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 in the 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 least in 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 mutations in 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 &''*. ##$R alpha might be of even greater interest as it's the target of a number of novel antiepileptic drugs &'(*. ##$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 seem to be a number of correlations. There's a large number of natural compounds that are ##$R agonists &'.*. These include, but aren't limited to< cannabinoids, terpenes, flavonoids, and saturated fats &'0, '5*. This is one e"ample of a commonality shared bet%een the use of cannabinoids, ketogenic diets, and Tulsi holy basil! in the treatment of epilepsy. They all contain ##$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*. $s this paper intends to illustrate, the reason that this might be important is that there is a large number of natural sources of ##$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 activation of ##$R alpha &'*.

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 have the 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 a look 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 of cannabinoids, 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 a large number of additional ##$R agonists present in any given cannabis plant, or botanic e"tract thereof &(, '5*. It is the opinion of this author, based on the research cited in this paper, that each ##$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. ?ne pharmacological 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 alpha agonists, 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 of the 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

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 multiple physiological 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: new therapeutic 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 large number 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*. $s an e"ample< d/limonene is not only a ##$R alpha agonist, but it can also increase the bioavailability of non %ater soluble lipids, like cannabinoids &(6, (7*. $nother e"ample %ould be beta/myrcene, %hich isn't kno%n to be a ##$R agonist, but is a sedative that has been sho%n to increase barbiturate sleep time &(8*. These t%o e"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 of this 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 phytocannabinoidterpenoid 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 of Tulsi 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, and that 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.

@or comprehensive lists of natural sources of natural ##$R ligands see< 1uang, EHerbal or Natural Medicines as Modulators of Pero isome Proliferator!cti"ated #eceptors and #elated Nuclear #eceptors for Therapy of Metabolic $yndrome. &'.*. $dditionally< 3hristensen, E%dentification of plant e tracts with potential antidiabetic properties: effect on human pero isome proliferatoracti"ated receptor &PP!#'( adipocyte differentiation and insulinstimulated glucose upta)e. &)(*. Other Legal Cannabinoids

$s it %as just mentioned above, natural cannabinoids have been discovered that are derived from sources other than cannabis &))*. There appears to be a gro%ing number of cannabinoids that continue to be identified, some of %hich %ill be highlighted here for their relevance to epilepsy. 4eta/caryophyllene, mentioned above, is found in a variety of natural sources including, but not limited to, cannabis and holy basil. 4eta/caryophyllene might be of interest as it's a full 34( agonists cannabinoid %ith anti/inflammatory properties!, and ##$R gamma agonist &(5, )'*. There are also t%o lesser ackno%ledged at least in the +est! cannabinoids that might be e:ually pertinent to this discussion. Magnolia officinalis has been used in 3hinese medicine for more than (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 by B$4$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 that supplements 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>$/induced seizure thresholdsG &.'*. In a separate study 1onokiol %as sho%n to be a neuroprotectant in oral dosages of )mgFkg %hich reduced inflammation and o"idative stress in mice, and Esignificantly increased AM>$/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.

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 e ist+ &))*. $dditionally, diet can effect endogenous cannabinoid levels, %hich might also provide alternative options for treatment. ;ee< Maccarrone, ,The endocannabinoid system and its rele"ance for nutrition., &..*. Concl sion

$ll in all, it appears that many cannabinoids may e"hibit antiepileptic properties, partly via the activation of ##$Rs, and B$4$ergic transmissions &'7, (., )8, .9, .'*. It appears as though some other alternative forms of epileptic treatment share a commonality in that they also involve ##$R activation &', )*. ##$R alpha might be of particular interest in the treatment of epilepsy &''*. ##$R agonists are abundant throughout the natural %orld &'.*. It's the opinion of this author that it appears possible that there are legal ine"pensive cannabinoids, and other ##$R agonists, that aren't yet fully being taken advantage of in the treatment of epilepsy. $gain, caution %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.

Note from author: This paper has not been peer re"iewed( nor is the author a licensed professional in the medical field. -ou.re encouraged to read the cited references which are all peer re"iewed( and are mostly a"ailable to read for free online "ia /oogle $cholar. -ou.re also encouraged to share( print( or transmit this paper in anyway you see fit. 0hile the topic of this paper and the ma1ority of citations relate to epilepsy( the a"ailable research in relation to phytocannabinoids and cancer is far greater. This includes legal phytocannabinoids.

$uthor< Hoe ;tone -mail< cannabinoidbasedtherapeuticsIgmail.com

References< '. 3ullingford, Tim. J#ero"isome proliferatoractivated receptor alpha and the ketogenic diet.J 2pilepsia .8.s7 (997!< 69/6(. (. Izzo, $ngelo $., et al. JAon/psychotropic plant cannabinoids< ne% therapeutic opportunities from an ancient herb.J Trends in pharmacological sciences )9.'9 (998!< 0'0/0(6. ). #rakash, #., and Aeelu Bupta. JTherapeutic uses of ?cimum sanctum 2inn Tulsi! %ith a note on eugenol and its pharmacological actions< a short revie%.J %ndian 1ournal of physiology and pharmacology .8.( (990!< '(0. .. 1elbig, Ingo, et al. JAavigating the channels and beyond< unravelling the genetics of the epilepsies.J The 3ancet Neurology 6.) (997!< ()'/(.0. 0. Michalik, 2iliane, et al. JInternational =nion of #harmacology. 2KI. #ero"isome proliferator/ activated receptors.J Pharmacological re"iews 07.. (995!< 6(5/6.'. 5. 3itraro, Rita, et al. J$ntiepileptic action ofL iM ALFiM/palmitoylethanolamine through 34' and ##$R/N receptor activation in a genetic model of absence epilepsy.J Neuropharmacology (9'(!. 6. 4ernardo, $ntonietta, and 2uisa Minghetti. J##$R/agonists as regulators of microglial activation and brain inflammation.J Current Pharmaceutical 4esign '(.' (995!< 8)/'98. 7. 3ollino, Massimo, et al. JModulation of the o"idative stress and inflammatory response by ##$R/C agonists in the hippocampus of rats e"posed to cerebral ischemiaFreperfusion.J 2uropean 1ournal of pharmacology 0)9.' (995!< 69/79. 8. ;hin, -un/Hoo, et al. JRole of o"idative stress in epileptic seizures.J Neurochemistry international 08.( (9''!< '((/')6. '9. Oezzani, $nnamaria, et al. JThe role of inflammation in epilepsy.J Nature #e"iews Neurology 6.' (9'9!< )'/.9. ''. Pu, Kin, et al. J$ctivation of cerebral pero"isome proliferator/activated receptors gamma e"erts neuroprotection by inhibiting o"idative stress follo%ing pilocarpine/induced status epilepticus.J 5rain research '(99 (997!< '.5/'07 '(. #uligheddu, Monica, et al. J##$R/$lpha $gonists as Aovel $ntiepileptic >rugs< #reclinical @indings.J Plo$ one 7.0 (9')!< e5.0.'. '). Mazzola, 3armen, et al. J@atty acid amide hydrolase @$$1! inhibition enhances memory ac:uisition through activation of ##$R/N nuclear receptors.J 3earning 6 Memory '5.0 (998!< ))(/))6. '.. 1uang, Tom 1sun+ei, et al. J1erbal or Aatural Medicines as Modulators of #ero"isome #roliferator$ctivated Receptors and Related Auclear Receptors for Therapy of Metabolic

;yndrome.J 5asic 6 clinical pharmacology 6 to icology 85.' (990!< )/'.. '0. Hump, >onald 4., and ;teven >. 3larke. JRegulation of gene e"pression by dietary fat.J !nnual re"iew of nutrition '8.' '888!< 5)/89. '5. Rad%an, Mohamed M., et al. JIsolation and characterization of ne% cannabis constituents from a high potency variety.J Planta medica 6..9) (997!< #/'0. '6. $mada, Aaoki, et al. J3annabidivarin 34>O! suppresses pentylenetetrazole #TQ!/induced increases in epilepsy/related gene e"pression.J Peer7 ' (9')!< e('.. '7. ?'sullivan, ;. -. J3annabinoids go nuclear< -vidence for activation of pero"isome proliferator activated receptors.J 5ritish 1ournal of pharmacology '0(.0 (996!< 065/07(. '8. -sposito B, et al, E3annabidiol reduces amyloid beta/induced neuroinflammation and promotes hippocampal neurogenesis through ##$R/gamma involvement,G P38$ 8ne( (9''. (9. ;chlosburg, Hoel -., ;teven B. Rinsey, and $ron 1. 2ichtman. JTargeting fatty acid amide hydrolase @$$1! to treat pain and inflammation.J The !!P$ 1ournal ''.' (998!< )8/... ('. ;un, Pan, and $ndy 4ennett. J3annabinoids< a ne% group of agonists of ##$Rs.J PP!# research (996 (996!. ((. Theodore, +illiam 1., et al. J;erotonin '$ receptors, depression, and memory in temporal lobe epilepsy.J 2pilepsia 0).' (9'(!< '(8/')). (). Mechoulam, Raphael. J3annabisSa valuable drug that deserves better treatment.J Mayo Clinic Proceedings. Ool. 76. Ao. (. Mayo @oundation, (9'(. (.. Ratona, IstvTn, et al. J>istribution of 34' cannabinoid receptors in the amygdala and their role in the control of B$4$ergic transmission.J The 7ournal of neuroscience ('.() (99'!< 8095/ 80'7. (0. Treiman, >avid M. JB$4$ergic mechanisms in epilepsy.J 2pilepsia .(.s) (99'!< 7/'(. (5. Russo, -than 4. JTaming T13< potential cannabis synergy and phytocannabinoidterpenoid entourage effects.J 5ritish 1ournal of pharmacology '5).6 (9''!< ')../')5.. (6. 4enet, 2eslie Q., Oincent H. +acher, and Reed M. 4enet. J=se of essential oils to increase bioavailability of oral pharmaceutical compounds.J =.;. #atent Ao. 0,550,)75. 8 ;ep. '886. (7. Hing, 2i, et al. J#reventive and ameliorating effects of citrus d/limonene on dyslipidemia and hyperglycemia in mice %ith high/fat diet/induced obesity.J 2uropean 1ournal of pharmacology 6'0.' (9')!< .5/00. (8. Burgel do Oale, T., et al. J3entral effects of citral, myrcene and limonene, constituents of essential oil chemotypes fromL iM 2ippia albaLFiM Mill.! A- 4ro%n.J Phytomedicine 8.7 (99(!< 698/6'..

)9. MUller, M., et al. J-ffect of eugenol on spreading depression and epileptiform discharges in rat neocortical and hippocampal tissues.J Neuroscience '.9.( (995!< 6.)/60'. )'. 4ento, $llisson @reire, et al. JV/3aryophyllene inhibits de"tran sulfate sodium/induced colitis in mice through 34( receptor activation and ##$RC path%ay.J The !merican 1ournal of pathology '67.) (9''!< ''0)/''55. )(. 3hristensen, Rathrine 4., et al. JIdentification of plant e"tracts %ith potential antidiabetic properties< effect on human pero"isome proliferatoractivated receptor ##$R!, adipocyte differentiation and insulinstimulated glucose uptake.J Phytotherapy #esearch ().8 (998!< ')'5/')(0. )). Bertsch, HUrg, Roger B. #ert%ee, and Oincenzo >i Marzo. J#hytocannabinoids beyond the 3annabis plantWdo they e"ist,.J 5ritish 1ournal of pharmacology '59.) (9'9!< 0()/0(8. ).. Pu, 1ua/1ui, et al. JBenetic diversity and relationship of endangered plantL iM Magnolia officinalisLFiM Magnoliaceae! assessed %ith I;;R polymorphisms.J 5iochemical $ystematics and 2cology )8.( (9''!< 6'/67. )0. $tanasov, $tanas B., et al. J1onokiol< $ non/adipogenic ##$RC agonist from nature.J 5iochimica et 5iophysica !cta &55!'-/eneral $ub1ects '7)9.'9 (9')!< .7')/.7'8. )5. Rempel, Oiktor, et al. JMagnolia -"tract, Magnolol, and Metabolites< $ctivation of 3annabinoid 34( Receptors and 4lockade of the Related B#R00.J !C$ Medicinal Chemistry 3etters ..' (9'(!< .'/.0. )6. ;hih, 3hing/Pu, and Tz/3hong 3hou. JThe antiplatelet activity of magnolol is mediated by ##$R/VFC.J 5iochemical Pharmacology (9'(!. )7. @uchs, $le"ander, Oiktor Rempel, and 3hrista -. MUller. JThe Aatural #roduct Magnolol as a 2ead ;tructure for the >evelopment of #otent 3annabinoid Receptor $gonists.J Plo$ one 7.'9 (9')!< e666)8. )8. 3hen, 3. R., et al. JMagnolol, a major bioactive constituent of the bark of Magnolia officinalis, e"erts antiepileptic effects via the B$4$Fbenzodiazepine receptor comple" in mice.J 5ritish 1ournal of pharmacology '5..0 (9''!< '0)./'0.5. .9. $le"eev, Mikhail, et al. JThe natural products magnolol and honokiol are positive allosteric modulators of both synaptic and e"tra/synaptic B$4$L subM $LFsubM receptors.J Neuropharmacology 5(.7 (9'(!< (096/(0'.. .'. 2in, Pi/Ruu, et al. J>ifferential inhibitory effects of honokiol and magnolol on e"citatory amino acid/evoked cation signals and AM>$/induced seizures.J Neuropharmacology .8.. (990!< 0.(/009. .(. 3ui, 1. ;., et al. J#rotective action of honokiol, administered orally, against o"idative stress in brain of mice challenged %ith AM>$.J Phytomedicine '..'9 (996!< 585/699. .). ;u, Qiren, et al. J1eat/induced degradation of magnolol and honokiol in supercritical fluid 3?X

(! e"traction of corte" Magnolia officinalis 1oupo!.J !cta pharmaceutica $inica )6.'' (99'!< 769/760. ... Maccarrone, Mauro, et al. JThe endocannabinoid system and its relevance for nutrition.J !nnual re"iew of nutrition )9 (9'9!< .()/..9.