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Cannabinoids And Epilepsy


in vivo
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A few weeks ago on the pediatrics cannabis forum there was a discussion about keto diets. I was unfamiliar with them, so I looked up a couple articles. As luck would have it I believe that they helped to shed some light on the physiological processes that might be involved with cannabinoids in relation to epilepsy. Here's a good example:

 

 

Second, in reaction to this PPARα binds to and hence

modulates specific downstream molecular targets. These

targets are segregated between DNA sequences and proteins.

Thus, fatty acid-bound PPARα directly interacts with

the DNA of promoters of selected target genes encoding

enzymes of intermediary metabolism, resulting in chronic

changes in cell metabolite response. In contrast, fatty acid bound

PPARα directly interacts with proteins involved either

in chronic genetic responses (e.g., inflammation) or

acute voltage-dependent responses (e.g., nociception). All

such responses have implications in epilepsy. Thus, chronic

PPARα-induced alterations in cell metabolites may favorably

perturb amino acid/neurotransmitter concentrations

(Cullingford, 2004). Chronic PPARα-induced antiinflammatory

actions may protect against convulsion-induced

cell damage (Chen et al., 2007). Acute PPARα-induced

antinociceptive action on membrane channels may favorably

perturb the nerve-cell membrane potential (LoVerme

et al., 2006).


http://onlinelibrary.wiley.com/doi/10.1111/j.1528-1167.2008.01840.x/full

 

 

Two main things came to my mind when I read that:

 

  1. Cannabinoids and endocannabinoids are PPAR agonists, as well as neurotransmitters.

  2. This is getting into gene expression..

 

Recently the CBD Project posted an article that discusses this topic. Here's a portion of it:

 

How does CBD regulate gene expression?

It is well accepted among cannabinoid scientists that CBD has little binding affinity for either CB1 or CB2, the canonical cannabinoid receptors, both of which are activated by THC. Instead, cannabidiol works its magic primarily through receptor-independent channels and by binding with various non-cannabinoid receptors.

Recent studies indicate that CBD influences the expression of some genes by directly activating PPAR-gamma, a non-cannabinoid receptor situated on the cell’s nucleus. CBD’s ability to activate PPAR-gamma has promising therapeutic implications, particularly with respect to cancer and metabolic disorders.

What are PPARs?

Peroxisome proliferator activated receptors (PPARs) are a group of three nuclear receptors — PPAR-alpha, PPAR-gamma, and PPAR-delta (the latter is not yet well-characterized). PPARs are triggered by hormones, endogenous fatty acids, and various nutritional compounds. When activated, PPARs bind to certain segments of DNA to promote or prevent transcription of specific genes.

Many of the genes regulated by PPARs are involved in energy homeostasis, lipid uptake and metabolism, insulin sensitivity, and other metabolic functions. Big Pharma recognizes the importance of these nuclear receptors. Thus far, two classes of pharmaceutical PPAR activators — fibrates and thiazolidinediones — have been approved by the U.S. Food and Drug Administration.

 

PPAR agonists

 

Several studies have documented CBD’s role as a PPAR-gamma agonist. Cannabidiol also promotes PPAR-alpha activity by inhibiting fatty acid amide hydrolase (FAAH). FAAH is a metabolic enzyme that breaks down several endogenous fatty acid compounds known as N-acylethanolamides. This important family of endogenous fatty acid molecules includes anandamide, the endocannabinoid that binds directly to the CB1 receptor (which is concentrated in the mammalian brain and central nervous system).

Two other N-acylethanolamides — N-palmitoylethanolamide (PEA) and N-oleoylethanolamide (OEA) – bind directly to PPAR alpha. By suppressing the FAAH enzyme and thereby increasing PEA and OEA levels, cannabidiol indirectly activates PPAR-alpha. Higher levels of PEA and OEA result in enhanced PPAR-alpha transmission. Deficient PPAR-alpha signaling has been linked to schizophrenia.

 

http://www.projectcbd.org/news/cbd-ppars-and-gene-expression-3/

 

That article focuses on CBD, but to my knowledge all cannabinoids are PPAR agonists. They're not all the same type of agonists, but agonists nonetheless. The same is true for cannabinoids identified outside of cannabis, as well a number of terpenes, and other natural compounds. This might be why the holy basil group has seen some limited success. It's possible that many of these treatments have a similarity in that the primary mechanism of action is via PPAR pathways. This might also suggest that families limiting themselves simply to cannabinoid based treatments from cannabis are potentially not capitalizing on what could be inexpensive alternatives and/or supplements.

Edited by in vivo
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I'm wondering if adding a few mg's of anandamide to cannabis oil would be noticable to a patient as it may help the CB1 receptor do it's job.

 

AEA; Anandamide (CAS 94421-68-8)

 

 

 

Arachidonoyl Ethanolamide (CAS 94421-68-8)

 

See more Receptor Biochemistry (372)

Fatty Acids (296)

Inhibitors (1043)

Receptor Agonist (243)

Endocrinology (360)

Neuroscience (1339)

 

 

Description

Arachidonoyl ethanolamide (AEA) is the ethanolamine amide of arachidonic acid, first isolated from porcine brain.1 AEA is an endogenous cannabinoid neurotransmitter that binds to both central cannabinoid (CB1) and peripheral cannabinoid (CB2) receptors.2 AEA inhibits the specific binding of [3H]-HU-243 to synaptosomal membranes with a Ki value of 52 nM, compared to 46 nM for Δ9-THC.1

1 Devane, W.A., Hanus, L., Breuer, A., et al. Isolation and structure of a brain constituent that binds to the cannabinoid receptor. Science 258 1946-1949 (1992).

 

2 Felder, C.C., Briley, E.M., Axelrod, J., et al. Anandamide, an endogenous cannabimimetic eicosanoid, binds to the cloned human cannabinoid receptor and stimulates receptor-mediated signal transduction. Proc Natl Acad Sci USA 90 7656-7660 (1993).

 

Synonyms AEA

Anandamide

 

Formal Name N-​(2-​hydroxyethyl)-​5Z,​8Z,​11Z,​14Z-​eicosatetraenamide

CAS Number 94421-68-8

Molecular Formula C22H37NO2

Formula Weight 347.5

Formulation A solution in ethanol

Purity ≥98%

Stability 1 year

Storage -20°C

Shipping Room temperature in continental US; may vary elsewhere

SMILES Copy CCCCC/C=C\C/C=C\C/C=C\C/C=C\CCCC(=O)​NCCO

InCHI Code Copy ​1S/C22H37NO2/c1-2-3-4-5-6-7-8-9-10-11-12-13-14-15-16-17-18-19-22(25)​23-20-21-24/h6-7,9-10,12-13,15-16,24H,2-5,8,11,14,17-21H2,1H3,(H,23,25)​/b7-6-,10-9-,13-12-,16-15-

InCHI Key Copy LGEQQWMQCRIYKG-DOFZRALJSA-N

 

 

 

https://www.caymanchem.com/app/template/Product.vm/catalog/90050

Edited by Restorium2
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Anandamide occurs in minute quantities in a number of organisms, from sea urchin roe, pigs' brains and mice livers. Surprisingly, 3 compounds that strongly resemble anandamide were found in dark chocolate! Compounds, such as N-acylethanolamines, that prevent the breakdown of anandamide have also been found in chocolate. Perhaps part of the pleasure we get from eating chocolate comes from the effect that the anandamide and N-acylethanolamines it contains has upon our brains...

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The fact that anandamide is a PPAR alpha agonist seems like it might make it an interesting candidate for the treatment of epilepsy. I want to say particularly in the case of absence seizures.

 

A new class of cannabomimetics alkylamides were recently discovered in echinacea purpurea, which is what it sounds like you might be referring to in dark chocolate. I believe there's a thread here with a paper on it. Now that they know to look for them, expect to see more and more identified over the years to come.

 

In regards to treatment supplements/replacements I feel as though all or some of the PPAR gamma agonists can likely be replaced by other natural compounds. The exception likely being CBD. At this point it appears that CBD has the broadest impact on gene expression. It might be that in some cases the CBD is directly responsible via PPAR gamma pathways, but it's also just as likely that indirectly by inhibiting FAAH, and increasing endocannainoid levels, it has a broader impact via its own 'entourage effect'. This would make sense as to why anecdotal reports indicate a broad range of successful with relatively specific individual requirements in terms of CBD dosages (0.25mg-5mg/lb). Too little and no effect, too much and you're potentially creating more havoc than homeostasis. Outside of CBD I wouldn't be surprised if in many cases all other cannabinoids derived from cannabis could be replaced. I'm fully aware that a larger number of families have seen a higher rate of success with closer to a 1:1 ratio, but PPAR gamma agonists appear to be a dime a dozen.

Edited by in vivo
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I see that they have found a synthetic antagonist for the CB1 receptor and it's in clinical trials to treat substance abuse, schizophrenia, and other disorders.

 

My thoughts are that we should find a natural source like pig brains. Head cheese? Could it be the answer? lol

Mmm. Head cheeese. Dem old polish meat markets in Bay City sold it to the workers at Da Chevy and Da IB to take in their lunch pails.

 

The more this shakes out, the more embarrassing it becomes for the naysayers. They should be lined up against a wall and shot with their eyes open for getting in the way of finding the benefits of this amazing plant.

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The fact that anandamide is a PPAR alpha agonist seems like it might make it an interesting candidate for the treatment of epilepsy. I want to say particularly absence seizures. That being said, contrary to previous assumptions, the physiological mechanisms involved are almost completely independent of CB1 and CB2.

 

A new class of cannabomimetics alkylamides were recently discovered in echinacea purpurea, which is what it sounds like you might be referring to in dark chocolate. I believe there's a thread here with a paper on it. Now that they know to look for them, expect to see more and more identified over the years to come.

 

In regards to treatment supplements/replacements I feel as though all or some of the PPAR gamma agonists can likely be replaced by other natural compounds. The exception likely being CBD. At this point it appears that CBD has the broadest impact on gene expression. It might be that in some cases the CBD is directly responsible via PPAR gamma pathways, but it's also just as likely that indirectly by inhibiting FAAH, and increasing endocannainoid levels, it has a broader impact via its own 'entourage effect'. This would make sense as to why anecdotal reports indicate a broad range of successful CBD dosages (0.25mg-5mg/lb). Too little and no effect, too much and you're potentially creating more havoc than homeostasis. Outside of CBD I wouldn't be surprised if in many cases all other cannabinoids derived from cannabis could be replaced. I'm fully aware that a larger number of families have seen a higher rate of success with closer to a 1:1 ratio, but PPAR gamma agonists appear to be a dime a dozen.

It could be that we can adjust what ratio is workable by using something as simple as dark chocolate in conjunction with cannabis as an adjuster. I believe that we are doing these experiments ourselves; Too much chocolate and you don't sleep well so you learn not to eat it before bed time. If you find that too much chocolate makes you not sleep well then you adjust your cannabinoids to offset that problem. Get the right combo and you find the sweet spot. I think the biggest hurdle/trick is that we are all different. Every single patient will need to be 'the adjuster' by paying attention to their reactions to changes.
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Mmm. Head cheeese. Dem old polish meat markets in Bay City sold it to the workers at Da Chevy and Da IB to take in their lunch pails.

 

The more this shakes out, the more embarrassing it becomes for the naysayers. They should be lined up against a wall and shot with their eyes open for getting in the way of finding the benefits of this amazing plant.

Live Strong has a good scrambled eggs with brains recipe. Use brains sparingly because the fatty lipids are not good for your blood flow.
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Say you have a pediatric patient; they're approximately 24 months, 24lbs, diagnosed with a rare form of epilepsy; they've unsuccessfully ran the gauntlet of traditional meds. Do you start with a 1:1 ratio, or do you start with closer to a 20:1? My vote would be for the latter.   

 

You might create a spray that's as close to .1mg/lb increments as possible to help ensure accurate dosing. Each 7 days increase the daily dose by .1mg/lb. The first week one spray per day, then two, etc. If that range isn't sufficient you can then make a spray that's closer to .2mg/lb. Much higher than that and you'd likely have to explore other delivery methods.

 

I suspect that even the cases where a 1:1 ratio is proven to be most effective, that a ratio closer to 20:1 would show some signs of improvement. Once you've found the point at which more CBD doesn't help, you'd lower that dose to a more effective range, and begin to explore additional PPAR agonists. Be they from chocolate or what have you. Specifically I'm most interested in magnolol and honokiol as alternatives, but your mileage may vary.

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I looked up Tulsi (Holy basil) Ocimum santum quickly and it appears that not only does it contain a number of terpenes that are PPAR agonists, one of them is beta-caryophyllene which is also a cannabinoid. This only solidifies my position in regards to the potential and immediate accessibility of little known alternatives.

 

http://www.ingentaconnect.com/content/ben/iadt/2013/00000012/00000006/art00002

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  • 3 weeks later...

I wrote my first amateur paper on this topic. It's in the blog section. It was also posted on Scribd and FB. I was contacted by one person that claimed to be in the medical field, the American Cannabis Nurse's Association, and a number of randoms. None of that really matters when compared to the parents. I feel so bad for these parents that are forced to go onto FB to attempt to find information. On top of that there's a lot of bad info and families potentially being preyed upon, which is frustrating, in a situation that requires a level head and compassion. Since this paper hasn't been peer reviewed I can't be certain how accurate this paper is. I tried to provide very few of my own opinions. I'm certain that it's incomplete (voltage-gated ion channels), but I believe it remains valid. A parent with a neuro involved in the Epidiolex study printed it off for him to read. I'm overjoyed to potentially get input from someone in such a position. I'd like to thank Zap for proof reading it for me, it really helped in creating a stronger paper.

 

It really should have been added that fish oil containing DHA and EPA has been shown to reduce seizures in a number of types of epilepsy. 

 

Another important point is that dietary linoleic acid increases anandamide and 2-AG which can be beneficial in some treatments. Particularly those types of epilepsy linked to low levels of anandamide.

 

It should also be noted that cannabinoids can illicit anti-convulsant and pro-convulsant effects. The pro-convulsant effects appear to be partly associated with activation of TRPV1. Increased levels of endocannbinoids, THC (and other cannabinoids), as well as terpenes/flavonoids present in a botanical extract can activate TRPV1. What seems important is that a recent study has shown that an inactive (1 microgram/kg) dose of capsazepine (a TRPV1 antagonist) has been shown to inhibit the pro-convulsant effects of cannabinoids by blocking TRPV1. Capsazepine (synthetic analogue of capsaicin) is still currently in clinical trials. However, α-Spinasterol is a natural TRPV1 antagonist found in spinach.

 

If you have the ability to identify and cross reference terpenes and flavonoids that are in botanical extracts for TRPV1 activity, that might prove beneficial.

 

http://michiganmedicalmarijuana.org/blog/587/entry-1090-cannabinoids-ketogenic-diets-holy-basil-and-the-ppar-connection/

Edited by in vivo
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I'd love to pick your brain. You're the only one I've seen mention using canna 4 as a rescue med. I think others are primarily using THC. What type of seizures have you seen it work with? This batch of concentrate is close to 10-1 (CBD/THC). Is that around what you've seen?

 

How does that relate to your recommendation for closer to a 1:1? Did you see minimal success with higher CBD ratios? Oral delivery and vape, or? I'd like to be able to learn from others as much as possible. It would be great if others could add input as well.  

 

I think it would be beneficial to put a survey together to gather as much data as possible, and share it with the community at large. I believe we might start to see generalized patterns in terms of which cannabinoids/ratios, and how much per lb, are most effective for specific types of epilepsy. 

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delta9  delta8   CBC     CBD      CBG    CBN    Total

5.70%  0.99%  3.65%  61.92% 1.26%  2.17% 75.69%

 

I think I've seen some of the flowers test close to 30:1, but I've not seen any concentrate from cannatonic #4 with that kind of ratio. The above is what my first batch tested at. Still waiting for the terpene profile.

 

Can you provide any insight into delivery methods/usage?   

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