Phytocannabinoids Beyond the Cannabis Plant – Do They Exist?

8/12/2019 Phytocannabinoids Beyond the Cannabis Plant Do They Exist?

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THEMED ISSUE: CANNABINOIDS

REVIEWPhytocannabinoids beyond the Cannabis plant dothey exist? bph_745 523..529 Jrg Gertsch 1, Roger G Pertwee 2 and Vincenzo Di Marzo 3

1 Institute of Biochemistry and Molecular Medicine, University of Bern, Bern, Switzerland, 2School of Medical Sciences, Instituteof Medical Sciences, University of Aberdeen, Foresterhill, Aberdeen, Scotland, UK, and 3 Endocannabinoid Research Group, Institute of Biomolecular Chemistry, Consiglio Nazionale delle Ricerche, Pozzuoli, NA, Italy

It is intriguing that during human cultural evolution man has detected plant natural products that appear to target key proteinreceptors of important physiological systems rather selectively. Plants containing such secondary metabolites usually belong tounique chemotaxa, induce potent pharmacological effects and have typically been used for recreational and medicinalpurposes or as poisons. Cannabis sativa L. has a long history as a medicinal plant and was fundamental in the discovery of theendocannabinoid system. The major psychoactive Cannabis constituent D9-tetrahydrocannabinol ( D9-THC) potently activatesthe G-protein-coupled cannabinoid receptor CB 1 and also modulates the cannabinoid receptor CB 2. In the last few years,several other non-cannabinoid plant constituents have been reported to bind to and functionally interact with CB receptors.Moreover, certain plant natural products, from both Cannabis and other plants, also target other proteins of the endocan-nabinoid system, such as hydrolytic enzymes that control endocannabinoid levels. In this commentary we summarize andcritically discuss recent ndings.British Journal of Pharmacology (2010) 160, 523529; doi:10.1111/j.1476-5381.2010.00745.xThis article is part of a themed issue on Cannabinoids. To view the editorial for this themed issue visithttp://dx.doi.org/10.1111/j.1476-5381.2010.00831.x

Keywords : phytocannabinoid; cannabinoid; plant natural products; Cannabis ; endocannabinoid system

Abbreviations: CB1, type-1 cannabinoid receptor; CB 2, type-2 cannabinoid receptor; CP55940, ()- cis -3-[2-hydroxy-4-(1,1-dimethylheptyl)phenyl]- trans -4-(3-hydroxypropyl)cyclohexanol; D9-THC, D9-tetrahydrocannabinol; DIM, 3,3 -diindolylmethane; ECS, endocannabinoid system; FAAH, fatty acid amide hydrolase; FDA, US Food and Drug Administration; G i/o, G-protein alpha subunit; GPR55, orphan receptor G-protein-coupled receptor 55; MAGL,monoacylglycerol lipase; NAEs, N -acylethanolamines; PPAR, peroxisome proliferator-activatedprotein; SR144528, (1S-endo)-5-(4-Chloro-3-methylphenyl)-1-((4-methylphenyl)methyl)-N-(1,3,3-trimethylbicyclo(2.2.1)hept-2-yl)-1H-pyrazole-3-carboxamide; SR141716A, N -(piperidin-1-yl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide hydrochloride; Tmax, time tomaximal concentration in plasma (pharmacokinetic parameter); TRPV1, transient receptor potential vanilloid-1receptor; WIN55212-2, ( R)-(+)-[2,3-dihydro-5-methyl-3-(4-morpholinylmethyl)pyrrolo-[1,2,3-de]-1,4-benzoxazin-6-yl]-1-naphtaleneylmethanone

Today we perceive the endocannabinoid system (ECS) as arather complex lipid signalling network in which differentproteins play distinct roles in the control or in the modula-tion of numerous physiological and pathophysiological

processes (Pertwee, 2005; Di Marzo, 2008). The ECS comprisesclassical cannabinoid receptors (CB 1 and CB 2), potentially alsothe orphan receptor GPR55, and arachidonic acid-derivedligands, which, however, also promiscuously target otherreceptors like, e.g. TRPV1 and PPAR-gamma (OSullivan, 2007;De Petrocellis and Di Marzo, 2010; Ross, 2009; Pertwee, 2010).Importantly, the enzymes degrading the endocannabinoidsanandamide and 2-arachidonoyl glycerol, namely fatty acidamide hydrolase (FAAH) and monoacylglycerol lipase(MAGL), have been shown to be promising therapeutic targets

(Di Marzo, 2008). Finally, there appears to be an anandamidecellular reuptake mechanism that can be blocked by specic

Correspondence: Jrg Gertsch, Institute of Biochemistry and Molecular Medi-cine, Bhlstrasse 28, University of Bern, 3012 Bern, Switzerland. E-mail:[email protected] molecular receptor nomenclature used throughout this commentary con- forms to the BJPs Guide to Receptors and Channels (Alexander et al ., 2009).Received 12 January 2010; revised 18 February 2010; accepted 23 February2010

British Journal of Pharmacology (2010), 160, 523529 2010 The AuthorsJournal compilation 2010 The British Pharmacological Society All rights reserved 0007-1188www.brjpharmacol.org


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inhibitors (Di Marzo, 2008). Both cannabinoid receptor ago-nists and antagonists have actual or potential therapeuticapplications (Di Marzo, 2008; Oesch and Gertsch, 2009;Pertwee, 2009). Cannabinoids are dened as the terpenophe-nolic constituents of Cannabis sativa L and until recently, the

phenylterpenoid D9-THC and some of its naturally occurringderivatives were the only plant natural products known todirectly interact with cannabinoid receptors. However, in thelast few years, several non-cannabinoid plant natural prod-ucts have been reported to act as cannabinoid receptorligands. This prompts us to dene phytocannabinoids as anyplant-derived natural product capable of either directly inter-acting with cannabinoid receptors or sharing chemical simi-larity with cannabinoids or both. Direct cannabinoid receptorligands are compounds that show high binding afnities (inthe lower nM range) for cannabinoid receptors and exertdiscrete functional effects (i.e. agonism, neutral antagonismor inverse agonism). By contrast, indirect ligands target either

key proteins within the ECS that regulate tissue levels of endocannabinoids or allosteric sites on the CB 1 receptor.Certain plant natural products, including some cannabinoids,possess at least some of these properties. Given the often highvariability of molecular pharmacological data obtained in dif-ferent laboratories and the distinct degrees of scrutiny of theexperimental setup, molecular pharmacological data onnatural products should always be interpreted with care(Gertsch, 2009). For example, the availability of CB receptorKO mice provides a powerful means of investigating theactual cannabimimetic nature of a particular compound invivo. This commentary focuses on natural products frommedicinal and dietary plants which have been reported tointeract with the ECS.

Fatty acid derivatives

Despite the fact that N -acylethanolamines (NAEs) (Table 1)from plants do not interact with CB receptors (plants do notgenerally produce arachidonic acid, which is the acyl scaf-fold favoured for CB interaction) they have beenshown to inhibit FAAH, thus leading to an increase inendocannabinoid tone. N -linoleoylethanolamide andN -oleoylethanolamide, which are found not only in choco-late ( Theobroma cacao L.) but also other plants (Di Marzoet al ., 1998), and the widespread NAE palmitoylethanola-mide, inhibit anandamide breakdown (Maurelli et al., 1995;Di Tomaso et al., 1996). Certain N -alkylamides (alkamides)from Echinacea spp. (Table 2) have been shown to interactfunctionally with the human CB 2 receptor with low nM tomM K i values (Gertsch et al., 2006). These N -isobutylamidesselectively act at the CB 2 receptor over the CB 1 receptor,leading to an increase in intracellular calcium which couldbe blocked by the selective CB 2 receptor inverse agonistSR144528, but they do not modulate the G a i signallingpathway. Intriguingly, CB 2 receptor-binding N -alkylamidesshow similar anti-inammatory effects as anandamide (e.g.inhibition of TNF- a ) at low nM concentrations (Raduneret al ., 2006). Certain Echinacea N -alkylamides inhibit anan-

damide reuptake in vitro (Chicca et al., 2009). Like ananda-mide, N -alkylamides also target PPAR-gamma (Spelman et al.,

2009). Different Echinacea N -isobutylamides are orally bio-available resulting in nM plasma levels in humans (Woelkartet al ., 2008). The polyacetylenic polyyne falcarinol, which isfound in different plants of the Apiaceae family (e.g. incarrots) shows signicant binding interactions with both

cannabinoid receptors, but appears to selectively undergo analkylation reaction with the CB 1 receptor ( K i value 1 h after one single oral administration (J.G., unpublisheddata). Orally administed b-caryophyllene ( < 5 mgkg - 1) pro-duces strong anti-inammatory and analgesic effects in wild-type mice but not in CB 2 receptor knockout mice, which is aclear indication that it may be a functional CB 2 ligand.Ongoing studies show that b-caryophyllene is effective atreducing neuropathic pain in a CB 2 receptor-dependentmanner (Zimmer et al., 2009). Therefore, the FDA approvedfood additive b-caryophyllene has the potential to become anattractive candidate for clinical trials targeting the CB 2 recep-tor (Gertsch, 2008). Interestingly, the diterpene salvinorin Afrom Salvia divinorum Epling & Jativa-M (Table 1) has beenreported to be a selective high-afnity kappa-opioid receptor(KOP) agonist, but recent data also suggest that it may interactwith a putative CB receptor/KOP heterodimer which may beformed during inammatory conditions (Fichna et al., 2009).To date, binding experiments have shown that salvinorin Ahas very low afnity for homomeric cannabinoid receptorsand does not inhibit endocannabinoid degradation (Capassoet al ., 2008). Consequently, further research is needed toestablish whether salvinorin A interacts with a putativecannabinoid/KOP heterodimeric receptor or whether the can-nabimimetic effects reported are indirectly mediated via KOP.More recently, two naturally occurring quinonoid triterpe-noids, pristimerin (Table 1) and euphol, were found to inhibitMAGL with high potency (IC 50 = 93 nM and 315 nM respec-tively) through a reversible mechanism (King et al., 2009). Asthis class of triterpenes is relatively frequent in nature, it maynot be unusual to nd indirect rather than direct agonists

of cannabinoid receptors among plant secondary metabolites.Several distinct triterpenes are known to modulate immune

Phytocannabinoids beyond the Cannabis plant524 J Gertsch et al

British Journal of Pharmacology (2010) 160 523529


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T a

b l e

1

P l a n t n a t u r a l p r o d u c t s t h a t h a v e b e e n s u g g e s t e d t o e x e r t c a n n a b i m i m e t i c e f f e c t s b u t d o n o t i n t e r a c t d i r e c t l y w i t h c a n n a b i n o i d ( C B ) r e c e p t o r s

S t r u c t u r e

N a m e

O r i g i n

C B r e c e p t o r a f n i t y

F u n c t i o n

I n v i v o e f c a c y

O t h e r

t a r g e t s ( E C S )

R e f e r e n c e s

R

NH

O H

O R =

l i n

o l e o y

l ; o

l e o y l ; p a

l m i t o y

l

N - a c y l e t h a n o l a m i n e s

W i d e s p r e a d i n p l a n t s

N o a f n i t y

F A A H i n h i b i t o r s

V a l i d a t e d i n C B 1

a n d C B 2 K O m i c e

G P R 5 5

M a u r e l l i e t a l . , 1 9 9 5 ; D i

T o m a s o e t a l . , 1 9 9 6 ;

D i M a r z o ,

2 0 0 8

I n d i r e c t c a n n a b i m i m e t i c s

O

O

O

H

O

H

H

O

O

O

S a l v i n o r i n A

S a l v i a d i v i n o r u m

I n s i g n i c a n t a f n i t y t o

C B r e c e p t o r s

I n d i r e c t c a n n a b i m i m e t i c

e f f e c t s a t C B 1

( m e c h a n i s m

u n k n o w n )

N o d a t a

K O P a g o n i s t

C a p a s s o e t a l . , 2 0 0 8 ;

F i c h n a e t a l

. , 2 0 0 9 ;

E p l i n g & J a t i v a - M

H O O

C O

2 C H

3

P r i s t i m e r i n

R e l a t i v e l y w i d e s p r e a d i n

t h e C e l a s t r a c e a e

N o d a t a

P o t e n t r e v e r s i b l e

N o d a t a

N o d a t a

K i n g e t a l . , 2 0 0 9

M A G L i n h i b i t o r ( I C

5 0

v a l u e < 1 0 0 n M )

O

O H

O H

H O

O H

O

K a e m p f e r o l


N o a f n i t y

F A A H i n h i b i t o r ( I C

5 0

v a l u e < 1 m M )

N o d a t a

N o d a t a

T h o r s e t a l . , 2 0 0 7 ; 2 0 0 8

H O

O H

O

H

T r a n s - r e s v e r a t r o l


p l a n t s ( e

. g .

V i t i s

v i n i f e r a L . )

I n s i g n i c a n t a f n i t y

I n s i g n i c a n t e f f e c t s

N o d a t a

N o d a t a

P r a t h e r e t a l

. , 2 0 0 9

O

O

H O

H 3

C O

O C H

3

O H

C u r c u m i n

C u r c u m a s p p .


I n s i g n i c a n t e f f e c t s

N o d a t a

N o d a t a

P r a t h e r e t a l

. , 2 0 0 9

O

H O

O H

O H

O H

O H

O H

O H

O H

O O

E p i g a l l o c a t e c h i n -

3 - O

- g a l l a t e


p l a n t s ( e

. g .

C a m e l l i a

s i n e n s i s L . )


N o d a t a

N o d a t a

N o d a t a

K o r t e e t a l . , 2 0 1 0

E C S , e n d o c a n n a b i n o i d s y s t e m ; F A A H

, f a t t y a c i d a m i d e h y d r o l a s e ; M A G L , m o n o a c y l g l y c e r o l l i p a s e .

Phytocannabinoids beyond the Cannabis plantJ Gertsch et al 525



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T a

b l e

2

P l a n t n a t u r a l p r o d u c t s t h a t h a v e b e e n s h o w n t o i n t e r a c t d i r e c t l y w i t h c a n n a b i n o i d ( C B ) r e c e p t o r s

S t r u c t u r e

N a m e

O r i g i n

C B r e c e p t o r a f n i t y

F u n c t i o n

I n v i v o e f c a c y

O t h e r t a r g e t s ( E C S )

R e f e r e n c e s

O

O H

H

H

D 9 - T

H C

C a n n a b i s s a t i v a L .

N o n - s e l e c t i v e C B 1 a n d

C B 2 a f n i t y ( K

i v a l u e s

< 5 0 n M ) ( h u m a n )

P a r i a l a g o n i s t G

i / o

V a l i d a t e d i n

C B 1 a n d C B 2

K O m i c e

G P R 5 5

M e c h o u l a m ,

1 9 8 6 ;

P e r t w e e ,

2 0 0 6

I n h i b i t i o n b y S R 1 4 1 7 1 6

a n d S R 1 4 4 5 2 8

P P A R s

D i f f e r e n t i o n c h a n n e l s

NH

O

N - a

l k y l a m i d e

E c h i n a c e a s p p .

S e l e c t i v e C B 2 a f n i t y ( K

i

v a l u e < 1 0 0 n M )

( h u m a n )

P a r i a l a g o n i s t

N o d a t a

P P A R - g

R a d u n e r e t a l

. , 2 0 0 6 ;

C h i c c a e t a l . , 2 0 0 9

[ C a 2

+ ] i

I n h i b i t i o n b y S R 1 4 4 5 2 8

I n h i b i t i o n o f A E A

t r a n s p o r t

P a r t i a l F A A H i n h i b t i o n

NH

O

N - a

l k y l a m i d e

E c h i n a c e a s p p .


i

v a l u e < 1 0 0 n M )

( h u m a n )

P a r i a l a g o n i s t [ C a 2

+ ] i

N o d a t a

P P A R - g

R a d u n e r e t a l

. , 2 0 0 6 ;

C h i c c a e t a l . , 2 0 0 9

I n h i b i t i o n b y S R 1 4 4 5 2 8

I n h i b i t i o n o f A E A

t r a n s p o r t

P a r i a l F A A H i n h i b i t i o n

H H

b - c a r y o p h y l l e n e



i

v a l u e < 2 0 0 n M )

( h u m a n )

F u l l a g o n i s t

V a l i d a t e d i n

C B 2 K O

m i c e

N o d a t a

G e r t s c h e t a l . , 2 0 0 8

G i / o

[ C a 2

+ ] i

H O

F a l c a r i n o l


A p i a c e a e ( e

. g . D

a u c u s

c a r o t a L . )

N o n - s e l e c t i v e C B 1

a f n i t y ( K

i v a l u e

< 1 m M ) ( h u m a n )

C B 1 r e c e p t o r - s e l e c t i v e

i n v e r s e ( c o v a l e n t )

a g o n i s t

N o d a t a

N o d a t a

L e o n t i e t a l

. , 2 0 1 0

I n h i b i t i o n o f A E A /

W I N 5 5 2 1 2 - 2

O

O

O

O

O

R u t a m a r i n

R u t a g r a v e o l e n s L .


i

v a l u e < 1 0 m M )

( h u m a n )

N o d a t a

N o d a t a

N o d a t a

R o l l i n g e r e t a l

. , 2 0 0 9

NH

N H

D I M 3

, 3 - d

i i n d o l y l m e t h a n e

m e t a b o l i t e f r o m

i n d o l e - 3 - c a r b i n o l


t h e

B r a s s i c a g e n u s


i

v a l u e @ 1

m M ) ( h u m a n )

P a r t i a l a g o n i s t a t C B 2

r e c e p t o r

N o d a t a

N o d a t a

Y i n e t a l . , 2 0 0 9

D 9 - T H

C i s s h o w n a s t h e m a j o r p h y t o c a n n a b i n o i d f r o m

C a n n a b i s s a t i v a L . b u t t h e r e a r e s e v e r a l o t h e r s t r u c t u r a l l y r e l a t e d c a n n a b i n o i d s t h a t i n t e r a c t w

i t h C B r e c e p t o r s .

D 9 - T H

C , D

9 - t e t r a h y d r o c a n n a b i n o l ; D I M

, 3 , 3 - d

i i n d o l y l m e t h a n e ; E C S , e n d o c a n n a b i n o i d s y s t e m ; F A A H

, f a t t y a c i d a m i d e h y d r o l a s e ; P P A R

, p e r o x i s o m e p r o l i f e r a t o r - a c t i v a t e d p r o t e i n .




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functions through yet unknown mechanisms (Rios, 2010)and it will thus be interesting to see in a more systematicstudy whether other similar triterpenoids are also able toinhibit MAGL.

Polyphenols

The dietary polyphenols trans-resveratrol and curcumin(Table 1) were reported to bind selectively to the human CB 1cannabinoid receptor with low nM K i values (5.9 nM and45 nM respectively) and to exert potent pharmacologicaleffects in mice similar to those induced by the CB 1 receptorinverse agonist rimonabant (Seely et al., 2009). Intrigued bythis unexpected nding, our research groups independentlymeasured the binding afnities of these compounds for CB 1and CB 2 receptors in our laboratories. In our experiments,trans-resveratrol and curcumin only displaced [ 3H]CP55 940

from cannabinoid receptors at high mM concentrations, sug-gesting that they lack signicant afnity for these receptors.Also polydatin, a glycosilated form of resveratrol, was inactivein these binding assays. Recently, the senior author of theoriginal report retracted the paper (Prather et al., 2009).Hence, neither trans-resveratrol nor curcumin interact func-tionally with the CB 1 receptor, despite the fact that thesecompounds appear to share the ability of the CB 1 receptorinverse agonist, rimonabant, to induce weight loss in mice.

More recently, catechin-derivatives were shown to bind tohuman cannabinoid receptors rather non-selectively at highmM concentrations (Korte et al., 2010). Among these, epigal-locatechin 3-gallate and (-)-epigallocatechin (Table 1) werereported to bind to the CB 1 receptor with K i values of 33.6 and35.7 mM respectively. However, these K i values may not becorrect. For the calculation of the K i values the Cheng-Prussof equation ( K i = IC50/1 +([S]/Kd) was not applied correctly. TheEC50 values used to calculate the K i values were approxima-tions as neither compound produced more than 60% radioli-gand displacement even at the highest concentration used.Catechins are very widespread plant secondary metaboliteswhich may provide nutritional health benets. The samegroup has recently reported similar CB 1 and CB 2 receptor K ivalues for delphinidin and cyanidin, two hydrophilic antho-cyanidins (Korte et al., 2009). In both reports, no functionaldata were shown. In our hands, avonoid-type compounds(catechins, anthocyanidins, avones) lead to negligible orvery high K i values, which likely reect a nonspecic molecu-lar denaturation of the protein surface rather than a func-tional binding interaction. Similar potentially artefactualeffects would most likely be observed with other GPCRs.

Plant polyphenols, such as phenylpropanoids (e.g. epigal-locatechin 3- O-gallate, curcumin, resveratrol) possess chemi-cal scaffolds which at mM concentrations bind to proteintargets in vitro with limited specicity. This is clearly reectedby numerous reports on protein binding interactions thatsuch compounds undergo in the mM range (Anand et al.,2008; Bisht et al., 2009). At the macroscopic level, polyphe-nols (i.e. tannins) have been used to tan leather by denaturingof proteins, and at the microscopic level mM concentrations of

polyphenols interact with multiple protein binding sites (viatheir hydroxyl groups) non-specically and therefore such

compounds score as frequent hitters in vitro. The great major-ity of established cannabinoid receptor ligands are highlylipophilic, which reects the nature of the active site withincannabinoid receptors. Thus, hydrophilic polyphenols likecatechins and anthocyanidins would clearly be atypical can-

nabinoid receptor ligands.More interesting are ndings that certain avonoids inhibit

fatty acid amide hydrolase (FAAH), which is the enzymeresponsible for the breakdown of the endogenous CB receptorligand anandamide (Thors et al., 2007; 2008). Both the isoa-vonoid genistein and the avonoids kaempferol (Table 1),7-hydroxyavone and 3,7-dihydroxyavone have beenshown to concentration-dependently inhibit anandamidehydrolysis in rat brain homogenates, albeit at relatively highconcentrations (IC 50 values between 2 and 10 mM). Neverthe-less, the authors of these studies showed a preliminarystructure-activity relationship with 7-hydroxyavone beingthe most potent inhibitor (IC 50 value < 1 mM).

An abundant literature is devoted to mechanisms underly-ing the biological activity of plant polyphenols (Landis-Piwowar and Dou, 2008; Bisht et al., 2009). However,although most benecial and potentially therapeutic effectsof trans-resveratrol, curcumin, catechins and kaempferol-typeavonoids are typically detected in the low mM range in vitro,all such compounds show limited bioavailability and poorpharmacokinetics in vivo with reported plasma concentra-tions in the low nM range (DuPont et al., 2004; Garcea et al.,2004; Boocock et al., 2007).

Other plant natural products with binding afnity

to the CB 2 receptorOther plant natural products have been shown to bind weaklyto the CB 2 receptor. These include the coumarin derivativerutamarin from the medicinal plant Ruta graveolens L. (Roll-inger et al., 2009) and 3,3 -diindolylmethane (DIM) (Table 2),which is an anticarcinogenic metabolite generated by inges-tion of indole-3-carbinol. Indole-3-carbinol is commonlyfound in Brassica vegetables. DIM has been shown to be aweak CB 2 receptor partial agonist (Yin et al., 2009).

Conclusions

There is no doubt that phytocannabinoids from Cannabishave greatly inuenced research on the ECS and without themilestone discovery that D9-THC is the main psychoactiveprinciple (reviewed in Mechoulam, 1986) many of the subse-quent discoveries in the eld of cannabinoid research wouldprobably not have been made. Furthermore, with the devel-opment of therapeutic Cannabis extracts, as with Sativex,this plant is also likely to provide new pharmaceutical appli-cations in the future. The question remains as to why Can-nabis sativa L. appears to be the only plant that produces ametabolite ( D9-THC acid) that readily leads to its decarboxy-lation product D9-THC, which is the most potent phytocan-nabinoid activator of the CB 1 receptor. Interestingly enough,

while nature may have been rather parsimonious in its pro-vision of botanical secondary metabolites that activate the




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CB1 receptor, there is an increasing number of plant-derivednatural products reported to target the CB 2 receptor to varyingdegrees. Flavonoids, which belong to natural polyphenolsthat readily interact with proteins, may target some of theproteins within the ECS, such as FAAH. However, no convinc-

ing evidence has been provided that polyphenols modulatecannabinoid receptors with signicant potency. The ndingthat certain triterpenes potently inhibit MAGL further adds tothe repertoire of plant-produced indirect cannabinoid recep-tor agonists. Although higher plants do not contain endocan-nabinoids and lack the classical G-protein-coupledcannabinoid receptors, they do express enzyme isoforms thatresemble some of the enzymes known to be important in theprocessing of endocannabinoids (Shrestha et al., 2006). Plantsproduce fatty acid amides, some of which are able to inhibitthe degradation of anandamide but do not generally bindwith signicant afnity to CB receptors (Gertsch et al., 2006;Di Marzo et al., 2007). At present, the only phytocannabinoid

that has been discovered to also exist in plants other thanCannabis is b-caryophyllene, which is among the most abun-dant plant essential oil components. Although D9-THC is apartial agonist at both CB 1 and CB 2 receptors, it has signicantlower efcacy at the CB 2 receptor. Another phytocannabinoid,D9-tetrahydrocannabivarin, has also recently been shown tobe a CB 2 receptor partial agonist, but is also a CB 1receptor antagonist (Bolognini et al., 2010). Therefore,b-caryophyllene, which is also one of the most abundantsecondary metabolites in Cannabis essential oil, could be con-sidered as a true CB 2 receptor-selective Cannabis constituent.During mammalian evolution contacts with direct CB 2receptor active plant metabolites like b-caryophyllene orindirect cannabinoid receptor agonists (FAAH and MAGLinhibitors) in diet may have led to hitherto unrecognizedphysiological effects. Although it is tempting to believe thatthese compounds exert benecial effects in humans, clinicalevidence is lacking. Future studies will have to determinewhether there are additional apparently nontoxic CB 2receptor-selective ligands in plants other than Cannabis andwhether they could in fact be exploited therapeutically.

Conict of interest

The authors state no conicts of interest.

References

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