyloid beta protein levels and eliminated the inflammatory response from the nerve cells caused by the protein, thereby allowing the nerve cells to survive.”


'''[https://www.ncbi.nlm.nih.gov/pubmed/24288245 Cannabidiol promotes amyloid precursor protein ubiquitination and reduction of beta amyloid expression in SHSY5YAPP+ cells through PPARγ involvement ]''' (Scuderi C, et al, 2014)

::“Cannabidiol (CBD), a Cannabis derivative devoid of psychotropic effects, has attracted much attention because it may beneficially interfere with several Aβ-triggered neurodegenerative pathways, even though the mechanism responsible for such actions remains unknown…..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. Obtained results also showed that all, here observed, CBD effects were dependent on the selective activation of PPARγ.”


'''[https://www.ncbi.nlm.nih.gov/pubmed/24030360 Cannabinoid effects on β amyloid fibril and aggregate formation, neuronal and microglial-activated neurotoxicity in vitro]'''
(Janefjord E, et al. 2014)

::“These findings indicate a neuroprotective action of CB [cannabinoid] ligands via actions at microglial and neuronal cells.”


'''[https://content.iospress.com/articles/journal-of-alzheimers-disease/jad140093 The Potential Therapeutic Effects of THC on Alzheimer's Disease]''' (Cao, Chuanhai, et al, 2014)

::“These sets of data strongly suggest that THC could be a potential therapeutic treatment option for Alzheimer's disease through multiple functions and pathways.”

 
'''[https://www.ncbi.nlm.nih.gov/pubmed/22163051 Cannabidiol reduces Aβ-induced neuroinflammation and promotes hippocampal neurogenesis through PPARγ involvement ]'''  (Esposito G, et al. 2011)
::“Peroxisome proliferator-activated receptor-γ (PPARγ) has been reported to be involved in the etiology of pathological features of Alzheimer's disease (AD). Cannabidiol (CBD), a Cannabis derivative devoid of psychomimetic effects, has attracted much attention because of its promising neuroprotective properties in rat AD models, even though the mechanism responsible for such actions remains unknown. This study was aimed at exploring whether CBD effects could be subordinate to its activity at PPARγ, which has been recently indicated as its putative binding site. CBD actions on β-amyloid-induced neurotoxicity in rat AD models, either in presence or absence of PPAR antagonists were investigated. Results showed that the blockade of PPARγ was able to significantly blunt CBD effects on reactive gliosis and subsequently on neuronal damage. Moreover, due to its interaction at PPARγ, CBD was observed to stimulate hippocampal neurogenesis. All these findings report the inescapable role of this receptor in mediating CBD actions, here reported.”


'''[https://bpspubs.onlinelibrary.wiley.com/doi/full/10.1038/sj.bjp.0707446 Alzheimer's disease; taking the edge off with cannabinoids? ]''' (V A Campbell and A Gowran, 2009)

Investigators at Ireland's Trinity College Institute of Neuroscience concluded:

::"Thus, cannabinoids offer a multi‐faceted approach for the treatment of Alzheimer's disease by providing neuroprotection and reducing neuroinflammation, whilst simultaneously supporting the brain's intrinsic repair mechanisms by augmenting neurotrophin expression and enhancing neurogenesis”


'''[https://www.ncbi.nlm.nih.gov/pubmed/18679164 Neuroprotective effects of the nonpsychoactive cannabinoid cannabidiol in hypoxic-ischemic newborn piglets. ]'''
(Alvarez FJ, et al, 2008)

Hypoxic-ischemic (HI) is the temporary occlusion of both carotid arteries plus hypoxia.

::“In conclusion, administration of CBD after HI reduced short-term brain damage and was associated with extracerebral benefits.”


'''[https://pubs.acs.org/doi/abs/10.1021/mp060066m A Molecular Link between the Active Component of Marijuana and Alzheimer's Disease Pathology ]''' (Lisa M. Eubanks, et al, 2006)

Investigators at The Scripps Research Institute in California reported that THC administration inhibits the enzyme responsible for the aggregation of amyloid plaque.
  
::“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.”


'''[http://stroke.ahajournals.org/content/36/5/1071.long Cannabidiol Prevents Cerebral Infarction Via a Serotonergic 5-Hydroxytryptamine1A Receptor–Dependent Mechanism]'''
(Kenichi Mishima et al, 2005)

::“These results suggest that cannabidiol may have, at least in part, a neuroprotective effect via the 5-HT1A receptor toward cerebral ischemia.”


'''[http://www.pnas.org/content/95/14/8268.full Cannabidiol and (−)Δ9-tetrahydrocannabinol are neuroprotective antioxidants]''' (A. J. Hampson, et al. 1998)

Glutamate is a neurotransmitter, however, under certain conditions, the concentration of glutamate can grow to levels that damage nerve cells and the brain.  This glutamate excitotoxicity is seen in neurodegenerative diseases, in patients with head injuries, and those who have had strokes.

::“This study reports that cannabidiol and other cannabinoids such as THC are potent antioxidants that protect neurons from glutamate-induced death without cannabinoid receptor activation.”

::“The neuroprotective actions of cannabidiol and other cannabinoids were examined in rat cortical neuron cultures exposed to toxic levels of the excitatory neurotransmitter glutamate. Glutamate toxicity was reduced by both cannabidiol, a nonpsychoactive constituent of marijuana, and the psychotropic cannabinoid (−)Δ9-tetrahydrocannabinol (THC).”

=== Cannabinoids and Inflammation ===

ApoE4 carriers are more predisposed to inflammation than non-carriers.  Dr Dale Bredesen, see [[Bredesen Protocol]] and [http://soler7.com/IFAQ/TheEndOfAlzheimers.html Summary of Dr Bredesen's book "The End of Alzheimer's"], has identified 3 separate types of Alzheimer’s Disease. Type 1 called “Inflammatory” is a common type in ApoE4 carriers.  Inflammation also promotes cardiovascular disease as well as many other ailments. It serves everyone well to keep inflammation low.

Cytokines are the signaling proteins synthesized and secreted by immune cells upon stimulation. They are the modulating factors that balance initiation and resolution of inflammation. One of the mechanisms of immune control by CBD during inflammation is stopping cytokine production by immune cells and lowering cytokine production by the T-helper cells Th1 and Th2. The inflammatory compound interleukin-6 (IL-6) can also be decreased in the presence of CBD.

Some studies: 

'''[https://www.ncbi.nlm.nih.gov/pubmed/21238581 Cannabidiol as an emergent therapeutic strategy for lessening the impact of inflammation on oxidative stress]''' (Booz GW, 2011)

::“Oxidative stress with reactive oxygen species generation is a key weapon in the arsenal of the immune system for fighting invading pathogens and initiating tissue repair. If excessive or unresolved, however, immune-related oxidative stress can initiate further increasing levels of oxidative stress that cause organ damage and dysfunction. Targeting oxidative stress in various diseases therapeutically has proven more problematic than first anticipated given the complexities and perversity of both the underlying disease and the immune response. However, growing evidence suggests that the endocannabinoid system, which includes the CB₁ and CB₂ G-protein-coupled receptors and their endogenous lipid ligands, may be an area that is ripe for therapeutic exploitation. In this context, the related nonpsychotropic cannabinoid cannabidiol, which may interact with the endocannabinoid system but has actions that are distinct, offers promise as a prototype for anti-inflammatory drug development. This review discusses recent studies suggesting that cannabidiol may have utility in treating a number of human diseases and disorders now known to involve activation of the immune system and associated oxidative stress, as a contributor to their etiology and progression. These include rheumatoid arthritis, types 1 and 2 diabetes, atherosclerosis, Alzheimer disease, hypertension, the metabolic syndrome, ischemia-reperfusion injury, depression, and neuropathic pain.”


'''[https://www.ncbi.nlm.nih.gov/pubmed/22163000 Cannabidiol reduces intestinal inflammation through the control of neuroimmune axis]''' (De Filippis D, et al, 2011)
 
::“Our results therefore indicate that CBD indeed unravels a new therapeutic strategy to treat inflammatory bowel diseases.”


'''[https://www.ncbi.nlm.nih.gov/pubmed/19199042 Cannabinoids, endocannabinoids, and related analogs in inflammation]''' (Burstein SH and Zurier RB, 2009)

::“This review covers reports published in the last 5 years on the anti-inflammatory activities of all classes of cannabinoids, including phytocannabinoids such as tetrahydrocannabinol and cannabidiol, synthetic analogs such as ajulemic acid and nabilone, the endogenous cannabinoids anandamide and related compounds, namely, the elmiric acids, and finally, noncannabinoid components of Cannabis that show anti-inflammatory action. It is intended to be an update on the topic of the involvement of cannabinoids in the process of inflammation.”

::“CONCLUSIONS  Possibly the very earliest literature reference on Cannabis describes its use as an anti-inflammatory agent. The Chinese emperor Shen-nung (ca. 2000 B.C.), in a work called Pen-ts’ao Ching, noted many of the effects of Cannabis in humans. Among other properties, it was claimed that cannabis “undoes rheumatism”, suggesting possible anti-inflammatory effects (122). The reports described in this review of the current literature provide support for the claims made by the ancient Chinese healers. These more recent publications include relief from chronic neuropathic pain, fibromyalgia, rheumatoid arthritis, and postoperative pain. In addition, a large body of preclinical data on all classes of cannabinoids, including the endogenous examples, point to a variety of therapeutic targets for cannabinoids and important roles for the endocannabinoids in the physiology of inflammation.”


'''[https://www.ncbi.nlm.nih.gov/pubmed/17384130 Cannabidiol attenuates high glucose-induced endothelial cell inflammatory response and barrier disruption]''' (Rajesh M, et al, 2007)
 
::“In this study we have investigated the effects of CBD on high glucose (HG)-induced, mitochondrial superoxide generation, NF-kappaB activation, nitrotyrosine formation, inducible nitric oxide synthase (iNOS) and adhesion molecules ICAM-1 and VCAM-1 expression, monocyte-endothelial adhesion, transendothelial migration of monocytes, and disruption of endothelial barrier function in human coronary artery endothelial cells (HCAECs). HG markedly increased mitochondrial superoxide generation (measured by flow cytometry using MitoSOX), NF-kappaB activation, nitrotyrosine formation, upregulation of iNOS and adhesion molecules ICAM-1 and VCAM-1, transendothelial migration of monocytes, and monocyte-endothelial adhesion in HCAECs. HG also decreased endothelial barrier function measured by increased permeability and diminished expression of vascular endothelial cadherin in HCAECs. Remarkably, all the above mentioned effects of HG were attenuated by CBD pretreatment. Since a disruption of the endothelial function and integrity by HG is a crucial early event underlying the development of various diabetic complications, our results suggest that CBD, which has recently been approved for the treatment of inflammation, pain, and spasticity associated with multiple sclerosis in humans, may have significant therapeutic benefits against diabetic complications and atherosclerosis.”


'''[https://link.springer.com/article/10.1007%2Fs00210-006-0033-x Cannabidiol is an allosteric modulator at mu- and delta-opioid receptors]''' (Markus Kathmann, et al, 2006)

An allosteric modulator is a substance which indirectly influences (modulates) the effects of a primary ligand (a molecule that binds to another, usually larger, molecule) that directly activates or deactivates the function of a target protein. As an allosteric modulator at mu- and delta-opioid receptors, CBD works to remove pain and reduce the effects of chronic inflammation.


=== Cannabinoids and Insulin Resistance ===

Insulin resistance has developed into a common condition largely as a result of recently introduced western dietary practices.  Diabetes, associated with insulin resistance, is on the rise, as is Alzheimer’s Disease, a health concern of ApoE4s.  Alzheimer’s has informally been referred to as Type 3 Diabetes and studies have shown that those with Alzheimer’s Disease have insulin resistance in the brain whether or not insulin resistance exists elsewhere in the body.  

[[File:Rate of diabetes.jpg|framed|right|From the Center for Disease Control (CDC), the prevalence of diagnosed diabetes increased from 0.93% in 1958 to 7.40% in 2015. In 2015, 23.4 million people had diagnosed diabetes, compared to only 1.6 million in 1958 Source: https://www.cdc.gov/diabetes/statistics/slides/long_term_trends.pdf The CDC has also reported a total of 93,541 Alzheimer’s deaths occurred in the United States in 2014 at an age-adjusted (to the 2000 standard population) rate of 25.4 deaths per 100,000 population, a 54.5% increase compared with the 1999 rate of 16.5 deaths per 100,000.  Source: https://www.cdc.gov/mmwr/volumes/66/wr/mm6620a1.htm?s_cid=mm6620a1_w ]]
A person can be insulin resistant without being Type 2 Diabetic, although by definition a person who is Type 2 Diabetic is insulin resistant.  Insulin resistance also exists in those who are prediabetic and those with Non-Alcoholic Fatty Liver Disease (NAFLD).  Insulin resistance is also correlated with cardiovascular disease, another ApoE4 health concern.  
Neurodegeneration researcher, Dr Dale Bredesen see [[Bredesen Protocol]] and [http://soler7.com/IFAQ/TheEndOfAlzheimers.html Summary of Dr Bredesen's book] in his book, '''''The End of Alzheimer’s''''' has identified a type of Alzheimer’s called “Type 1.5 Glyccotoxic” where he finds glucose levels chronically high and a high level of insulin resulting in insulin resistance.  [[Insulin Resistance]] is also associated with increased inflammation, which is also one of the types of Alzheimer’s, see above section on Cannabinoids and Inflammation.

It serves everyone well to keep chronic inflammation low, but especially ApoE4 carriers.  

So how can cannabis help?  As popular fitness expert and blogger Ben Greenfield in the article [https://bengreenfieldfitness.com/article/supplements-articles/how-to-use-cbd-oil/ Get all the Health Benefits of Smoking Weed without actually Smoking Weed] describes:
::“Your pancreas secretes the hormones glucagon and insulin to regulate blood sugar by signaling your liver to break down fat into sugar (glucagon) or to store sugar as fat (insulin). These hormones work as a pair to maintain homeostasis, and they stimulate the release of each other through a complex feedback mechanism. While THC primarily increases glucagon and blood sugar, CBD lowers insulin levels, and it is this CBD action that helps to explain why marijuana users tend to eat more calories but do not gain any extra weight, have less obesity and have lower rates of type II diabetes than non-users, and is also why some diabetics find that marijuana makes it easier to manage their blood sugar. …By lowering pancreatic insulin release, CBD may alleviate or prevent the progression of type II diabetes and blood sugar disorders.”

Some studies:

'''[http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0176416 Cannabis use is associated with reduced prevalence of non-alcoholic fatty liver disease: A cross-sectional study  ]''' (Adeyinka Charles Adejumo,2017)

Non-alcoholic fatty liver disease (NAFLD) occurs when a liver accumulates fat (not due to alcohol) which leads to abnormalities in liver function. In NAFLD the liver is insulin resistant, it is not regulated by insulin appropriately and this condition often precedes Type 2 Diabetes.  

::“'''Conclusions'''.  To the best of our knowledge, this is the first population-based cross-sectional study of hospitalized patients to explore the associations between CU [cannabis use] and NAFLD. Our analyses revealed a strong relationship between cannabis use and reduced prevalence of NAFLD in patients. Due to our inability to draw direct causation effects from our cross-sectional studies, we suggest prospective basic and human studies to decipher the mechanistic details of how the various active ingredients in cannabis modulate NAFLD development.”


'''[https://onlinelibrary.wiley.com/doi/abs/10.1002/oby.20973 Cannabis use in relation to obesity and insulin resistance in the Inuit population ]''' (Gerard Ngueta, et al, 2014)

In a cohort of 786 Inuit (Arctic aboriginal) adults ages 18 to 74, investigators from the Conference of Quebec University Health Centers reported that subjects who consumed cannabis in the past year were more likely to possess a lower body mass index (BMI), lower fasting insulin, and lower HOMA-IR (Homeostatic Model Assessment of Insulin Resistance) as compared to those who did not. 

::“'''Results'''. Cannabis use was highly prevalent in the study population (57.4%) and was statistically associated with lower body mass index (BMI) (P < 0.001), lower % fat mass (P < 0.001), lower fasting insulin (P = 0.04), and lower HOMA‐IR (P = 0.01), after adjusting for numerous confounding variables. Further adjustment for BMI rendered fasting insulin and HOMA‐IR differences statistically nonsignificant between past‐year cannabis users and nonusers. Mediation analysis showed that the effect of cannabis use on insulin resistance was indirect, through BMI. In multivariate analysis, past‐year cannabis use was associated with 0.56 lower likelihood of obesity (95% confidence interval 0.37‐0.84).”


'''[https://www.amjmed.com/article/S0002-9343%2813%2900200-3/abstract The Impact of Marijuana Use on Glucose, Insulin, and Insulin Resistance among US Adults ]''' (Elizabeth A. Penner, MD, MPH, et al, 2013) 

Researchers at Harvard Medical School and the Beth Israel Deaconess Medical Center in Boston assessed the relationship between marijuana use and fasting insulin, glucose, and insulin resistance in a sample of 4,657 male subjects. 

::“'''Conclusions'''. We found that marijuana use was associated with lower levels of fasting insulin and HOMA-IR [Homeostatic Model Assessment of Insulin Resistance], and smaller waist circumference.”

'''[http://bmjopen.bmj.com/content/2/1/e000494.full Decreased prevalence of diabetes in marijuana users: cross-sectional data from the National Health and Nutrition Examination Survey (NHANES) III ]''' (Tripathi B Rajavashist, et al, 2012)

::“'''Results'''. Marijuana users had a lower age-adjusted prevalence of DM [diabetes mellitus] compared to non-marijuana users (OR 0.42, 95% CI 0.33 to 0.55; p<0.0001). The prevalence of elevated C reactive protein (>0.5 mg/dl) was significantly higher (p<0.0001) among non-marijuana users (18.9%) than among past (12.7%) or current light (15.8%) or heavy (9.2%) users. In a robust multivariate model controlling for socio-demographic factors, laboratory values and comorbidity, the lower odds of DM among marijuana users was significant (adjusted OR 0.36, 95% CI 0.24 to 0.55; p<0.0001).

::'''Conclusions'''. Marijuana use was independently associated with a lower prevalence of DM. Further studies are needed to show a direct effect of marijuana on DM.”


'''[https://www.ncbi.nlm.nih.gov/pubmed/16698671 Cannabidiol lowers incidence of diabetes in non-obese diabetic mice]''' (Weiss L, et al, 2006)

::“Cannabidinoids are components of the Cannabis sativa (marijuana) plant that have been shown capable of suppressing inflammation and various aspects of cell-mediated immunity. Cannabidiol (CBD), a non-psychoactive cannabidinoid has been previously shown by us to suppress cell-mediated autoimmune joint destruction in an animal model of rheumatoid arthritis. We now report that CBD treatment significantly reduces the incidence of diabetes in NOD [Non-obese diabetic] mice from an incidence of 86% in non-treated control mice to an incidence of 30% in CBD-treated mice. CBD treatment also resulted in the significant reduction of plasma levels of the pro-inflammatory cytokines, IFN-gamma and TNF-alpha.”

=== Cannabinoids and Stress ===
Lifestyle strategies recommended to ApoE4s include:  diet, exercise, sleep and '''stress'''.  Stress releases hormones that are good when needed, say in a flight or fight situation, but when the body is constantly stressed, then negative health issues result.  Studies in humans have demonstrated that CBD dosage reduces anxiety. Reducing stress reduces cortisol and corticotropin-releasing factor (CRF) , and improves functioning of the HPA (hypothalamic-pituary-adrenal) axis. SEE [[Stress]] and under Bredesen Protocol [[Reduce stress]]

[[File:Effects of stress on the body 5x4.jpg|framed|right|Stress can effect the body in many ways]]

It important to point out that a THC-rich strain of marijuana will actually increase, not decrease, stress unless there is enough CBD present to balance out the stress-increasing effect of the THC. Combining CBD with THC takes the anxiety edge off THC. This is due to the action of CBD on 5HT1A and TRPV1 receptors, both of which are involved in mitigating the anxiolytic (anxiety reducing), panic and fear responses to stress.

anxiolytic = anxiety reducing

Some studies:

'''[https://www.ncbi.nlm.nih.gov/pubmed/24923339 Antidepressant-like and anxiolytic-like effects of cannabidiol: a chemical compound of Cannabis sativa]''' (de Mello Schier AR, et al, 2014)

::“Cannabidiol (CBD) is a constituent non-psychotomimetic [psychotomimetic = drugs that are capable of producing an effect on the mind similar to a psychotic state] of Cannabis sativa with great psychiatric potential, including uses as an antidepressant-like and anxiolytic-like compound. The aim of this study is to review studies of animal models using CBD as an anxiolytic-like [anxiety-reducing] and antidepressant-like compound. Studies involving animal models, performing a variety of experiments on the above-mentioned disorders, such as the forced swimming test (FST), elevated plus maze (EPM) and Vogel conflict test (VCT), suggest that CBD exhibited an anti-anxiety and antidepressant effects in animal models discussed.”


'''[https://www.ncbi.nlm.nih.gov/pubmed/22729452 Cannabidiol, a Cannabis sativa constituent, as an anxiolytic drug ]'''  (Schier AR, et al, 2012)

::'''RESULTS''': Studies using animal models of anxiety and involving healthy volunteers clearly suggest an anxiolytic-like [anxiety-reducing] effect of CBD. Moreover, CBD was shown to reduce anxiety in patients with social anxiety disorder.


'''[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2697769/ 5-HT1A receptors are involved in the cannabidiol-induced attenuation of behavioural and cardiovascular responses to acute restraint stress in rats ]''' (Leonardo BM Resstel, et al, 2009)

::"'''Conclusion and implications'''. The results suggest that CBD can attenuate acute autonomic responses to stress and its delayed emotional consequences by facilitating 5-HT1A receptor-mediated neurotransmission."


'''[https://www.ncbi.nlm.nih.gov/pubmed/14583744 Effects of cannabidiol (CBD) on regional cerebral blood flow]''' (Crippa JA, et al, 2004)
 
::"Animal and human studies have suggested that cannabidiol (CBD) may possess anxiolytic [anxiety-reducing] properties, but how these effects are mediated centrally is unknown. The aim of the present study was to investigate this using functional neuroimaging. Regional cerebral blood flow (rCBF) was measured at rest using (99m)Tc-ECD SPECT in 10 healthy male volunteers, randomly divided into two groups of five subjects. Each subject was studied on two occasions, 1 week apart. In the first session, subjects were given an oral dose of CBD (400 mg) or placebo, in a double-blind procedure. ... These results suggest that CBD has anxiolytic properties, and that these effects are mediated by an action on limbic and paralimbic brain areas.”


'''[https://www.ncbi.nlm.nih.gov/pubmed/8257923 Effect of cannabidiol on plasma prolactin, growth hormone and cortisol in human volunteers]''' (Zuardi AW, et al, 1993)

::“This decrease in cortisol levels was significantly attenuated after CBD (basal measurement = 10.5 +/- 4.9 micrograms/dl; 120 min after 300 mg CBD = 9.9 +/- 6.2 micrograms/dl; 120 min after 600 mg CBD = 11.6 +/- 11.6 micrograms/dl). CBD was also found to have a sedative effect as determined by the self-evaluation scales. The present results suggest that CBD interferes with cortisol secretion.”

=== Cannabinoids and Sleep ===
Getting a good night's rest is a critical to overall good health.  A good night’s sleep reduces inflammation and improves insulin sensitivity.  It protects your immune system, and restores the body. Sleep is particularly important for brain health. Good sleep helps remove amyloid beta (Aβ) and reduces oxidative stress.  See [[Sleep]] and under Bredesen Protocol [[Optimize sleep]]  

But studies show various results in addressing the use of cannabinoids for sleep. 

CBD can produce a relaxing calmness.  Combining small doses of CBD with common natural sleep-inducing compounds like melatonin, magnesium, or lemon balm, can produce an even more relaxed state. Larger doses of CBD without additional agents have been known to enhance sleep or combat insomnia.

However, some studies have demonstrated that CBD can be a “wake-inducing” agent, meaning it keeps you alert and awake, although one study indicated CBD promoted wakefulness when lights were on and sleep with the lights off thus assisting when dealing with excessive daytime sleepiness. 

THC can help but might have negative effects in the long run.  Of the two strains of marijuana that contain THC: indica and sativa, the indica strain produces a greater sedative effect because it contains higher levels of a terpene called “myrcene.” Myrcene influences the permeability of cell membranes, and helps THC cross the blood-brain barrier more easily. 


'''[https://www.ncbi.nlm.nih.gov/pubmed/28349316 Cannabis, Cannabinoids, and Sleep: a Review of the Literature]'''  (Babson KA, et al, 2017)

::“Preliminary research into cannabis and insomnia suggests that cannabidiol (CBD) may have therapeutic potential for the treatment of insomnia. Delta-9 tetrahydrocannabinol (THC) may decrease sleep latency [the length of time that it takes to accomplish the transition from full wakefulness to sleep] but could impair sleep quality long-term. Novel studies investigating cannabinoids and obstructive sleep apnea suggest that synthetic cannabinoids such as nabilone and dronabinol may have short-term benefit for sleep apnea due to their modulatory effects on serotonin-mediated apneas. CBD may hold promise for REM sleep behavior disorder and excessive daytime sleepiness, while nabilone may reduce nightmares associated with PTSD and may improve sleep among patients with chronic pain. Research on cannabis and sleep is in its infancy and has yielded mixed results. Additional controlled and longitudinal research is critical to advance our understanding of research and clinical implications”


'''[https://www.ncbi.nlm.nih.gov/pubmed/24520411 Endocannabinoid modulation of cortical up-states and NREM sleep]'''  (Pava MJ et al, 2014)

::“Overall, these findings demonstrate that the EC [Endocannabinoid] system actively regulates cortical up-states and important features of NREM [non rapid eye movement] sleep such as its duration and low frequency cortical oscillations.”


'''[https://www.ncbi.nlm.nih.gov/pubmed/23343597 Effects of acute systemic administration of cannabidiol on sleep-wake cycle in rats]''' (Chagas MH, et al, 2013)

::"'''CONCLUSION''': The systemic acute administration of CBD appears to increase total sleep time, in addition to increasing sleep latency [the length of time that it takes to accomplish the transition from full wakefulness to sleep] in the light period of the day of administration.


'''[https://www.ncbi.nlm.nih.gov/pubmed/16844117 Cannabidiol, a constituent of Cannabis sativa, modulates sleep in rats ]''' (Murillo-Rodríguez E, 2006)

The environment may also influence CBD’s effect on sleep. In this study CBD was administered to rats with the lights on and the lights off.  CBD promoted wakefulness when lights were on and sleep with the lights off. This study suggests CBD may be helpful to treat patients suffering from somnolence (excessive daytime sleepiness).

::“In conclusion, we found that CBD modulates waking via activation of neurons in the hypothalamus and DRD [dorsal raphe nucleus]. Both regions are apparently involved in the generation of alertness. Also, CBD increases DA [dopamine] levels as measured by microdialysis and HPLC [High performance liquid chromatography] procedures. Since CBD induces alertness, it might be of therapeutic value in sleep disorders such as excessive somnolence [excessive daytime sleepiness].”


'''[https://www.ncbi.nlm.nih.gov/pubmed/16521031?dopt=Abstract Delta-9-tetrahydrocannabinol for nighttime agitation in severe dementia ]''' (Walther S, et al, 2006)

Nighttime agitation occurs frequently in patients with dementia and presents a significant burden on caregivers. Clinical trials demonstrate that cannabinoid therapy can mitigate certain AD symptoms. For instance, investigators at Berlin Germany's Charite Universitatmedizin, Department of Psychiatry and Psychotherapy, reported that the daily administration of 2.5 mg of synthetic THC - Dronabinol (Marinol), over a two-week period reduced nocturnal motor activity and agitation in AD patients in an open-label pilot study.

::“'''CONCLUSIONS''': The study suggests that dronabinol [synthetic THC (Marinol)] 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.”


'''[https://www.ncbi.nlm.nih.gov/pubmed/15118485 Effect of Delta-9-tetrahydrocannabinol and cannabidiol on nocturnal sleep and early-morning behavior in young adults]''' (Nicholson AN, et al, 2004) 

::"Fifteen milligrams THC would appear to be sedative, while 15 mg CBD appears to have alerting properties as it increased awake activity during sleep and counteracted the residual sedative activity of 15 mg THC."


'''[https://www.ncbi.nlm.nih.gov/pubmed/7028792?dopt=Abstract Hypnotic and antiepileptic effects of cannabidiol]'''  (Carlini EA and Cunha JM, 1981)
::“Doses of 40, 80, and 160 mg cannabidiol were compared to placebo and 5 mg nitrazepam in 15 insomniac volunteers. Subjects receiving 160 mg cannabidiol reported having slept significantly more than those receiving placebo; the volunteers also reported significantly less dream recall; with the three doses of cannabidiol than with placebo.”

=== Cannabinoids and Hormonal Balance ===
It seems the main reason why we create endocannabinoids is to create balance in the body – homeostasis. If there’s a system that’s working too fast or too slowly, the cannabinoids work to slow down or speed up appropriately to bring the body into balance.  Granted, knowledge on this system is far from mature, according to [http://www.marijuanatimes.org/the-endocannabinoid-system-a-history-of-endocannabinoids-and-cannabis/ The Endocannabinoid System: A History of Endocannabinoids and Cannabis ]   the first cannabinoid receptor was found in 1988, the first endocannabinoid was discovered in 1992 and the second cannabinoid receptor was found in 1993.  So our knowledge is no doubt immature, but it does appear the ECS impacts the endocrine system, thus affecting a number of hormones.  See [[Hormone balance]] under Bredesen Protocol


'''[https://www.ncbi.nlm.nih.gov/pubmed/21824982 The role of the endocannabinoid system in the neuroendocrine regulation of energy balance]''' (Bermudez-Silva FJ, et al, 2012)

::"Here we critically discuss the role of the endocannabinoid signalling in brain structures, such as the hypothalamus and reward-related areas, and its interaction with neurotransmitter and neuropeptide systems involved in the regulation of food intake and body weight. The ECS has been found to interact with peripheral signals, like leptin, insulin, ghrelin and satiety hormones and the resulting effects on both central and peripheral mechanisms affecting energy balance and adiposity will be described. Furthermore, ECS dysregulation has been associated with the development of dyslipidemia, glucose intolerance and obesity; phenomena that are often accompanied by a plethora of neuroendocrine alterations which might play a causal role in determining ECS dysregulation. Despite the withdrawal of the first generation of cannabinoid type 1 receptor (CB1) antagonists from the pharmaceutical market due to the occurrence of psychiatric adverse events, new evidence suggests that peripherally restricted CB1 antagonists might be efficacious for the treatment of obesity and its associated metabolic disorders."


'''[https://www.ncbi.nlm.nih.gov/pubmed/21055418 Role of the endocannabinoid system in food intake, energy homeostasis and regulation of the endocrine pancreas ]''' (Li C, et al, 2011)

::"More recently, it has become apparent that both CB1 and CB2 receptors are more widely expressed than originally thought, and the capacity of endocannabinoids to regulate energy balance also occurs through their interactions with cannabinoid receptors on a variety of peripheral tissues. In general, pathological overactivation of the ECS contributes to weight gain, reduced sensitivity to insulin and glucose intolerance, and blockade of CB1 receptors reduces body weight through increased secretion of anorectic signals and improved insulin sensitivity."


'''[https://www.ncbi.nlm.nih.gov/pubmed/20134190 Endocannabinoid system participates in neuroendocrine control of homeostasis]''' (De Laurentiis A, et al, 2010)

::“The endocannabinoid system is a new intercellular system that modulates several neuroendocrine actions. Endocannabinoids (eCB) are released as retrograde messengers by many neurons, including hypothalamic magnocellular neurons and cannabinoid receptors are localized within these neurons, as well as in the anterior and posterior pituitary lobes, suggesting an eCB role in the production and release of OXT [oxytocin] and VP [vasopressin].”
 

'''[https://www.ncbi.nlm.nih.gov/pubmed/18508995 Endocannabinoids in endocrine and related tumours ]''' (Bifulco M, et al, 2008)

::"The endocannabinoid system is involved in a broad range of functions and in a growing number of physiopathological conditions. Indeed, recent evidence indicates that endocannabinoids influence the intracellular events controlling the proliferation of numerous types of endocrine and related cancer cells, thereby leading to both in vitro and in vivo antitumour effects."



'''[https://www.ncbi.nlm.nih.gov/pubmed/16306385 The emerging role of the endocannabinoid system in endocrine regulation and energy balance]''' ( Pagotto U, et al, 2006)

::“An increasing amount of data highlights the role of the system in the stress response by influencing the hypothalamic-pituitary-adrenal axis and in the control of reproduction by modifying gonadotropin release, fertility, and sexual behavior. The ability of the endocannabinoid system to control appetite, food intake, and energy balance has recently received great attention, particularly in the light of the different modes of action underlying these functions.”