Patent ID: 12194020

The authors provide evidence that: 1) N-arachidonoylethanolamide (anandamide, AEA) significantly (P<0.05) and dose-dependently inhibited hair shaft elongation and hair matrix keratinocyte proliferation. 2) CB1binding activity is found in the HF epithelium, concentrated in the outer root sheath keratinocytes (but not so much in the fibroblasts of the HF dermal papilla. 3) transcription of the CB1gene but not the CB2gene was observed by RT-PCR in human scalp HFs. and 4) AEA stimulates apoptosis of cultured human HF. When anagen and catagen phase results were compared, CB1but not CB2transcription and expression are upregulated in catagen phase. Taken together these data suggest cannabinolic activity is important in phase timing and maintenance, CB1, and not CB2is the more relevant cannabinoid receptor of this pair. Previous data had suggested another cannabinoid receptor, TRPV1, when activated inhibits hair shaft elongation (growth) and induces apoptosis-driven catagen regression. Thus both TRPV1 and CB1are candidates for action in hair loss and hairline regression.

This paper also reports endocannabinoid synthesis of CB1of dissected HF approximated that of cardiac tissue, but that CB2synthesis was about half that of cardiac. With respect to comparative effects of endogenous cannabinoid and those of THC this paper teaches: “THC significantly inhibited hair shaft elongation in a dose-dependent fashion, suppressed proliferation of HF keratinocytes, and induced both hair matrix keratinocyte apoptosis and premature catagen development. These data, therefore, suggest that exocannabinoids can mimic the hair growth-inhibitory effects of endocannabinoids.” These and other data led authors of this paper to conclude: “AEA (which may even be produced within human HF), and the—notoriously abused—exocannabinoid, THC, both inhibit human hair shaft elongation and induce apoptosis-driven HF involution (catagen) in vitro.”

The cannabinoid blockade of the DHT driven androgenic alopecic effects would suggest that applying exocannabinolic compounds or increasing endocannabinoid synthesis. However, in view of this 2007 paper and other similar teachings, the DHT inferred understanding that exposure of a scalp HF to an endo- or exo-cannabinoid would result in noticeable increase in hair growth, including at least either number of active follicles or hair length is shown to be faulty.

AEA and other cannabinoids exert their impacts in various manners. One important manner, especially with respect to HF is production of nitric oxide (NO). Both AEA and 2AG have been shown to be effective NO inducers. NO is probably most noted for its involvement in male erection and as a target of erectile dysfunction drugs. NO is implicated as the main vasoactive nonadrenergic, noncholinergic neurotransmitter and chemical mediator of penile erection. In this capacity, NO activates soluble guanylyl cyclase thereby initiating a chain of events that causes the smooth muscle of corpora cavernosa to relax and absorb blood. Released by nerve and endothelial cells in the corpora cavernosa of the penis, NO activates soluble guanylyl cyclase, which increases 3′,5′-cyclic guanosine monophosphate (cGMP) levels.

In addition to modulating NO levels, AEA also mediates the inhibition of LPS-induced AA and prostaglandin apparently through a CB2activation pathway. In contrast, 2AG itself may serve as an AA precursor for metabolism by COX2 to PGE2countering PGD2synthesis.

Activation of CB1and/or CB2as well as TRPV1 results in increased NO. Increasing NO by these methods overcomes or bypasses the inhibitory effects of DHT and shifts HFs away from the catagenic phase and more towards the anagenic.

AEA is also stored esterified to phosphatidylethanolamines and is released by the action of phospholipase D. AEA or another cannabinoid of choice may be delivered as the drug itself or as a pro-drug, e.g., AEA may be effectively delivered as, for example, a pro-drug C20:4-N-arachidonoyl-phosphatidylethanolamine for conversion to AEA by the a/J3-hydrolase 4 pathway; a prodrug C20:4-N-arachidonoyl-phosphatidylethanolamine for conversion to AEA by the soluble phospholipase A2 pathway; a pro-drug C20:4-N-Arachidonoyl-phosphatidylethanolamine for conversion to AEA by the protein tyrosine phosphatase 22/SH2-containing inositol-5-phosphatase pathway; a pro-drug C20:4-N-arachidonoyl-phosphatidylethanolamine for conversion to AEA by the N-arachidonoyl-phosphatidylethanolaminephospholipase D pathway; AEA epoxide, already a CB2agonist, may be activated by cytochrome p450; etc.

Compounds such as secretoneurin that are known to stimulate NO production and release but have not yet been characterized to identify all receptors to which it binds are considered as cannabinolic compounds when their application has results in line with those of known cannabinoids. The term “cannabinoid active” is thus used to include compounds with cannabinolic activity regardless of whether they have been identified as binding a cannabinoid receptor.

Inhibiting MAGL and/or FAAH, preferably by topical application, but alternatively by systemic application can prolong the effects of the hair stimulating cannabinoids.

Directing more AA which is often considered the rate limiting compound to destinies other than PGD2is one means of minimizing the PGD2anti-hair growth effect and will rebalance the HF metabolism back towards the anagenic phase. In this vein, a membrane-bound glutathione (GSH)-dependent PGE2synthase (mPGES), continuation enzyme of the cyclooxygenase 2 (COX2)-mediated PGE2biosynthetic pathway is one available tool. mPGES activity can be increased markedly at least in macrophages in response to various proinflammatory stimuli. In these circumstances, mPGES was functionally coupled with the induced COX2 in a marked preference to the constitutively expressed COX1, especially when AA was limited. Thus mild stress, such as a cannabinolic exposure may help tilt the COX pathways away from PGD2production. Coupling this with an inhibitor more specific for COX2 will produce stronger beneficial anagenic effect. At least with AEA there is evidence that the PGE2directed COX2 synthetic pathway is preferred over the COX1 pathway capable of making PGD2. MIngYu, et al in “Synthesis of Prostaglandin E2 Ethanolamide from Anandamide by Cyclooxygenase-2” report that AEA did not serve as a substrate for COX1, but also that it did not compete with available AA in the COX1 pathway either. Excess or AEA undergoing removal advantageously does not risk feeding the PGD2induced hair growth inhibition. PGD2binds the GPR44 receptor. Interfering with this interaction, e.g., by reducing or blocking ligand or receptor or inhibiting downstream effects of the receptor bonding may be used as an adjunct or alternative to cannabinoid induced NO. Resveratrol has been shown to significantly suppress PGD2at low concentrations readily obtainable through oral dosing. In general, use of the terms COX2 inhibitor and COX1 inhibitor are meant to indicate that the inhibitor inhibits the numbered COX to a greater degree than the other COX. For example, valeryl salicylate would be considered a COX1 inhibitor because of its selective inhibition of the 1 isoform over that of the 2 isoform. Similar COX1 inhibitors include, but are not limited to: Cox-1 Inhibitor II, FR122047 hydrate, resveratrol, SC 560, etc. (Although resveratrol has capacity to inhibit COX2 also, resveratrol has greater inhibitory potency against COX1.) Meloxicam sodium salt would be a COX2 inhibitor. While ibuprofen, ketoprofen and sulfidics would be considered COX inhibitors, COX1/2 inhibitors or COX1 and COX2 inhibitors.

Two kinetically distinct prostaglandin biosynthetic responses, the immediate and delayed phases, imply involvement of different sets of the biosynthetic enzymes whose expression and activation are tightly regulated. In immediate PG biosynthesis, which occurs within several minutes after stimulation with agonists that increase cytoplasmic Ca′ levels, cytosolic phospholipase A2 (cPLA2) is required for supplying membrane sourced AA to COX1. In the delayed and prolonged PG biosynthesis, which proceeds for a long time period after a stimulus, COX2, is an absolute requirement irrespective of the constitutive presence of COX1. cPLA2 and several inducible secretory phospholipase A2 isozymes cooperatively contribute to supply the AA to COX2. This preference of COX2 over COX1 may rest in the ability of COX2 to metabolize lower levels of AA to PGH2than the higher [AA] required for COX1-directed catalysis. Bimaprost (discussed above as an eyelash thickener) appears to work through this effect. There is evidence that at least some stress inducers not only divert AA to PGE2production, but also induce another parallel AA consuming pathway to produce prostacyclin (PGI2).

In the last decade or so we have come to recognize that prostaglandin D2 (PGD2) plays a primary role in hair loss. Scalp mast cells produce this prostaglandin. Two to three fold increases in scalp PGD2are reported in bald individuals. Like the endogenous endocannabinoids, PGD2synthesis includes arachidonic acid (AA) as a raw material in its synthetic pathway.

Arachidonic acid is acted on by a cyclooxygenase (COX1 or COX2) to form prostaglandin G2(PGG2) which is rapidly COX converted to PGH2. PGH2is a source of thromboxanes (e.g., TXA2) (thromboxin synthase), PGD2, PGE2, PGF2and PGI2(prostacyclin synthase).

Two enzymatic steps are performed on the COX to convert AA to PGH2. A cyclooxygenase portion catalyzes the conversion of AA to PGG2followed by peroxidase activity that reduces PGG2to PGH2. COX1 and COX2 are two known isoforms capable of converting AA to PGH2 through a similar catalytic site and mechanism. A third Cox isoform, COX3, is encoded in the COX1 gene but with retention of intron 1 in the mRNA. The physiological function of this third isoform or possible other COX isoforms is unknown.

COX1 is constitutively expressed in most tissues and may regulate various homeostatic functions there. COX2 is inducible in many tissues and when induced regulates PG production during several acute responses such as inflammation. In general, non-steroidal anti-inflammatory drugs (NSAIDS) such as aspirin inhibit both COX1 and COX2. But inhibitors more selective for either COX1 or COX2 are available and under development.

After PGH2is synthesized the wide variety of PGs and related compounds including, but not limited to: thromboxanes, PGD2, PGE2, PGF2, PGI2, etc., can be produced in accord with the specific PG synthase enzymes present. For example, PGF-synthase enzyme has been cloned and is a member of the aldo-keto reductase family of enzymes that includes 20α-hydroxysteroid dehydrogenase.

COX2-dependent biological responses has received much attention in the past few years, because numerous pharmacological, biological and genetic studies have suggested that this inducible COX isozyme is involved in various human diseases, including inflammation and cancer and in a transformational patent case involving the University of Rochester. Generally, the main PG species produced during the delayed or induced response is PGE2. Since COX2 inhibitors would reduce PGE2more profoundly than other PGs (e.g., PGD2), COX2 inhibition is not a preferred adjunct to the present invention unless this increased PGD2synthesis is overcome or avoided.

PGES activity can be found in both cytosolic and membrane-associated fractions of most cells and tissues. This enzyme uses the anti-oxidant compound glutathione (GSH) as a cofactor for its catalytic effect. The first isolated and characterized PGES however showed preferential functional coupling with COX1.

A human microsomal GST-like 1 (MGST-L1) has now been identified and characterized as a member of the MAPEG (membrane-associated proteins involved in eicosanoid and GSH metabolism) superfamily. MGST-L1 exhibits significant PGES activity and is inducible using IL-1 in some cells. MGST-L1 appears identical to a membrane-associated PGES (mPGES), which has now been detected in lipopolysaccharide (LPS)-stimulated macrophages. MGST-L1/mPGES expression is strongly induced in vitro and in vivo. This mPGES/MGST-L1 is preferentially linked with COX2 pathways, promoting delayed and induced immediate PGE2biosynthesis rather than the inhibitory PGD2. Furthermore, sustained expression of both COX2 and mPGES/MGST-L1 leads to aberrant cell growth. Our results indicate the presence of two segregated PGE2-biosynthetic routes, the cPLA2-COX1-cPGES/p23 and cPLA2-COX2-mPGES/MGST-L1 pathways, in the same cell.

The two main cannabinoids produced in mammalian, including human, body tissues are anandamide aka N-arachidonoylethanolamine (AEA). Both AEA and the phytocannabinoid, THC, have similar agonistic potency with respect to CB1. THC is more potent with respect to the CB2receptor but apparently exerts its well-known psychotropic effects through the CB1receptor.

AEA is also an exogenous phytocannabinoid found in many spices and foods such as chocolate. Endogenous AEA activity is increased by palmitoylethanolamide (PEA) which apparently does not bind CB1or CB2but may be additive or synergistic when both are present, possibly through AEA synthesis induction by PEA. One metabolic pathway for AEA is enzymatic oxygenation by cytochrome P450 hydroxylates and by lipoxygenases to yield hydroperoxy- and hydroxy-derivatives of AEA. AEA also serves as a substrate for cyclooxygenase-2 resulting in the PGE2derivative of AEA. An enzyme responsible for continuous removal of AEA and related cannabinoids is fatty acid amide amidohydrolase (FAAH).

The other predominant cannabinoid in mammals, especially in the neurological system is 2-Arachidonylglycerol (2AG). Whereas AEA has a binding preference for CB1over CB2, 2AG has similar agonistic affinity for each.

2AG can be metabolized rapidly to yield arachidonic acid and glycerol. Rapid elimination of 2AG from the extracellular fluid would be expectedly advantageous given that 2AG exhibits potent biological activities directed at or in diverse tissues and cells. Any misdirected excess 2AG might exert deleterious and undesirable effects. A capacity for rapid clearance of 2AG soon after generation is essential to prevent unwanted consequences.

2AG appears to be primarily metabolized at least in some tissues by a monoacylglycerol lipase, as are other monoacylglycerols. In similarity with AEA, FAAH is available to metabolize 2AG as well. 2AG can be metabolized to 2-arachidonoyl LPA through the action of a kinase(s) to recycle 2AG in the form of glycerophospholipids such as PI. COX2 and 12-lipoxygenase can oxygenate 2AG to yield oxygenated products of 2AG (prostaglandins glyceryl ester and 12(S)-hydroperoxyeicosa-5,8,10,14-tetraenoic acid glyceryl ester).

Use of topical PGE2was reported by Kapoor et al, 2008 wherein a gel (0.25 mg/g) commercially available as a sterile translucent gel preparation containing dinoprostone 0.50 mg/2 g was applied 2×/day to treat vitilago. They report “PGE2enhances basic fibroblast growth factor (bFGF) mRNA expression in a dose-dependent fashion”. Results of the study hoping to restore pigmentation to patches of light skin show successful outcomes with a trend towards improved outcomes towards the cephalic portion as opposed to extremities.

Side effects of CB1activity including, but not limited to: reduced anxiety, increased stress tolerance, food craving. The drug, rimonabant, developed by Sanofi as a weight loss drug, a cannabinoid receptor blocker, was withdrawn from the European market because of possible increased depression and at least successful suicide. Though not proven, there is suggestive evidence that CB1and/or CB2activity may be an important endogenous control on bouts of depression including some associated with PTSD.

Haplosamate derivatives are the first naturally derived cannabinomimetic compound belonging to steroid family. They represent another new chemical class of cannabinoid receptor ligands. This group of steroids includes but is not limited to: haplosamate A and haplosamate B.

Haplosamate A and desulfohaplosamate have opposite effects. Haplosamate A has strong affinity for CB1. Desulfohaplosamate has higher affinity for CB2. The 7-monoacetylated derivative of haplosamate A exhibits affinity to both CB1and CB2cannabinoid receptors in comparison to its parent compound. However, acetylation at C-4 or dialdehyde derivative results in the loss of affinity on both CB1and CB2.

While less dramatic than anabolic steroid injection, activation of CB1and CB2results in release of epinephrine, corticosteroids, and immune calming IL-10, while decreasing pro-inflammatory IL-2. Steady supplementation with one or more synthetic or phytocannabinoid has effects that can be used to substitute for chronically used corticosteroid immune suppression, but will have a more natural control and fewer side effects. Cannabinoid mediated responses include a general calming of local (e.g., dermal, iliac, bowel, gastric, mucosal, etc.) pro-inflammatory mediators including, but not limited to: myeloperoxidase, CXCL8, IL-1β, TNF, etc.Cannabishas also been shown to suppress the immune system by activating myeloid-derived suppressor cells (MDSCs). MDSCs may help dampen the hyperactive immune system.

A class of modulating biomolecules has been characterized as “endocannabinoids”. The name is derived from the receptors active in this system that also being to products from thecannabisplant. Originally two cannabinoid receptors were recognized in humans/mammals because THC, a psychoactive cannabinoid substance fromCannabiswas found to interact with these proteins. These were dubbed: cannabinoid receptor 1 (CB1) and cannabinoid receptor 2 (CB2). AEA and 2AG were recognized as predominant endocannabinoids binding these receptors. CB1immunoreactive neurons were found in close proximity to ileal Peyer's patches and were localized in some submucosal blood vessels. However, subsequent discoveries have revealed other endobiologic compounds also binding these receptors and them additional receptors which interact with AEA and 2AG and the additional recognized compounds with endocannabinoid activity.

GPR55and CB1receptors modulate each other's signaling properties. GPR55 forms heteromers with another 7× transmembrane spanning/GPCR which then interacts with CB1. GPR55-CB1heterodimer acts as a modified cannabinoid receptor that cells form to modulate activities in response to exogenous cannabinoid. This plasma membrane response is independent of cannabinoid effects on internal organelles including, but not limited to: mitochondria, peroxisomes, endoplasmic reticulum, golgi, etc.

Palmitoylethanolamide (PEA) is an endocannabinoid especially capable of downregulating mast cell activation and inflammation. AEA is also an effective endogenous agonist for the central cannabinoid receptor CB1on mast cells. PEA activity may be through CB2and other cannabinoid receptors. PEA and AEA bind to CB2but AEA may be more effective when bound to CB1. This provides evidence that PEA and/or its derivatives may be used to provide anti-inflammatory therapeutic strategies specifically targeted at mast cells.

The endocannabinoid system (ECS) is an important lipid based signaling and immunomodulator system. Lipophilic compounds, those that can readily cross plasma membranes are prime activators of these endocannabinoid pathways. Research relating to medical uses of marijuana and traditional medicines has shown that at least compounds that bind CB1and CB2participate in modulating many physiological responses including, but not limited to: appetite, respiration, metabolism, inflammation, allergy, pain, neurotransmission, etc. The ECS is comprised of G-protein coupled receptors (GPCRs) including, but not limited to: CB1, CB2, TRPV1, TRPV2, TRPV3, TRPV4, TRPA1, TRPM8, GPR55, GPR18, etc.

Two notable catabolic enzymes, fatty acid amide hydrolase (FAAH) and monoglycerol lipase (MAGL), are involved in the breakdown of anandamide and 2AG, respectively. Simply put, less FAAH and MAGL means more AEA and 2AG. So inhibitors of these catabolic enzymes, for example by nutmeg extracts, slows breakdown and raises the available levels of AEA and 2AG generally boosting cannabinoid receptor signaling. FAAH and MAGL inhibition therefore can be used in reducing or managing pain, anxiety, hypertension and various inflammatory conditions.

In general, many plant species, especially those used for spices, have anti-allergy/anti-inflammatory activities. E.g., nutmeg interacts with the endocannabinoid system by inhibiting certain key enzymes that catabolize (break down) the two main endocannabinoids, anandamide and 2AG.

URB597 inhibits FAAH, the principle enzyme involved in degrading the lipid molecule AEA into its arachidonoyl and ethanolamide components. FAAH is a significant step in the pathway for creating prostaglandin ethanolamide compounds including D2 ethanolamide. Inhibiting FAAH raises natural AEA levels and leads to long-term cannabinoid receptor activation and pain relief. URB937, is another p-hydroxyphenyl-O-arylcarbamate that targets FAAH. FAAH is also responsible for the metabolism of other fatty acid amides e.g., N-oleoylethanolamine (OEA) and N-palmitoylethanolamine (PEA). FAAH inhibition maintains or increases tissue levels of anandamide in vivo.

Examples of FAAH inhibitors include but are not limited to: AM374, ARN2508, BIA 10-2474, BMS-469908, CAY-10402, JNJ-245, JNJ-1661010, JNJ-28833155, JNJ-40413269, JNJ-42119779, JNJ-42165279, LY-2183240, cannabidiol, MK-3168, MK-4409, MM-433593, OL-92, OL-135, PF-622, PF-750, PF-3845, PF-04457845, PF-04862853, RN-450, SA-47, SA-73, SSR-411298, ST-4068, TK-25, URB524, URB597 (KDS-4103), URB694, URB937, VER-156084, V-158866, AM3506, AM6701, CAY10435, CAY10499, IDFP, JJKK-048, JNJ-40355003, JNJ-5003, JW618, JW651, JZL184, JZL195, JZP-372A, KML29, MAFP, MJN110, ML30, N-arachidonoyl maleimide, OL-135, OL92, PF-04457845, SA-57, ST4070, URB880, URB937, etc.

β-caryophyllene, a phytocannabinoid, and/or its oxides act as full agonists of the CB2-receptor where they exert anti-inflammatory and analgesic effects that are mediated through CB2, but not CB1. Another phytocannabinoid, salvinorin A, from the plant speciesSalvia divinorumextract is a terpenoid that interacts with a cannabinoid receptor, not yet characterized that apparently forms only in inflammatory conditions. This uncharacterized receptor also acts as a κ-opioid receptor. Many sages produce similar compounds with some activity, but whose activities have not been followed in detail to identify receptor interactions. Myrcene is a major constituent of the essential oil of hops and appears to be related to opioid “high” possibly by agonizing opioid receptors or possibly by antagonizing opioid degradation. Plant sources are hops, verbena andcannabis. Myrcene is also found in lemongrass, thyme and mango. Echinacea contains multiple N-alkylamides that have cannabinoid mimetic effects.

Cannabigerol class: cannabigerolic acid (CBGA) (antibiotic); cannabigerolic acid monomethylether (CBGAM); cannabigerol (CBG) (antibiotic, antifungal, anti-inflammatory, analgesic); cannabigerol monomethylether (CBGM); cannabigerovarinic acid (CBGVA); cannabigerovarin (CBGV).

Cannabichromene class: Cannabichromenic acid (CBCA); cannabichromene (CBC) (antibiotic, antifungal, anti-inflammatory, analgesic); cannabichromevarinic acid (CBCVA); cannabichromevarin (CBCV); Cannabidiolic acid (CBDA) (antibiotic); cannabidiol (CBD) ((antioxidant, anxiolytic, antispasmodic, anti-inflammatory, analgesic); cannabidiol monomethylether (CBDM); cannabidiol C4(CBD-C4); cannabidivarinic acid (CBDVA); cannabidivarin (CBDV); cannabidiorcol (CBD-C1); Δ9-tetrahydrocannabinolic acid A (THCA-A); Δ9-tetrahydrocannabinolic acid B (THCA-B); 6a,10a-trans-6a,7,8,10a-tetrahydro-6,6,9-trimethyl-3-pentyl-6H-dibenzo[b,d]pyran-1-ol, (Δ9tetrahydrocannabinol, THC) (analgesic, antioxidant, antiemetic, anti-inflammation); Δ9-tetrahydrocannabinolic acid-C4 (THCA-C4); Δ9-tetrahydrocannabinol-C4 (THC-C4); Δ9-tetrahydrocannabivarinic acid (THCVA); Δ9-tetrahydrocannabivarinic (THCV); Δ7-cis-isotetrahydrocannabivarin; Δ9-tetrahydrocannabiorcolic acid (THCA-C1); tetrahydro-cannabiorcol (THC-C1).

Δ8-tetrahydrocannabinol class: Δ8-tetrahydrocannabinolic acid (Δ8-TCA); Δ8-tetrahydrocannabinol (Δ8-THC).

Cannabicyclol class: cannabicyclol (CBL); cannabicyclolic acid (CBLA); cannabicyclovarin (CBLV).

Cannabielsoin class: cannabiesoic acid A (CBEA-A); cannabiesoic acid B (CBEA-B); cannabielsoin (CBE).

Cannabinol and cannabinodiol class: cannabinolic acid (CBNA); cannabinol (CBN); cannabinol methylether (CBNM); cannabinol-C4 (CBN-C4); cannabivarin (CBV); cannabinol-C2 (CBN-C2); cannabiorcol (CBN-C1); cannabinodiol (CBND); cannabidivarin (CBDV).

Cannabitriol class: cannabitriol (CBT); 10-Ethoxy-9-hydroxy-Δ-6a-tetrahydrocannabinol (10-EHDT); 8,9-dihydroxy-delta-6a-tetrahydrocannabinol (8,9-DHDT); cannabitriolvarin (CBTV); ethoxy-cannabitriolvarin (CBTVE).

Miscellaneous class: dehydrocannabifuran (DCBF); cannabifuran (CBF); cannabichromanon (CBCN); cannabicitran (CBT); 10-oxo-Δ-6a-tetrahydrocannabinol (OTHC); Δ9-cis-tetrahydrocannabinol (cis-THC); 3,4,5,6-tetrahydro-7-hydroxy-α-α-2-trimethyl-9-n-propyl-2,6-methano-2H-1-benzoxocin-5-methanol (2H-iso-HHCV); cannabiripsol (CBR); Trihydroxy-Δ9-tetrahydrocannabinol (triOH-THC).

LEA, PEA and OEA will bind to one or more of the endogenous cannabinoid receptors, but they are also important because they maintain AEA activity through their inhibition of the FAAH enzyme that is responsible for degrading AEA. N-alkylamides exert selective effects on the CB2, and have been shown to exert anti-inflammatory effects similar to AEA. Echinacea contains multiple N-alkylamides that have mimetic effects.

At least 20 flavonoid compounds, including, but not limited to: apigenin, quercetin, canniflavin A and canniflavin B, β-sitosterol, vitaxin, isovitexin, kaemferol, luteolin and orientin have been identified in thecannabisplant.

Magnolol, a biphenyl neolignan fromMagnolia officinalis, magnolol acts as a partial agonist for CB2, while honokiol is less potent but has full agonistic activity at CB1and antagonistic properties at CB2. Malyngamide B binds both CB1and CB2, with moderate potencies as an agonist anti-inflammatory compound. While many cannabinoids support nitric oxide (NO) production magnolol inhibits NO production with an IC50˜6.2 μM.

NO is a free radical formed from L-arginine by converting it to L-citrulline via nitric oxide synthase (NOS) enzymes. The reaction product of NO with superoxide generates potent oxidizing agent, peroxynitrite which is the main mediator of tissue and cellular injury. When NO and O2−(nitric oxide free radical and superoxide anion free radical) react peroxynitrite, a powerful oxidant capable of eliciting major cell and tissue injury, results. Despite this and other possible deleterious outcomes, over the past four or five decades NO has been acknowledged as a molecule of extreme importance in intracellular and intercellular communication, slowing proliferation of, for example, smooth muscle cells; controlling platelet and endothelial adhesion; acting as a neurotransmitter; modulating mitochondrial membrane permeability; etc. As examples of NO activities, NO induced PGE2activity is part of the pathway through which the body senses dehydration and signals remedial actions across multiple organs and systems; responding to toxic events such as ethanol intoxication; a relation between cannabinoids and NO is part of joint cartilage maintenance; NO is one compensatory compound involved in multiple pathways to minimize deleterious effects of heart failure; mtNOS appears active in inducing apoptosis in infected cells; NO is closely controlled in a recovering cell following an ischemic event, sometimes support cell recovery while sometimes encouraging apoptosis; NO is part of the path for restoring proper protein folding through its actions on at least HSP70; NO controls mitochondrial growth, synthesis and fusion following intense exercise; NOS activity is induced following sleep deprivation releasing NO in support of REM sleep stages.

NO has a short half-life in aqueous solution undergoing reactions with superoxide as mentioned above to form peroxynitrite, auto-oxidize in water to form nitrous anhydride (N2O3), acidify to form nitrous acid and nitrite, lose the radical electron to form nitrosonium, etc. NO is particularly reactive with heme irons, e.g., to control lipid oxygenase reactions. NO is an important intercellular messenger through its activation of soluble guanyl cyclase leading to enzymatic and ion channel activations. NO reversibly inhibits many enzymes, especially heme containing or free radical activated enzymes; when involved in apoptosis, NO is involved in multiple paths including, but not limited to: mitochondrial membrane permeability, mitochondrial fusion/fission balance, production of ROS and other oxidative compounds, activation of ASK1-JNK1 branch point, etc.; the NFκB ligand, RANKL is up regulated in response to depressed calcium levels; stress induced NO helps the cytoskeleton direct proteins and other biomolecules to the golgi and other organelles.

The relation by which cannabinoids, e.g., AEA, mediate intracellular and extracellular events through activating NO synthesis is well-conserved evolutionarily. Plants, invertebrate animals and vertebrate animals all demonstrate this relationship. The evidence generally involves assessing NO signaling changes upon exposure to a cannabinoid compound and blocking these changes with specific inhibition of a relevant NOS enzyme. The activities and enzymes may differ between organisms, but the endocannabinoid/NOS relationship and resultant NO production are conserved. The ubiquity of applications of the NO signaling systems is further evidenced by the incorporation of an NOS enzyme in the mitochondrial inner membrane where it is implicated in peroxynitrite formation and cytochrome c oxidase reaction rates.

Cannabinolic phyto-compounds or derivatives include but are not limited to: abinene, α-pinene, 4,8-dimethyl-1,7-nonadien-4-ol, 2-hydroxy-4-methyl-valeric, acid methyl ester, octanal, O-cymene, eucalyptol, α-phellandrene, cis-sabinene, hydroxide, myrcenol, terpinen-4-ol, α-terpineol, β-thujene, ç-terpinene, trans-α-ocimene, carveol, β-citral, guanidine, geraniol, bornyl, acetate, β-pinene, thymol, geranic, acid methyl ester, α-terpinyl acetate, d-limonene, eugenol, geranyl acetate, dihydrocarvyl acetate, α-ylangene, cis-dodec-5-enal, 3-phenyl-2-propenoic, acid methyl ester, β-elemene, c, vanillin, epoxy-α-terpenyl acetate, butanoic, acid 2-methyl-, 3,7-dimethyl-2,6-octadienyl ester, 1-methyl-4-(1-acetoxy-1-methylethyl)-cyclohex-2-enol, 1,2,3,4,4a,5,6,8a-octahydro-4a,8-dimethyl-2-(1-methylethenyl)-, [2r-(2à,4aà,8aá)]-naphthalene, p-mentha-1(7),8-dien-2-ol, ç-muurolene hydroxy-α-terpenyl acetate, nerolidol, geranyl bromide, (−)-α-panasinsene, pyrocatechol, ç-elemene, 9,10-dehydro-isolongifolene, à-calacorene, cis-verbenol acetic, acid, 1-methyl-1-(4-methyl-5-oxo-cyclohex-3-enyl)ethyl ester, alloaromadendrene, z,z-2,6-dimethyl-3,5,7-octatriene-2-ol, 4-epi-cubedol, 2-oxabicyclo[2.2.2]octan-6-ol, 1,3,3-trimethyl-acetate, patchoulane, farnesol, caryophyllene oxide, cis-lanceol, ledene oxide-(ii), farnesol acetate, 6-epi-shyobunol, falcarinol, phytol, aromadendrene oxide-(2), heptacosane, longipinene, epoxide, hentriacontane, decamethyl-cyclopentasiloxane, geranyl, isobutyl, hexamethyl-cyclotrisiloxane, 1-docosene, tetratetracontane, dodecamethyl-cyclohexasiloxane, etc.

Supplementation with cannabinoid active substances can facilitate the cells' and the organisms mitochondrial rebalancing.

Marihuana inhibits dihydrotestosterone binding to the androgen receptor.

According to the study, bald men tend to have an abnormal amount of a protein called prostaglandin D2 on their scalps. This protein and its derivatives block hair growth.

The conversion of AEA to prostaglandins (PG) including, but not limited to: D2, E2, F2, G2, H2, I2, J2, etc. antagonizes the cadherin inflammation calming functions. H2 is readily converted to D2, E2, F2, I2, F1α, and thromboxanes. D2 is a major prostaglandin produced by mast cells and binds to the receptors PTGDR (DP1) and CRTH2 (DP2). This recruits Th2 cells, eosinophils, and basophils leading to an inflammatory response. D2 is a critical component in development of allergic disease responses such as asthma and therefore is of prime interest. E2/F2, I2/F1α and thromboxanes are separate production branch offshoots from H2 that can compete with D2 production.

PGD2inhibitors are a class of chemical components that exert an inhibitory effect on the synthesis, release, or effects of PGD2in vitro or in vivo. PGD2inhibition was researched in the context of treating asthma, allergic rhinitis and similar disease states. Such compounds and those for example listed and described in US Application 20150072963, US Application 20160346186 and/or US Application 20110021599, the contents of each where they relate to PGD2inhibitors herein incorporated in the entirety of their relevant disclosures by reference, advantageously formulated or reformulated for topical administration are preferred components of applications of the present invention.

Prostaglandin D2-glycerol ester was found to decrease macrophage activation, and this effect was dependent on ABDH[HD]6 activity (α/β-hydrolase domain 6; see also ABHD 12) that revert 2AG (second cannabinoid after AEA).

In gut tissue, activation of CB1receptors by cannabinoids, plant-derived, endogenous or synthetic, effectively reduces both gastric acid secretion and gastric motor activity, and decreases the formation of gastric mucosal lesions induced by stress, pylorus ligation, nonsteroidal anti-inflammatory drugs (NSAIDs) or alcohol, partly by peripheral, partly by central mechanisms. Similarly, indirect activation of cannabinoid receptors through elevation of endocannabinoid levels by globally acting or peripherally restricted inhibitors of their ligand metabolizing enzymes (FAAH, MAGL) or by inhibitors of their cellular uptake reduces the gastric mucosal lesions induced by NSAIDs in a CB1receptor-dependent fashion.

Use of cannabinolic compounds for medical treatments is growing. Already several plant-derived cannabinoids are used in the medical practice, such as Δ9-THC (dronabinol) and its synthetic analogue, nabilone, against chemotherapy-induced nausea and emesis, and as appetite stimulants (e.g. in AIDS patients). CBD combined with Δ9-THC (nabiximols) is used to relief neuropathic pain and spasticity in multiple sclerosis, and as an adjunctive analgesic treatment in advanced cancer pain.

Synthetic cannabinoid derivatives may differ from the natural ones in several aspects, e.g. in pharmacokinetic properties or in binding affinity to the different cannabinoid receptors. For example methanandamide, an amidase resistant chiral analogue of AEA possesses higher metabolic stability than its parent compound. WIN 55,212-2, an aminoalkylindole derivative is a potent agonist at both CB1and CB2receptors and one of the most frequently used synthetic cannabinoids. It produces effects similar to those of Δ9-THC, although it has an entirely different chemical structure. Differences in binding affinity to different cannabinoid receptors may result in selective agonists at CB1or CB2receptors. For example, ACEA (arachidonoyl-2′-chloroethylamide) prefers CB1receptors, while JWH 133 (3-(1′,1′-Dimethylbutyl)-1-deoxy-delta8-THC), or GP1a (1-(2′,4′-dichlorophenyl)-6-methyl-N-piperidine-1-yl-1,4-dihydroindeno[1,2-c]pyrazole-3-carboxamide) are selective for CB2receptors. Moreover, differences in distribution may result either in global actions or peripherally restricted effects, such as the peripherally acting CB1/2agonist AZD 1940 and AZD 1704.

Activation of CB1and CB2receptors can be achieved not only through binding by the natural and synthetic cannabinoids provided, but also secondarily, by elevating of the level of existing endocannabinoids in the vicinity of cannabinoid receptors, e.g., by blocking their degradation and/or uptake. AEA and 2AG levels are regulated in vivo by catabolic enzymes, e.g., FAAH, which hydrolyzes AEA into AA and ethanolamine, and monoacylglycerol lipase (MAGL), which is the main effector of 2AG hydrolysis. However, we must remember additional enzymes, e.g., the COX, lipooxygenases and cytochrome P450 enzymes that is a given circumstance may also have or be induced to have a significant role in degradation of the endocannabinoids. Extracellular cannabinoids are constantly removed from circulation or interstitium but uptake into the cells and metabolism.

To date over 120 cannabinoids, the so-called phytocannabinoids (pCB), have been isolated from thecannabisplant. Most phytocannabinoids share common structural features that include a dibenzopyran ring and a hydrophobic alkyl chain. The most abundant cannabinoids in the plant are Δ9-tetrahydrocannabinol (Δ9-THC or simply, THC), Δ8-tetrahydrocannabinol (Δ8-THC), cannabinol (CBN), cannabidiol (CBD), cannabigerol (CBG), and cannabichromene (CBC), Δ9-tetrahydrocannabivarin (THCV), cannabivarin (CBV), cannabidivarin (CBDV). Despite their lower presence in the plant, other phytocannabinoids such as cannabinodiol (CBND), cannabielsoin (CBE), cannabicyclol (CBL) and cannabitriol (CBT) have also been the subjects of study in the last decades.

The different phytocannabinoids show different relative affinities for CB1and CB2receptors. In addition, over the last years, receptor targets outside the classic endocannabinoid system have been identified as binding sites and action centers for certain plant cannabinoids. These compounds have been shown to interact with other G-protein coupled receptors such as the putative cannabinoid receptors GPR55 or GPR18, and other well-known GPCRs such as the opioid or the serotonin receptors. In addition, several papers have reported the ability of certain phytocannabinoids to modulate nuclear receptors, ligand-gated ion channels or transient receptor potential (TRP) channels, among others.

For example, in the synthetic realm, SR141716A, the first reported CB1 antagonist displays nanomolar CB1affinity (Ki=1.98±0.13 nM), but very low affinity for CB2. SR141716A has acts as a competitive antagonist and an inverse agonist in cells transfected with exogenous CB1receptor, and in cells endogenously expressing CB1. Several additional CB1antagonists have been reportedly synthesized, including, but not limited to: LY-320135, 0-1184, CP-272871, URB447, a class of benzocycloheptapyrazoles, a novel series of 3,4-diarylpyrazolines and biarylpyrazolyl oxadiazoles. A first peptide CB1inverse agonist, hemopressin (HP; PVNFKFLSH) (SEQ ID No. 1), has also been reported.

Additional endocannabinoids identified to date include N-arachidonoyl dopamine (NADA) and virodhamine. N-arachidonoyl-dopamine (NADA) is an endogenous “capsaicin-like” substance in mammalian nervous tissues. NADA activates cannabinoid CB1receptors, but not the dopamine D1and D2receptors. Virodhamine is arachidonic and ethanolamine joined by an ester linkage.

The CB2receptor in general recognizes the same structural groups of cannabinoid agonists as CB1, with differing affinities in some cases, for example CB2has higher affinity for aminoalkylindoles.

The discussion of specific combinations of treatments, protocols, compounds and/or exemplary uses are for illustration of how the present invention might be applied in one or more specific circumstances. Such are not intended to exclude other potential embodiments not specifically discussed herein.

Application 62/609,384 and Ser. No. 15/954,582 are hereby incorporated by reference in their entireties. The CRF submitted herewith as a .txt document has identical sequence disclosure for the 3 applications, the content of which is incorporated by reference in its entirety and is reproduced on the following page.