Cannabinoids, Ketogenic Diets, Holy Basil, and the PPAR Connection

7/22/2019 Cannabinoids, Ketogenic Diets, Holy Basil, and the PPAR Connection

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Cannabinoids, Ketogenic Diets, Holy Basil, and the PPAR Connection

Recently there's been a lot of talk, and even more confusion, about the use of cannabinoids inthe treatment of pediatric epilepsy. The science behind the possible physiological mechanisms

involved seem to have been all but entirely left out of this discussion. Though this paper is not meant

to be definitive, this is an attempt by a layman to inject some science into this ongoing discussion.More importantly this is directed at all of the families that desperately need facts and suggestions, not

politics and debate.

There seems to be a glaring commonality shared by a number of alternative forms of treatment

being utilized in pediatric epilepsy. In the case of cannabinoids, ketogenic diets, and Tulsi holy basil!

the physiological mechanisms involved, as they relate to epilepsy, appear to e"ert their effects, at leastin part, via ##$R path%ays &,(,)*. +hat are ##$Rs, and %hat do they have to do %ith epilepsy

PPARs

-pilepsy is far from fully understood, but current science may lead one to believe that mutationsin genes play a larger role than previously thought &*. #ero"isome proliferator/activated receptors##$Rs! regulate the e"pression of genes &0*. The physiological mechanisms involved are not yet fully

understood as they relate to epilepsy. 1o%ever, there appear to be a number of interesting implications.

2o% levels of endogenous naturally occurring in the body! cannabinoids that are 34 and##$R alpha agonists activators! have been linked to epilepsy &5*. ##$R agonists are believed to be

regulators of brain inflammation and o"idative stress &6, 7*. 4oth have implications to epilepsy &8,9*.

This is in part %hy ##$R gamma is suspected to be a neuroprotective agent in epilepsy &*. ##$Ralpha might be of even greater interest as it's the target of a number of novel antiepileptic drugs &(*.

##$R alpha activation is also believed to enhance memory ac:uisition &)*. ;o %hile there doesn't

appear to be an entirely clear understanding of the physiological mechanisms involved, there does seemto be a number of correlations.

There's a large number of natural compounds that are ##$R agonists &*. These include, but

aren't limited to< cannabinoids, terpenes, flavonoids, and saturated fats &0,5*. This is one e"ample ofa commonality shared bet%een the use of cannabinoids, ketogenic diets, and Tulsi holy basil! in the

treatment of epilepsy. They all contain ##$R agonists, and in turn modulate gene e"pression &, (, )*.

+hy does this matter #hytocannabinoids natural plant derived cannabinoids! have many of

the same pharmacological characteristics as endogenous cannabinoids, including ##$R activation &(,

5*. $s this paper intends to illustrate, the reason that this might be important is that there is a largenumber of natural sources of ##$R agonists, some of %hich include cannabinoids that originate outside

of the cannabis plant.

Ketogenic Diet

This paper %on't delve into the physiological mechanisms that are suspected to be involved %ith

ketogenic diets, in relation to epilepsy, other than to point out that it's believed to involve the activationof ##$R alpha &*.


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Cannabis

4otanical e"tracts from cannabis can contain a variety of cannabinoids &5*. The use of

cannabinoids derived from cannabis appear to continue to prove their effectiveness in the treatment of

epilepsy &6*. =nfortunately, due to the politics surrounding cannabis, not all families currently havethe legal access to the cannabinoids that they so desperately need. =ntil each ;tate has recognized the

therapeutic value of cannabis, and every family has legal access, it may be beneficial to attempt to

identify alternative options for treatment. Though it's highly speculative, it seems %orth%hile to take alook at the possible physiological mechanisms involved %ith cannabinoids derived from cannabis in an

attempt to identify other possible alternatives. #rior to getting into possible alternatives, let's revie%

some of the research on the primary cannabinoids in cannabis, as they relate to epilepsy.

$lmost 099 compounds have been identified from cannabis &5*. 4otanical e"tracts from

cannabis contain varying amounts and types of compounds %hich are primarily composed ofcannabinoids, terpenes, and flavonoids. $s %ill be illustrated, many of these compounds are ##$R

agonists. +hile %e'll limit our discussion of cannabis to 34> and T13, it's %orth noting that there is alarge number of additional ##$R agonists present in any given cannabis plant, or botanic e"tractthereof &(, 5*. It is the opinion of this author, based on the research cited in this paper, that each ##$R

agonist may have the ability to impact the degree of effectiveness of any given botanical e"tract.

34> is currently the cannabinoid being most heavily e"plored in the treatment of epilepsy. ?nepharmacological characteristic of 34> is that it's a ##$R gamma agonist &7*. 34> is believed to

reduce neuroinflammation and promote neurogenesis via ##$R gamma &8*.

#ossibly of greater importance is that 34> suppresses fatty acid amide hydrolase @$$1!,

%hich in turn increases the levels of an endogenous cannabinoid, anandamide, a ##$R alpha and

gamma dual agonist &7*. In addition, @$$1 inhibition increases A/palmitoylethanolamide #-$!,and A/oleoylethanolamide ?-$! levels, both of %hich are ##$R alpha agonists &(9,(*. 2o% #-$

levels in the brain have been linked to absence epilepsy and it has been suggested as a candidate for

treatment &5*. In general, ##$R alpha agonists might be of particular interest in the treatment of

epilepsy as they're currently being e"plored as ne% antiepileptic drugs &*.

?ne e"planation for the effectiveness of 34> in the treatment of epilepsy might be based on the

fact that you're getting, one ##$R gamma, one dual ##$R alpha and gamma, and t%o ##$R alphaagonists, all from the pharmacological effects of one cannabinoid. Aot to mention any other

cannabinoids, terpenes, and flavonoids present in a botanical e"tracts from cannabis that may also be

##$R agonists.

$nother potentially favorable pharmacological characteristic of 34> is that it's a 01T$/

receptor serotonin! agonist &(*. >epression and memory deficits in patients %ith temporal lobe

epilepsy have been linked to lo% 01T$ activation &((*.

The elephant in the room as it relates to cannabis is T13. 2ike 34>, T13 is a ##$R gamma

agonist &7*. T13 is most kno%n for its activation of 34 receptors %hich are associated %ith some ofthe psychoactive effects of cannabis. It should be noted that 34> is an effective 34 agonist blocker

and is believed to mitigate the psychoactive effects of T13 &()*. 1o%ever, 34 directly activates

B$4$ergic synaptic transmissions &(*. #erturbing B$4$ C/$minobutyric acid! levels has


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implications to epilepsyD B$4$ agonists are kno%n to inhibit seizures, %hile antagonists are kno%n to

induce seizures &(0*. This seems to indicate a potentially favorable indirect action of 34 agonists.

These studies are but a fe% that seem to suggest that both 34> and T13 modulate multiplephysiological mechanisms that relate to epilepsy. In addition to T13 and 34> there are other

cannabinoids present in cannabis that it might be helpful to understand the pharmacological

characteristics of. @or more information see< Izzo, ENon-psychotropic plant cannabinoids: newtherapeutic opportunities from an ancient herb&(*.

Terpenes and Flavonoids

$ large number of terpenes and flavonoids are present in cannabis &5*. Many of the same

terpenes and flavonoids present in cannabis are abundant throughout the natural %orld. There is a largenumber of terpenes and flavonoids that are ##$R agonists &*. In addition to acting as ##$R

agonists, terpenes and flavonoids display a host of other pharmacological characteristics that it might

be helpful to be a%are of, if they're present in botanical e"tracts &(5*. $s an e"ample< d/limonene is notonly a ##$R alpha agonist, but it can also increase the bioavailability of non %ater soluble lipids, like

cannabinoids &(6, (7*. $nother e"ample %ould be beta/myrcene, %hich isn't kno%n to be a ##$Ragonist, but is a sedative that has been sho%n to increase barbiturate sleep time &(8*. These t%oe"amples are simply meant to illustrate the relevance of terpenes and flavonoids present in cannabis,

there are many others that it might be %ise to consider as %ell.

To outline the characteristics of each individual terpene and flavonoid is beyond the scope ofthis paper, and has been discussed in length by others. Readers interested in learning more about the

synergistic relationship bet%een cannabinoids, terpenes, and flavonoids are suggested to read< Russo,

ETaming THC: potential cannabis synergy and phytocannabinoid terpenoid entourage effects. &(5*.

>o they have to be from 3annabis Ao. -ssential oils are primarily made up of terpenes and

flavonoids. There's a small group of families reporting, on @acebook, limited success %ith the use ofTulsi holy basil! in the treatment of epilepsy. 2et's e"amine one possible e"planation for this.

?cimum sanctum, or Tulsi holy basil!, has a %ide variety of chemotypes. 1o%ever, it's

possible to find essential oils from one particular chemotype that may be of particular interest.?cimum sanctum ct eugenol has t%o main constituents %ith implications to epilepsy. The primary

constituent is eugenol. -ugenol is a ##$R gamma agonist, and is being studied for use in the treatment

of epilepsy and cephalic pain &)9*. The second most prominent constituent is beta/caryophyllene.4eta/caryophyllene is not only a terpene, but it's also a cannabinoid, and a ##$R gamma agonist &)*.

The successes %ith holy basil, %hile limited in range and scope, might indicate an entire realm of

natural alternatives that are currently being overlooked by and large.

There's a large number of sources for essential oils. 1o%ever, most are for e"ternal use only. It

%ould also be highly advisable to find a supplier that provides B3FM; analysis, as %ell as a distill date,

on all of their essential oils. This can help to ensure that there is a kno%n :uantity of constituents, andthat they haven't degraded. The constituents and ratios can vary significantly bet%een batches of

essential oils, and they often have t%o to five year shelf lives.

3aution %ould be advised as it's also possible that there can be allergic or other%ise adverse

reactions to any and all natural compounds. >ue diligence is re:uired, and consultation %ith a

physician prior to incorporating any ne% variables into a health a %ellness regiment is recommended.


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@or comprehensive lists of natural sources of natural ##$R ligands see< 1uang, EHerbal or

Natural Medicines as Modulators of Peroisome Proliferator !cti"ated #eceptors and #elated Nuclear

#eceptors for Therapy of Metabolic $yndrome.&*. $dditionally< 3hristensen, E%dentification ofplant etracts with potential antidiabetic properties: effect on human peroisome proliferator acti"ated

receptor &PP!#'( adipocyte differentiation and insulin stimulated glucose upta)e. &)(*.

Other Legal Cannabinoids

$s it %as just mentioned above, natural cannabinoids have been discovered that are derivedfrom sources other than cannabis &))*. There appears to be a gro%ing number of cannabinoids that

continue to be identified, some of %hich %ill be highlighted here for their relevance to epilepsy.

4eta/caryophyllene, mentioned above, is found in a variety of natural sources including, but not

limited to, cannabis and holy basil. 4eta/caryophyllene might be of interest as it's a full 34( agonists

cannabinoid %ith anti/inflammatory properties!, and ##$R gamma agonist &(5,)*.

There are also t%o lesser ackno%ledged at least in the +est! cannabinoids that might bee:ually pertinent to this discussion. Magnolia officinalis has been used in 3hinese medicine for morethan (999 years &)*. Magnolia officinalis root bark e"tracts contain magnolol and honokiol, both of

%hich are cannabinoids, and ##$R agonists &)0,)5,)6*. These t%o cannabinoids are %idely available

and have a gro%ing body of research that indicate that they may have untapped potential in the

treatment of epilepsy.

Magnolol is a novel lead structure for cannabinoid receptors agonists, and is a ##$R betaFdelta

and gamma agonist &)6, )7*. ?ne study found that magnolol inhibits epileptiform activity mediated byB$4$D it %as sho%n that 9 and 79mgFkg Esignificantly delayed the onset of myoclonic jerks and

generalized clonic seizures, and decreased the seizure stage and mortalityG &)8*. $nother study found

that magnolol and honokiol both enhance B$4$ergic neurotransmissions, and asserts thatsupplements that contain magnolol and honokiol might be Eeffective an"iolytics, sedatives, and anti/

convusantsG &9*. It also stated the need for caution as possible side effects and drug interactions might

be e"pected.

?ne pharmacological characteristic of 1onokiol is that it's a ##$R gamma agonists &)0*. $

study conducted on mice found that both honokiol and magnolol at a rate of and 0mgFkg

Esignificantly increased AM>$/induced seizure thresholdsG &*. In a separate study 1onokiol %assho%n to be a neuroprotectant in oral dosages of )mgFkg %hich reduced inflammation and o"idative

stress in mice, and Esignificantly increased AM>$/induced seizure thresholdsG &(*.

These studies seem to indicate that magnolol and honokiol, like other cannabinoids, have been

identified as modulating multiple physiological mechanisms that relate to epilepsy. The fact that other

botanical e"tracts of cannabinoids have a gro%ing body of scientific and anecdotal! data %ith

favorable implications to epilepsy might also be seen as an indication of their potential. In addition to##$R activation, magnolol and honokiol have many of the same pharmacological characteristics

including 34 and 34( activation! %hen compared to some of the cannabinoids derived from

cannabis &)0*.

$ consideration %hen sourcing magnolol and honokiol is that both have shelf lives of less than

t%o years &)*. This might dra% into :uestion the :uality of the majority of =; sources.


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There may be other natural sources of cannabinoids %orth considering as %ell. Readers

interested in learning more about other natural cannabinoids are suggested to read< Bertsch,

EPhytocannabinoids beyond the Cannabis plant*do they eist+&))*. $dditionally, diet can effectendogenous cannabinoid levels, %hich might also provide alternative options for treatment. ;ee$/induced seizures.JNeuropharmacology8. (990!

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Cannabinoids, Ketogenic Diets, Holy Basil, and the PPAR Connection