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 exert their effects, at least in part, via PPAR pathways [1, 2, 3]. What are PPARs, and what do they have to do with epilepsy?
Epilepsy is far from fully understood, but current science may lead one to believe that mutations in genes play a larger role than previously thought . Peroxisome proliferator-activated receptors (PPARs) regulate the expression of genes . The physiological mechanisms involved are not yet fully understood as they relate to epilepsy. However, there appear to be a number of interesting implications.
Low levels of endogenous (naturally occurring in the body) cannabinoids that are CB1 and PPAR alpha agonists (activators) have been linked to epilepsy . PPAR agonists are believed to be regulators of brain inflammation and oxidative stress [7, 8]. Both have implications to epilepsy [9, 10]. This is in part why PPAR gamma is suspected to be a neuroprotective agent in epilepsy . PPAR alpha might be of even greater interest as it's the target of a number of novel antiepileptic drugs . PPAR alpha activation is also believed to enhance memory acquisition . So while 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 PPAR agonists . These include, but aren't limited to: cannabinoids, terpenes, flavonoids, and saturated fats [15, 16]. This is one example of a commonality shared between the use of cannabinoids, ketogenic diets, and Tulsi (holy basil) in the treatment of epilepsy. They all contain PPAR agonists, and in turn modulate gene expression [1, 2, 3].
Why does this matter? Phytocannabinoids (natural plant derived cannabinoids) have many of the same pharmacological characteristics as endogenous cannabinoids, including PPAR activation [2, 16]. As this paper intends to illustrate, the reason that this might be important is that there is a large number of natural sources of PPAR agonists, some of which include cannabinoids that originate outside of the cannabis plant.
This paper won't delve into the physiological mechanisms that are suspected to be involved with ketogenic diets, in relation to epilepsy, other than to point out that it's believed to involve the activation of PPAR alpha .
Botanical extracts from cannabis can contain a variety of cannabinoids . The use of cannabinoids derived from cannabis appear to continue to prove their effectiveness in the treatment of epilepsy . Unfortunately, due to the politics surrounding cannabis, not all families currently have the legal access to the cannabinoids that they so desperately need. Until each State 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 worthwhile to take a look at the possible physiological mechanisms involved with cannabinoids derived from cannabis in an attempt to identify other possible alternatives. Prior to getting into possible alternatives, let's review some of the research on the primary cannabinoids in cannabis, as they relate to epilepsy.
Almost 500 compounds have been identified from cannabis . Botanical extracts from cannabis contain varying amounts and types of compounds which are primarily composed of cannabinoids, terpenes, and flavonoids. As will be illustrated, many of these compounds are PPAR agonists. While we'll limit our discussion of cannabis to CBD and THC, it's worth noting that there is a large number of additional PPAR agonists present in any given cannabis plant, or botanic extract thereof [2, 16]. It is the opinion of this author, based on the research cited in this paper, that each PPAR agonist may have the ability to impact the degree of effectiveness of any given botanical extract.
CBD is currently the cannabinoid being most heavily explored in the treatment of epilepsy. One pharmacological characteristic of CBD is that it's a PPAR gamma agonist . CBD is believed to reduce neuroinflammation and promote neurogenesis via PPAR gamma .
Possibly of greater importance is that CBD suppresses fatty acid amide hydrolase (FAAH), which in turn increases the levels of an endogenous cannabinoid, anandamide, a PPAR alpha and gamma dual agonist . In addition, FAAH inhibition increases N-palmitoylethanolamide (PEA), and N-oleoylethanolamide (OEA) levels, both of which are PPAR alpha agonists [20, 21]. Low PEA levels in the brain have been linked to absence epilepsy and it has been suggested as a candidate for treatment . In general, PPAR alpha agonists might be of particular interest in the treatment of epilepsy as they're currently being explored as new antiepileptic drugs .
One explanation for the effectiveness of CBD in the treatment of epilepsy might be based on the fact that you're getting, one PPAR gamma, one dual PPAR alpha and gamma, and two PPAR alpha agonists, all from the pharmacological effects of one cannabinoid. Not to mention any other cannabinoids, terpenes, and flavonoids present in a botanical extracts from cannabis that may also be PPAR agonists.
Another potentially favorable pharmacological characteristic of CBD is that it's a 5HT1A-receptor (serotonin) agonist . Depression and memory deficits in patients with temporal lobe epilepsy have been linked to low 5HT1A activation .
The elephant in the room as it relates to cannabis is THC. Like CBD, THC is a PPAR gamma agonist . THC is most known for its activation of CB1 receptors which are associated with some of the psychoactive effects of cannabis. It should be noted that CBD is an effective CB1 agonist blocker and is believed to mitigate the psychoactive effects of THC . However, CB1 directly activates GABAergic synaptic transmissions . Perturbing GABA (γ-Aminobutyric acid) levels has implications to epilepsy; GABA agonists are known to inhibit seizures, while antagonists are known to induce seizures . This seems to indicate a potentially favorable indirect action of CB1 agonists.
These studies are but a few that seem to suggest that both CBD and THC modulate multiple physiological mechanisms that relate to epilepsy. In addition to THC and CBD there are other cannabinoids present in cannabis that it might be helpful to understand the pharmacological characteristics of. For more information see: Izzo, “Non-psychotropic plant cannabinoids: new therapeutic opportunities from an ancient herb” .
Terpenes and Flavonoids
A large number of terpenes and flavonoids are present in cannabis . Many of the same terpenes and flavonoids present in cannabis are abundant throughout the natural world. There is a large number of terpenes and flavonoids that are PPAR agonists . In addition to acting as PPAR agonists, terpenes and flavonoids display a host of other pharmacological characteristics that it might be helpful to be aware of, if they're present in botanical extracts . As an example: d-limonene is not only a PPAR alpha agonist, but it can also increase the bioavailability of non water soluble lipids, like cannabinoids [27, 28]. Another example would be beta-myrcene, which isn't known to be a PPAR agonist, but is a sedative that has been shown to increase barbiturate sleep time . These two examples are simply meant to illustrate the relevance of terpenes and flavonoids present in cannabis, there are many others that it might be wise to consider as well.
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 between cannabinoids, terpenes, and flavonoids are suggested to read: Russo, “Taming THC: potential cannabis synergy and phytocannabinoid‐terpenoid entourage effects.” .
Do they have to be from Cannabis? No. Essential oils are primarily made up of terpenes and flavonoids. There's a small group of families reporting, on Facebook, limited success with the use of Tulsi (holy basil) in the treatment of epilepsy. Let's examine one possible explanation for this.
Ocimum sanctum, or Tulsi (holy basil), has a wide variety of chemotypes. However, it's possible to find essential oils from one particular chemotype that may be of particular interest. Ocimum sanctum ct eugenol has two main constituents with implications to epilepsy. The primary constituent is eugenol. Eugenol is a PPAR gamma agonist, and is being studied for use in the treatment of epilepsy and cephalic pain . The second most prominent constituent is beta-caryophyllene. Beta-caryophyllene is not only a terpene, but it's also a cannabinoid, and a PPAR gamma agonist . The successes with holy basil, while 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. However, most are for external use only. It would also be highly advisable to find a supplier that provides GC/MS analysis, as well as a distill date, on all of their essential oils. This can help to ensure that there is a known quantity of constituents, and that they haven't degraded. The constituents and ratios can vary significantly between batches of essential oils, and they often have two to five year shelf lives.
Caution would be advised as it's also possible that there can be allergic or otherwise adverse reactions to any and all natural compounds. Due diligence is required, and consultation with a physician prior to incorporating any new variables into a health a wellness regiment is recommended.
For comprehensive lists of natural sources of natural PPAR ligands see: Huang, “Herbal or Natural Medicines as Modulators of Peroxisome Proliferator‐Activated Receptors and Related Nuclear Receptors for Therapy of Metabolic Syndrome.” . Additionally: Christensen, “Identification of plant extracts with potential antidiabetic properties: effect on human peroxisome proliferator‐activated receptor (PPAR), adipocyte differentiation and insulin‐stimulated glucose uptake.” .
Other Legal Cannabinoids
As it was just mentioned above, natural cannabinoids have been discovered that are derived from sources other than cannabis . There appears to be a growing number of cannabinoids that continue to be identified, some of which will be highlighted here for their relevance to epilepsy.
Beta-caryophyllene, mentioned above, is found in a variety of natural sources including, but not limited to, cannabis and holy basil. Beta-caryophyllene might be of interest as it's a full CB2 agonists cannabinoid (with anti-inflammatory properties), and PPAR gamma agonist [26, 31].
There are also two lesser acknowledged (at least in the West) cannabinoids that might be equally pertinent to this discussion. Magnolia officinalis has been used in Chinese medicine for more than 2000 years . Magnolia officinalis root bark extracts contain magnolol and honokiol, both of which are cannabinoids, and PPAR agonists [35, 36, 37]. These two cannabinoids are widely available and have a growing 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 PPAR beta/delta and gamma agonist [37, 38]. One study found that magnolol inhibits epileptiform activity mediated by GABA; it was shown that 40 and 80mg/kg “significantly delayed the onset of myoclonic jerks and generalized clonic seizures, and decreased the seizure stage and mortality” . Another study found that magnolol and honokiol both enhance GABAergic neurotransmissions, and asserts that supplements that contain magnolol and honokiol might be “effective anxiolytics, sedatives, and anti-convusants” . It also stated the need for caution as possible side effects and drug interactions might be expected.
One pharmacological characteristic of Honokiol is that it's a PPAR gamma agonists . A study conducted on mice found that both honokiol and magnolol at a rate of 1 and 5mg/kg “significantly increased NMDA-induced seizure thresholds” . In a separate study Honokiol was shown to be a neuroprotectant in oral dosages of 3mg/kg which reduced inflammation and oxidative stress in mice, and “significantly increased NMDA-induced seizure thresholds” .
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 extracts of cannabinoids have a growing body of scientific (and anecdotal) data with favorable implications to epilepsy might also be seen as an indication of their potential. In addition to PPAR activation, magnolol and honokiol have many of the same pharmacological characteristics (including CB1 and CB2 activation) when compared to some of the cannabinoids derived from cannabis .
A consideration when sourcing magnolol and honokiol is that both have shelf lives of less than two years . This might draw into question the quality of the majority of US sources.
There may be other natural sources of cannabinoids worth considering as well. Readers interested in learning more about other natural cannabinoids are suggested to read: Gertsch, “Phytocannabinoids beyond the Cannabis plant–do they exist?” . Additionally, diet can effect endogenous cannabinoid levels, which might also provide alternative options for treatment. See: Maccarrone, "The endocannabinoid system and its relevance for nutrition." .
All in all, it appears that many cannabinoids may exhibit antiepileptic properties, partly via the activation of PPARs, and GABAergic transmissions [18, 24, 39, 40, 41]. It appears as though some other alternative forms of epileptic treatment share a commonality in that they also involve PPAR activation [1, 3]. PPAR alpha might be of particular interest in the treatment of epilepsy . PPAR agonists are abundant throughout the natural world . It's the opinion of this author that it appears possible that there are legal inexpensive cannabinoids, and other PPAR agonists, that aren't yet fully being taken advantage of in the treatment of epilepsy. Again, caution would be advised as it's also possible that there can be allergic or otherwise adverse reactions to any and all natural compounds. Due diligence is required, and consultation with a physician prior to incorporating any new variables into a health a wellness regiment is recommended.
Note from author:
This paper has not been peer reviewed, nor is the author a licensed professional in the medical field. You're encouraged to read the cited references which are all peer reviewed, and are mostly available to read for free online via Google Scholar. You're also encouraged to share, print, or transmit this paper in anyway you see fit.
While the topic of this paper and the majority of citations relate to epilepsy, the available research in relation to phytocannabinoids and cancer is far greater. This includes legal phytocannabinoids.
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