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Endocannabinoids and pregnancy

March 2010
Clinica Chimica Acta 411(13-14):921-30

DOI:10.1016/j.cca.2010.03.012

Source
PubMed

Authors:

Anthony Taylor

Leicester University and Nottingham Trent University

Akwasi Atakora Amoako

The University of Queensland

Katerina Bambang

Liverpool Women's NHS Foundation Trust

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Acylethanolamides such as anandamide (AEA), and monoacylglycerols like 2-arachidonoylglycerol are endocannabinoids that bind to cannabinoid, vanilloid and peroxisome proliferator-activated receptors. These compounds, their various receptors, the purported membrane transporter(s), and related enzymes that synthesize and degrade them are collectively referred to as the "endocannabinoid system (ECS)". Poorly defined cellular and molecular mechanisms control the biological actions of the ECS. Over the last decade evidence has been emerging to suggest that the ECS plays a significant role in various aspects of human reproduction. In this review, we summarize our current understanding of this role especially the involvement of AEA and related ECS elements in regulating oogenesis, embryo oviductal transport, blastocyst implantation, placental development and pregnancy outcomes, and sperm survival, motility, capacitation and acrosome reaction. Additionally, the possibility that plasma and tissue AEA and other cannabinoids may represent reliable diagnostic markers of natural and assisted reproduction and pregnancy outcomes in women will be discussed.

Chemical structures of the most psychoactive component of marijuana (Δ 9tetrahydrocannabinol, the major endocannabinoids, and the "entourage compounds".

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concentrations in different human biomatrices related to reproduction and the reproductive tract.

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Invited critical review

Endocannabinoids and pregnancy

Anthony H. Taylor, Akwasi A. Amoako, Katerina Bambang, Tulay Karasu, Alpha Gebeh, Patricia M.W. Lam,

Timothy H. Marzcylo, Justin C. Konje ⁎

Endocannabinoid Research Group, Reproductive Sciences Section, University of Leicester, Leicester, United Kingdom

abstractarticle info

Article history:

Received 18 December 2009

Received in revised form 9 March 2010

Accepted 9 March 2010

Available online 17 March 2010

Keywords:

Anandamide

Endocannabinoids

Pregnancy

Reproduction

Acylethanolamides such as anandamide (AEA), and monoacylglycerols like 2-arachidonoylglycerol are

endocannabinoids that bind to cannabinoid, vanilloid and peroxisome proliferator-activated receptors. These

compounds, their various receptors, the purported membrane transporter(s), and related enzymes that

synthesize and degrade them are collectively referred to as the “endocannabinoid system (ECS)”. Poorly

deﬁned cellular and molecular mechanisms control the biological actions of the ECS. Over the last decade

evidence has been emerging to suggest that the ECS plays a signiﬁcant role in various aspects of human

reproduction. In this review, we summarize our current understanding of this role especially the

involvement of AEA and related ECS elements in regulating oogenesis, embryo oviductal transport,

blastocyst implantation, placental development and pregnancy outcomes, and sperm survival, motility,

capacitation and acrosome reaction. Additionally, the possibility that plasma and tissue AEA and other

cannabinoids may represent reliable diagnostic markers of natural and assisted reproduction and pregnancy

outcomes in women will be discussed.

Contents

1. Introduction . . . . . . . . . . .................................................. 921

2. The endocannabinoid system (ECS).................................................. 922

3. Endocannabinoids and gametogenesis . . . . . ........................................... 923

3.1. Oogenesis . . . . . . . . .................................................. 923

3.2. Spermatogenesis . . . . . .................................................. 924

4. Endocannabinoids, early embryo-blastocyst development and oviductal transport . . . . . . . ..................... 924

4.1. Endocannabinoids and early embryo development . . . . . . . . . . . . . . . . . . ..................... 924

4.2. Endocannabinoids and transport through the Oviduct . . . . . . . . . . . . . . . . . ..................... 924

5. Endocannabinoids and implantation ................................................. 925

6. Endocannabinoids in early pregnancy................................................. 925

7. Endocannabinoids in the maintenance of pregnancy and labour. . . . . . . . . . . . . . . . ..................... 925

8. Feto-placental changes in endocannabinoid levels ........................................... 926

9. Possible “immunocannabinoid”system actions in pregnancy . . . . . . . . . . . . . . . . . ..................... 926

10. Conclusions . . . . . . . . . . .................................................. 927

Conﬂicts of interest . . . . . . . . . . .................................................. 927

References . . .............................................................. 927

1. Introduction

Endocannabinoids are endogenous ligands that bind to the same

receptors as the most psychoactive agent in marijuana, delta-9-

tetrahydrocannabinol (Δ

-THC). The use of marijuana, an illicit drug

in the UK and USA [1,2], appears to be increasing [3,4]. Marijuana use

is associated with infertility in males and females, spontaneous

miscarriages, placental abruption, preterm birth, stillbirths [5–7] and

Clinica Chimica Acta 411 (2010) 921–930

⁎Corresponding author. Endocannabinoid Research Group, Reproductive Sciences

Section, Department of Cancer Studies and Molecular Medicine, University of Leicester,

Robert Kilpatrick Clinical Sciences Building, Leicester Royal Inﬁrmary, Leicester,

Leicestershire, LE2 7LX UnitedKingdom. Tel.: +44 116 252 5826;fax: + 44 116252 5824.

E-mail address: jck4@le.ac.uk (J.C. Konje).

doi:10.1016/j.cca.2010.03.012

Contents lists available at ScienceDirect

Clinica Chimica Acta

journal homepage: www.elsevier.com/locate/clinchim

Author's personal copy

delivery of low birth weight babies [8]. The fact that marijuana has

severe consequences on pregnancy, would suggest that the endoge-

nous ligands of the receptors are involved in the modulation of

reproduction. Recently, comprehensive studies by us and others have

indicated that endocannabinoids (especially the prototypical endo-

cannabinoid, N-acyl arachidonoylethanolamide [anandamide, AEA];

Fig. 1), are actively involved in the process of reproduction and

pregnancy. This review will examine the role of cannabinoids in

pregnancy, from gametogenesis through to birth with special focus

upon the effects of endocannabinoids and the endocannabinoid

system on these processes.

2. The endocannabinoid system (ECS)

The isolation of a speciﬁc cannabinoid receptor in the porcine brain

(termed CB

), that is responsible for mediating the pharmacological

effects of Δ

-THC [9], initiated the search for the endogenous ligands.

The ﬁrst ligand identiﬁed that could imitate the pharmacology of Δ

THC at the CB

receptor was anandamide [10] (Fig. 1). Subsequently,

isolation of a second cannabinoid receptor (CB

)associatedwiththe

immune system [11] preceded the identiﬁcation of a second major

endocannabinoid, 2-arachidonoylglycerol (2-AG) (Fig. 1).Both AEA and

2-AG have afﬁnity for CB

and CB

[12], although with differentavidities.

More recently, other bioactive endocannabinoids have been identiﬁed

including O-arachidonoylethanolamine (virodhamine) [13],N-arachi-

donoyl dopamine [14] and most recently N-acyl taurines, such as N-

arachidonoyl taurine [15]. In addition, several endocannabinoid

congeners have been identiﬁed which have greatly reduced afﬁnity

for CB

and CB

yet elicit endocannabinoid-like activities. These include

oleoylethanolamide (OEA) and palmitoylethanolamide (PEA) (Fig. 1),

which are thought to elicit their endocannabinoid-like activities

through the so-called ‘entourage effect’, by either inhibition of

endocannabinoid catabolism [16], or reducing cellular uptake of AEA

thus leading to increased AEA concentrations [17,18]. Of all the possible

endocannabinoids, 2-AG and AEA are the most frequently studied, with

quantiﬁed levels in human tissues for 2-AG being consistently 10–100

times higher than those of AEA [19–21]. AEA, the entourage lipids OEA

and PEA, and to a lesser extent 2-AG have been quantiﬁed in human

biological ﬂuids including plasma and serum, seminal plasma, cerebro-

spinal ﬂuid, follicular ﬂuid, oviductal ﬂuid, amniotic ﬂuid, ovarian cyst

ﬂuid, milk and peritoneal ﬂuid, but seem to be absent from urine and

saliva [22–28].

The ligands only comprise part of the endocannabinoid system;

the enzymes concerned with endocannabinoid synthesis and degra-

dation, a putative membrane transport system and the receptors

through which they elicit their physiological effects complete the

various components (Fig. 2). Endocannabinoids are synthesised on

demand from membrane phospholipids precursors and are not stored

[29].

In most tissues, the main rate-limiting step in AEA synthesis is the

conversion of N-arachidonoyl phosphatidylethanolamine (NAPE) into

AEA by a speciﬁc phospholipase D enzyme (NAPE-PLD) [30,31].

However, the continued synthesis of AEA in NAPE-PLD knockout mice

highlighted alternative pathways for the formation of AEA [32]. These

pathways involve either hydrolysis of NAPE by phospholipase C to

yield phosphoAEA which is dephosphorylated by a protein tyrosine

phosphatase [33] or sequential acyl hydrolysis of NAPE and lysoNAPE

by abhydrolase domain containing 4 (Abh4) to form glycerophospho-

NAPE, which is then hydrolysed to AEA by a phosphodiesterase [34].

The synthesis of other endocannabinoids, especially the monoacyl

glycerol, 2-AG, is less well-deﬁned, but also thought to occur on

demand. For example, 2-AG is produced via diacylglycerol from

arachidonic acid-rich phospholipid precursors by the sequential

actions of phospholipase C and diacylglycerol lipase [35].

Degradation of AEA and 2-AG to free arachidonic acid is primarily

by the serine hydrolases fatty acid amide hydrolase (FAAH) [36] and

monoacylglycerol lipase (MAGL) [37–39], respectively. In addition to

hydrolysis, AEA has been shown to be metabolised by cyclooxygenase

2 to prostamides, ethanolamide derivatives of prostaglandins [40],

and by the cytochrome P450 isozyme CYP2D6 to several epoxide

metabolites [41], which are thought to have their own physiological

actions. Endocannabinoid degradation requires transport of the

endocannabinoids into cells and how these cross the plasma

membrane is still open to debate [42,43]. Current theories include

carrier protein-mediated transport [44], diffusion driven by metab-

olism by FAAH [45], diffusion driven by compartmentalization of

intracellular AEA [46] and endocytosis [47].

Endocannabinoids predominantly exert their effects through bind-

ing to the cannabinoid receptors (CB

and GPR55). These seven-

transmembrane G-protein coupled receptors differ signiﬁcantly in their

distributions. Although CB

was initially localized in the nervous system

and CB

in the spleen,these receptors are now knownto be more widely

distributed throughoutthe body [48–58]. These receptors seem to signal

ligand occupancy by coupling inhibitory Gα

i/o

proteins which inhibit

adenylate cyclase activity, thus reducing intracellular cAMP concentra-

tions [59]. In addition, agonist binding to CB receptors also leads to

activation of MAP kinases, which may partly explain the extensive

pathophysiological roles ascribed to endocannabinoids such as cell cycle

progression, apoptosis, cell differentiation and oncogenesis [60,61].

Stimulation of CB receptors can also cause rapid, transient elevation of

intracellular Ca

concentrations via phospholipase C, the inhibition of

voltage-gated Ca

channelsand activation of K

channels[31].Butthis

may not be the only effects endocannabinoids exert, as they bind to and

activate other types of receptors. For example, the transient receptor

potential vanilloid type 1 (TRPV1), a ligand-gated non-selective cation

channel that can be activated by a number of stimuli including heat and

pH and is involved in the transmission and modulation of pain, also

binds endocannabinoids, especially AEA and N-arachidonoyl dopamine

[62]. Similarly, both endocannabinoids and entourage compounds bind

to and activate the G-protein coupled receptor GPR55, which is

considered a putative cannabinoid receptor [63] because compounds

Fig. 1. Chemical structures of the most psychoactive component of marijuana (Δ

tetrahydrocannabinol, the major endocannabinoids, and the “entourage compounds”.

922 A.H. Taylor et al. / Clinica Chimica Acta 411 (2010) 921–930

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other than endocannabinoids also bind to this receptor. The so-called,

‘entourage endocannabinoids,’OEA and PEA, also bind to peroxisome

proliferator-activated receptors (PPAR). In particular, they activate the

PPARαisoform to modulate cell differentiation, lipid metabolism and

regulate food intake [64].

3. Endocannabinoids and gametogenesis

3.1. Oogenesis

The recent demonstration of the endocannabinoid system in the

human ovary has attracted a growing interest into the exact role of the

endocannabinoids in mammalian folliculogenesis [65].CB

and CB

receptors have been localized in oocytes at all stages of maturation

and the AEA synthetic enzyme NAPE-PLD and the hydrolytic enzyme

FAAH have also been localized in the growing secondary and tertiary

follicles and corpora lutea and albicantes [65]. In addition, AEA has

been quantiﬁed in human follicular ﬂuid [28] and its concentration

found to be strongly correlated to oocyte maturation and quality in

women undergoing infertility treatment [66]. The exact molecular

mechanism by which endocannabinoids modulate ovarian folliculo-

genesis remains speculative, but it is believed that they act through a

combination of central and peripheral mechanisms related to the

actions of gonadotrophins. Evidence for this comes from the now

dated studies showing that Δ

-THC exerted an adverse effect on

oocyte development and ovulation [67] in which Δ

-THC was shown

to interrupt the hypothalamic-pituitary-ovarian axis [68–70] and

suppress plasma follicle-stimulating hormone (FSH) and pre-ovula-

tory luteinizing hormone (LH) surge [71–73], causing an ovulation in

humans [74],rats[75], rabbits and rhesus monkeys [76].The

reduction in gonadotrophin production results in poor quality oocytes

being retrieved during in-vitro fertilization [77]. Since it is known that

cAMP accumulation is required for normal follicular development,

maturation and ovulation [78] and Δ

-THC acting through the CB

receptor normally has an inhibitory effect on cAMP levels, then the

inhibitory effect of Δ

-THC on folliculogenesis may be mediated via its

inhibition of adenylate cyclase, thereby reducing tissue concentra-

tions of cAMP, as has recently been shown in cultured rat granulosa

cells [79,80].

Other evidence also suggests that the endocannabinoid system,

which regulates energy balance by modulating appetite, food intake

and glucose metabolism [81–84] could interact with gametogenesis

through nutritional control. Obesity is commonly associated with

menstrual irregularities, chronic oligo-anovulation and infertility [85]

and regular ovulation is restored after simple management strategies

aimed at weight reduction leading to improved natural conception

[86,87]. Simultaneously, insulin resistance is a cardinal feature of

obesity-associated ovulatory dysfunction in the presence or absence

of polycystic ovary syndrome [88] and androgen hypersecretion, as a

result of hyperinsulinaemia, leads to altered ovarian physiology and

ovulatory dysfunction [89]. Activation of CB

receptors in pancreatic

beta cells by AEA induces glucose intolerance, insulin hypersecretion

and insulin resistance in rats [90,91], suggesting that activation of the

ECS in the pancreas might explain some forms of female infertility.

The use of CB

antagonists (such as Accomplia®; rimonabant) for the

treatment of obesity, and its metabolic consequences, has been shown

to be very effective in reducing body weight or controlling leptin

concentrations [92,93] although with some serious adverse side

effects that have led to its discontinuance [94]. It is therefore clear that

oogenesis could be disrupted through perturbations of the complex

interplay that exists between the endocannabinoids, leptin produc-

tion and obesity. For example, sustained stimulation of CB

in the

hypothalamus by AEA or 2-AG has been observed in leptin-deﬁcient

mice, with elevation of hypothalamic levels of AEA and 2-AG which

Fig. 2. Components of the endocannabinoid system: The ligands 2-acylglycerol (2AG) and anandamide (AEA) are show as blue and red spheres respectively. The putative, but not yet

identiﬁed endocannabinoid membrane transporter (EMT) is shown as a bi-directional regulator. The enzymes responsible for the synthesis and degradation of AEA (N-acyl

transferase (NAT) and N-arachidonoyl phosphatidylethanolamine phospholipase D (NAPE-PLD) and fatty acid amide hydrolase (FAAH-1/2)) and of 2-AG (Di-acyl glycerol lipase

(DAG) and monoacyl glycerol lipase (MAGL)), convert these two endocannabinoids into arachidonic acid (AA; green spheres) and ethanolamine (silver spheres) or AA and glycerol

(yellow spheres), respectively. Cyclooxygenase 2 (COX-2) converts AEA into prostaglandin ethanolamines. Glycerol is acted upon by phospholipase C to produce diacylglycerols that

are reconverted into 2AG by DAGL. AEA once internalised may interact with the cytoplasmic domain of the transient vanilloid receptor type 1 (TRPV1) channel protein to alter

intracellular calcium levels. To aid clarity the possible signalling pathways of cannabinoid receptor (CBR) signalling have been omitted.

923A.H. Taylor et al. / Clinica Chimica Acta 411 (2010) 921–930

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was reversed after leptin treatment [95]. Since FAAH is regulated in

some tissues by leptin [96–101] then these data are highly suggestive

of regulatory networks between leptin, FAAH and endocannabinoids

existing in the hypothalamus that are responsible for the exquisite

control of folliculogenesis. Nevertheless, this area of research is at an

early stage and further work is required to understand the complex

network of central and peripheral actions of endocannabinoids with

regard to ovarian function.

3.2. Spermatogenesis

Accumulating evidence suggest that endocannabinoids may also

modulate male reproductive function [102]. The ﬁrst indication for

this comes from studies of chronic marijuana users, where transient

adverse reproductive toxicity occurs and Δ

-THC directly inhibits

sperm motility and viability in vitro [103]. In experimental animals,

-THC induces impotence in rats [104], decreases rat testicular

weight [105,106], decreases testosterone production which impairs

spermatogenesis and sperm motility [107,108] and in mice similarly

reduces the production of spermatozoa that tend to have abnormal

morphology [109].

The exact mechanism by which Δ

-THC inhibits spermatogenesis

remains speculative but may involve a complex cross-talk between

FSH, LH and cannabinoids [110].Δ

-THC inhibits the release of FSH

and LH from the pituitary gland and consequently [111–114] thereby

inhibits spermatogenesis and testosterone production. By contrast, 2-

AG and to a greater extent AEA, mimic Δ

-THC by inhibiting FSH, LH

and prolactin release from the pituitary gland [115–120] suggesting a

common mechanism of action in both the hypothalamus and

pituitary. CB

and CB

receptors have been demonstrated in

gonadotrophs within the hypothalamus [121] whilst the anterior

pituitary gland expresses CB

and TRPV1 receptors [115–117]

supporting a direct endocannabinoid effect on gonadotrophin

production in the male, similar to that observed in the female.

There is also some evidence of a direct effect of cannabinoids on

the testis [122–126]. Recent interest in the localization of the

endocannabinoid system within male reproductive tissues and

measurement of endocannabinoids in ﬂuids of several mammalian

species has been the subject of intense interest, as well as provoking

controversy. For example, spermatogenic output depends on a

balance between cell proliferation and apoptosis and although,

functional CB

has been identiﬁed in rodent Sertoli and Leydig cells,

suggesting that endocannabinoids are produced by the testis and may

play a crucial role in spermatogenesis and testosterone production

[127,128], the predominant cannabinoid receptor found in mamma-

lian Sertoli cells is CB

, which has anti-apoptotic effects and counter-

acts the pro-apoptotic effects that occur through the TRPV1 receptor

(also present in the Sertoli cell), thereby protecting the germinal

epithelium and germ cells from apoptosis, promoting meiotic

progression [127] and ensuring increased spermatogenic output

[126,128–131]. The recent demonstration and cloning of testis-

speciﬁc functional isoforms of the CB

and CB

receptor that have

differential ligand binding properties [132,133] may help to resolve

some of these controversies.

4. Endocannabinoids, early embryo-blastocyst development and

oviductal transport

The oviduct is central to the process of human reproduction and

plays a critical role in oocyte fertilization and pre-implantation

embryo development during its passage to the uterus [134]. Events

occurring during oviductal transport must be co-ordinated such that

the blastocyst is ready for implantation when it arrives in the uterine

cavity and the latter is ready to receive the blastocyst, usually 6 days

post-fertilization [134]. These critical events are synchronised and

regulated by several endocrine, paracrine and autocrine factors

[96,135] of which the endocannabinoid system has been identiﬁed

as one of the key hormone–cytokine/receptor signalling systems

[79,136–140].

4.1. Endocannabinoids and early embryo development

In the mouse, FAAH is expressed at the 2-cell stage of the early pre-

implantation embryo [136,141,142] while NAPE-PLD, CB

,CB

and are

expressed at later stages. As development proceeds to the blastocyst

stage FAAH levels are signiﬁcantly up regulated. In homozygous FAAH

knockout mice, embryos recovered from oviducts on day 3 of

pregnancy showed delayed and asynchronous development com-

pared to wild type mice [142] suggesting that low levels of AEA are

beneﬁcial and high levels detrimental to blastocyst development

[136,141]. Furthermore, in vitro culture of mouse blastocysts with AEA

indicated that 7nM concentrations of AEA allowed blastocyst

hatching, and 28nM concentrations prevented blastocyst hatching

and induced apoptosis [138]. These data suggest that AEA synthesis by

NAPE-PLD and its degradation by FAAH in embryos and within

oviducts has to be well synchronised such that a locally appropriate

“anandamide tone”is created to permit normal embryo development

and oviductal transport [138]. Furthermore, studies with CB receptor

knockout mice suggest that CB receptor signalling is important in

oviductal transport and blastocyst development. For example, on day

4 of pregnancy, only 60–70% of CB

knockout, CB

knockout and CB

double knockout embryos were blastocysts, whereas most of the

wild type embryos were blastocysts [143]. Data on the effects of

endocannabinoids on human embryo/blastocyst development are,

however, lacking. Nevertheless, the observation that low plasma

levels of AEA and high levels of FAAH in peripheral mononuclear cells

observed during the putative “implantation window”in humans

[66,144,145] suggests that the ECS also plays a similar role in human

embryo development.

4.2. Endocannabinoids and transport through the Oviduct

signalling has been shown to play a crucial role in oviductal

transport of embryos. Studies on CB

,CB

and CB

/CB

double

knockout mice showed that only those lacking CB

protein had a

large number of embryos in the morula or blastocyst stage retained in

their oviducts on day 4 of pregnancy whereas CB2 knockout and wild

type mice had none retained, providing evidence that oviductal

transport is delayed in CB

deﬁcient mice [140,143] and that CB

probably not involved in oviductal transport. This was conﬁrmed by

studies using wild type mice treated with the CB

receptor antagonist

(SR141716) with retention of embryos in the oviducts but not when

the CB

antagonist (SR144528) was used [140].

The mechanism whereby endocannabinoids might affect normal

transport is currently unclear. Transport of embryos through the

oviduct is aided by a peristaltic wave of oviductal smooth muscle

movement regulated by the sympathetic nervous system [146]. The

demonstration of CB

co-localization with adrenergic receptors in

rodent oviduct, suggests that endocannabinoids could affect cate-

cholamine function [140]. Indeed, excess sympathetic stimulation has

been shown to lead to increased smooth muscle contraction and

impaired embryo transport at the isthmus-uterine junction [140]. The

overstimulation of the oviductal smooth muscle with potassium

chloride led to a 33% overﬂow of radio-labelled noradrenaline into the

oviducts of CB

knockout mice, an effect that was signiﬁcantly higher

compared to that in CB

knockout and wild-type oviducts [140],

suggesting that CB

signalling negatively regulates neuronal nor-

adrenaline release to directly modulate tubal motility. The authors

suggest that aberrations in the endocannabinoid system could

therefore form a mechanistic basis for ectopic pregnancy, where

there is no obvious tubal damage.

924 A.H. Taylor et al. / Clinica Chimica Acta 411 (2010) 921–930

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In humans, CB

has been localized in the Fallopian tube smooth

muscle wall and CB

transcript levels were found to be signiﬁcantly

lower in the Fallopian tubes of patients with ectopic pregnancy

compared to non pregnant controls [147]. Furthermore, that study

examined 2 polymorphisms of the CB

gene and found a possible

association between the 1359G/A polymorphism and ectopic preg-

nancy. The small numbers involved make a deﬁnitive association

difﬁcult, but if larger studies support a possible genetic predisposition

to ectopic pregnancy due to CB

dysfunction, then genetic screening of

women could lead to the identiﬁcation or directed therapies for

women at risk of this life-threatening condition [147].

5. Endocannabinoids and implantation

It is now acknowledged that the endocannabinoid system is

critical in the process of implantation [66,79,110,139,147–154].

Successful implantation depends on an accurate interaction between

the endometrium and the implanting blastocyst. Firstly, it requires a

receptive uterine environment and secondly, an activated blastocyst,

capable of invasion and subsequent implantation [155–157].

Implantation occurs about six to seven days after fertilization and

in order for the process to begin, the blastocyst needs to emerge from

the zona pellucida (‘blastocyst hatching’) thereby exposing a

trophoblast capable of invasion [152,155], followed by apposition

with the endometrium, adhesion and ﬁnally, trophoblast invasion

[155]. Animal studies have established that AEA regulates the

‘window’during which the uterus is receptive [29,79,139,157].As

the blastocyst enters the uterus, it is differentially affected by local

physiological AEA concentrations. At low concentrations, AEA acti-

vates ERK signalling in dormant mouse blastocysts, whereas high

levels of AEA inhibit calcium mobilisation [141]. Furthermore, low

AEA levels promote blastocyst growth. Studies by Paria et al.have

shown that trophoblasts exposed to low levels of endocannabinoids

show accelerated growth and differentiation as well as increased rates

of zona hatching [137,158,159]. These effects are mediated via CB

receptors. Trophoblasts also expresses CB

receptors whose function

in this tissue is currently unknown [158,160]. At the same time, lower

AEA levels and elevated levels of FAAH occur in the uterus at

implantation sites [159] when compared to the inter-implantation

sites, which have much higher levels of AEA and lower levels of FAAH.

There is indirect evidence that during apposition, the mouse

blastocyst produces an unidentiﬁed lipid [161] that induces the

changes in FAAH and NAPE-PLD enzyme expression conducive for

attachment and initial invasion and thus the changes in localized AEA

concentrations at the implantation site [157,162]. Evidence that local

AEA concentrations are critical to implantation comes from studies

demonstrating that embryos exposed to high levels of AEA in the

uterus suffer embryotoxicity, reduced trophoblast proliferation and

implantation failure [158,160,162].

Similarly, women in an in vitro fertilization programme who have

successful implantation, have low serum AEA levels associated with

elevated levels of FAAH in their peripheral lymphocytes at 6 weeks

gestation [163,164]. The process is likely being controlled by the

expression and activity of lymphocytic FAAH. Indeed, it has been

suggested that the decreased activity and expression of FAAH in

peripheral lymphocytes could be used as an early marker for ﬁrst

trimester miscarriage [164]. These data are mirrored by the studies of

Trabucco et al.who showed that placental tissue from women

following spontaneous miscarriage had very low levels of FAAH and

increased expression of the CB

receptor [151]. These ﬁndings are

corroborated by observations that higher plasma AEA levels in women

with threatened miscarriage are associated with a subsequent

spontaneous miscarriage [165].

Plasma AEA levels ﬂuctuate during the menstrual cycle

[23,24,144,145]. Recently our group showed that plasma AEA levels

declined during the implantation window in women with a successful

pregnancy after IVF treatment and in women with normal menstrual

cycles [66,144,145]. During this period, FAAH has been shown to have

the highest activity, whereas there is no change in CB

binding, or

AMT and NAPE-PLD activity [145]. Interestingly, FAAH and proges-

terone show the same ﬂuctuations during the menstrual cycle [145].

This is conﬁrmed by the ﬁnding that progesterone up-regulates the

FAAH gene [166,167], but contradicted by the ﬁnding that serum

progesterone was not correlated with plasma AEA levels during the

menstrual cycle or in women with positive implantation in an IVF

treatment programme [144]. There were, however, positive correla-

tions between the levels of 17β-estradiol, FSH and LH, suggesting that

implantation could be regulated by changes in the levels of these

hormones and their inﬂuence of AEA levels in the uterus [144].

Research so far indicates that the endocannabinoid system is an

important regulator for implantation and successful pregnancy.

Endocannabinoid signalling is under tight control and any disruption

of this balance may lead to reproductive failure. The delicate

intricacies related to how endocannabinoids regulate implantation

and whether this is a direct inﬂuence or via T lymphocyte function

remains to be elucidated.

6. Endocannabinoids in early pregnancy

Although Δ

-THC is known to cross the placenta and affect human

pregnancies, it was not known if the effect was via actions on

trophoblast activity. Recently, however, we demonstrated that Δ

THC acts directly on the human BeWo cytotrophoblast cell line to

inhibit cell growth and the transcription of genes involved in growth

and apoptosis [168], via the relatively unstudied CB

receptor [169].

Indeed, using human cell line models of the 1st and 3rd trimester

trophoblast and the pregnant rat model, we have shown that in

human cells AEA inhibits cell proliferation via the CB

receptor by the

differential modulation of histone deactylase 3 (HDAC3) expres-

sion [170]. AEA at concentrations in excess of 15 μM stimulate HDAC3

expression in ﬁrst trimester trophoblast cells and inhibit HDAC3

expression in third trimester trophoblasts. These data support the

observations that Δ

-THC has differential effects on the ﬁrst and third

trimester trophoblast [171,172], and that differential CB receptor

expression in the rat placenta occurs during gestation [173]. Indeed,

treatment of rats with varying doses of AEA in excess of 10 μM induces

trophoblast cell apoptosis via the CB

receptor [173]. These data

suggest that there may be subtle differences in the actions of exo- and

endo-cannabinoids in the placenta in the human and rat and that a

complex interplay between AEA concentrations and implantation of

the blastocyst and subsequent placentation is important during early

pregnancy. Indeed, in studies of IVF-ET women, where the introduc-

tion of the embryo can precisely be timed and implantation can be

closely followed [66], plasma AEA levels initially increase, presumably

to aid blastocyst hatching and implantation, but then subsequently

fall, presumably to prevent trophoblast apoptosis and so aid retention

of the developing embryo. It therefore seems that a critical balance in

endocannabinoid levels, which has been shown to be vital to

successful pregnancy, is required for early trophoblast development

and subsequently that of the placenta.

7. Endocannabinoids in the maintenance of pregnancy and labour

The fact that the use of marijuana is associated with preterm

labour, prolonged pregnancy, fetal growth restriction, stillbirth and

placental abruption suggest that the endocannabinoid system is

involved in late pregnancy and labour. We have quantiﬁed AEA levels

during pregnancy and found that the levels are low in the ﬁrst

trimester (similar to the levels measured in the luteal phase of the

menstrual cycle) and are maintained at these low levels until the

beginning of the 3rd trimester when they start to rise. They then rise

by almost 2- to 4-fold with the onset of labour (Table 1;[23,24,174]).

925A.H. Taylor et al. / Clinica Chimica Acta 411 (2010) 921–930

Author's personal copy

In the rat, CB1, CB

and TRPV1 expression ﬂuctuates in the decidua

in a predictable pattern from a high level on days 10–12 of pregnancy

to a lower level towards the end of pregnancy [173]. Simultaneously,

plasma AEA levels are not signiﬁcantly altered, but local tissue levels

of AEA and PEA, but not OEA are increased at two points through

pregnancy; on day 10, when the placenta and decidua regress to make

room for the developing embryo and on day 19 when the activation of

the myometrium is initiated in preparation for parturition on day 21

[175]. These observations suggest that local production of endocan-

nabinoids may be associated with the apoptosis-induced regression of

the decidua in the rat and the preparation of parturition events. These

rodent data together with the aforementioned increase of plasma AEA

levels indicated in the 3rd trimester of pregnancy suggest that plasma

AEA levels could be elevated in women with incipient preterm labour,

preterm premature rupture of membranes or cervical insufﬁciency,

obstetrical problems that are almost impossible to predict. Data

emerging from our laboratory support this suggestion, as women at

high risk of preterm birth, or presenting with abdominal pain

consistent with the Braxton Hicks myometrial contractions indicative

of impending preterm labour, that subsequently went on to deliver

preterm have higher levels of plasma AEA than those that continue to

term [174]. Indeed, those who delivered quicker (less than 6 days)

have even higher plasma AEA levels than those that took longer to

deliver but still delivered prematurely. These data are consistent with

studies performed in the CB

knockout mouse, in which delivery

occurs preterm (i.e. 1 day early) and could be prevented by changing

cortisol and progesterone levels, suggesting that the entire endocan-

nabinoid system, (i.e. not only endocannabinoid levels), is involved in

the timing of parturition [176]. The alternative observation that other

endocannabinoids are present in the uterus at this important time

during pregnancy, and the apparent increase in plasma AEA levels in

women in labour, even if they had been induced [177], suggest that

the ‘entourage effect’is in action and that FAAH activity is maximised

at this point and that FAAH is dealing with the other endocannabi-

noids that exist at higher levels than AEA [19–21,28]. This might

explain the apparent discrepancy between increasing lymphocyte

numbers during the latter stages of pregnancy [178] and the increased

levels of plasma AEA during labour. The obvious extension of these

observations is that CB

receptor mutations [147] and CB

signalling

or FAAH mutations or activities may be important in the timing of

birth and hence an important area of study for perinatologists. In our

opinion, this understudied area of endocannabinoid research needs

urgent investigation.

It is not clear what elevated plasma AEA levels mean in relation to

parturition. Three main tissue-speciﬁc events occur during the

parturition process; myometrial activation, cervical ripening and

fetal membrane rupture. The actions of endocannabinoids in

myometrial activation, cervical ripening and fetal membrane are

unclear due to the paucity of data. Studies on oxytocin-stimulated

myometrial muscle strips demonstrated a relaxant effect of both Δ

THC and AEA through CB

[179]. Recently, we demonstrated that AEA

increased the production of phosphorylated ERK in primary human

myometrial cells and a human myometrial cell line, without changes

in intracellular calcium levels [180]. Such changes in the myometrial

cell should result in myometrial relaxation as was suggested by

Dennedy and colleagues [179]. The data suggest that the myometrium

is a possible endocannabinoid target during the latter stages of

pregnancy. The fetal membranes and placenta at term are also obvious

targets as these tissues express the cannabinoid receptors [181] and

contain signiﬁcant amounts of AEA (Table 1).

8. Feto-placental changes in endocannabinoid levels

Levels of FAAH in both the human placenta and the maternal

circulation increase towards the end of the ﬁrst trimester of

pregnancy, before declining by the early second trimester [163,182].

Furthermore, high levels of FAAH have been observed in the villous

cytotrophoblast [183]. Its expression in the syncytiotrophoblast

suggest that FAAH in these cells help prevent the transfer of AEA

from maternal blood [182], which, to some degree, has been

suggested as a protective mechanism for the developing fetus [182].

Previous studies have suggested that circulating FAAH and AEA levels

may be critical to the outcome of early pregnancy [163,164]. As stated

earlier, decreased expression and activity of FAAH in peripheral blood

lymphocytes maybe an early marker of spontaneous miscarriage

[163]. The importance of FAAH in early placental development has

been supported by a recent study that demonstrated the expression of

FAAH and CB

(rather than CB

) receptors in the human ﬁrst trimester

placenta. This study also provided evidence that the endocannabinoid

regulation within placental tissue is independent of the maternal

immune system [182]. We recently demonstrated the presence of

both CB

and CB

receptors and FAAH immunoreactive protein in ﬁrst

trimester trophoblast which was supported by the presence of

transcripts for these genes in the tissue [183]. The apparent

discrepancy between these two studies could be related to the

antibodies used, as has been documented [184]. Nevertheless,

cannabinoid receptors are expressed by placental tissue from the

early ﬁrst trimester right through to term [181–183]. Interestingly,

levels of AEA fall progressively during pregnancy [23,24], supporting

other evidence that low systemic levels are required for normal

pregnancy progression [163]. Therefore, exposure to the exocanna-

binoid Δ

-THC could lead to inappropriate activation of the CB

mediated pathways in the placental trophoblast.

9. Possible “immunocannabinoid”system actions in pregnancy

Although the involvement of the endocannabinoid system in

reproduction may be direct, it may also be through modulation of the

immune system. Despite a great interest in the role of cannabinoids

within the immune system [57,185–189], the possible relationship

between endocannabinoids and immunity, especially in relation to

reproductive events, remains to be clearly determined. For successful

implantation and maintenance of pregnancy, the embryonic/fetal

allograft [190,191] has to be tolerated by the maternal immune

Table 1

Anandamide concentrations in different human biomatrices related to reproduction

and the reproductive tract.

Biomatrix/Tissue AEA (nM)

Ref

Seminal Plasma

12.1 [28]

Follicular ﬂuid Immature oocyte 0.36–1.96 [65]

Mature oocyte 0.25–2.78 [65]

Oviductal ﬂuid

10.7 [28]

Endometrium ?

Myometrium ?

Cervix ?

Vagina ?

Hypothalamus

86.3–87.6 [21]

Pituitary

Plasma (menstrual cycle) Follicular Phase 1.45–1.68 [23,24,143]

Ovulation 1.26–4.04 [143]

Luteal Phase 0.77–0.87 [23,24,143]

Plasma (pregnancy) 1st trimester 0.89–0.91 [23,24]

2nd trimester 0.44–0.91 [23,24]

3rd trimester 0.44–1.14 [23,24]

Term not in labour 0.68–1.27 [23,24]

Term in active labour 2.30–2.50 [23,24]

Placenta

0.98–4.54 [215]

Fetal Membranes

0.42–2.83 [215]

Amniotic ﬂuid 0.01–0.18 [26,215]

Umbilical artery plasma 0.32–1.53 [26,215]

Umbilical vein plasma 0.38–1.84 [26,215]

Maternal Plasma at term 0.59–1.91 [26,215]

AEA = anandamide;

in pmol/g wet weight;

only a single human study performed;

? = data unknown.

926 A.H. Taylor et al. / Clinica Chimica Acta 411 (2010) 921–930

Author's personal copy

system through mechanisms that might involve the endocannabinoid

system [169]. For example, arachidonic acid (AA), a local immuno-

modulatory molecule [192], is released from cultured mouse

macrophage cells by Δ

-THC and AEA through a CB

-dependent

mechanism and by nitric oxide (without raising AEA levels) indicating

that both CB receptor-dependent and -independent mechanisms are

involved in this possible immunomodulatory pathway [193,194].

Maccarrone et al. [195] also demonstrated that bacterial lipopolysac-

charide down regulates FAAH expression in human peripheral

lymphyocytes, an effect that was not inﬂuence by AEA-induced

activation of the cannabinoid receptors, whilst mast cells absorb AEA

in a saturable process that activates intracellular FAAH and AEA

degradation [196]. Additionally, the physiological protection of the

fetus from rejection is believed to be dependent on a type 2 T-helper

(Th2) cell immune response at the fetal–maternal interface [197]. The

initial state of pregnancy is nevertheless characterised by immuno-

suppression after an early inﬂammatory state during implantation

[198]. Indeed, the demonstration that monocytes [199] and leuko-

cyte/macrophages [200,201] numbers increase towards the end of

pregnancy suggest an inﬂammation–immunosuppression–inﬂamma-

tion phenotype during pregnancy [202]. The production of plasma

AEA mimics this inﬂammation–immunosuppression–inﬂammation

pattern during implantation, the 2nd and 3rd trimesters of pregnancy

and just before labour [23,24,66]. Such data suggest that immune cells

may take part in regulating the peripheral endocannabinoid system or

local endocannabinoid homeostasis and vice versa.

Many studies have demonstrated that, in the main, endocannabi-

noids suppress the production of inﬂammatory cytokines in innate

and adaptive immune responses both in animal models and in human

cell cultures [186,203,204]. Immunosuppression is one of the most

important steps involved in early pregnancy [205] and evidence of a

reduction in interleukin-1β, -10, and -12 levels in animal models of

inﬂammatory disease [206–208] suggests that similar reductions in

the levels of these cytokines in reproductive tissues may occur in

response to local endocannabinoid production, although this is yet to

be directly determined. However, cannabinoids have also been

demonstrated to increase the production of IL-1, -4, -6 and -10

cytokines either in the presence of bacteria [204,207,209] or alone

[210,211], suggesting that in vivo, cannabinoids may either suppress

or enhance the production of pro-inﬂammatory agents, depending on

either the nature of the pro-inﬂammatory stimulus or the type of

cannabinoid present. These changes may arise from the predominant

effect of cannabinoids on helper T-cell (Th) biasing [186,203] whereby

Th-1 cell activity is suppressed and Th-2 cell activity is increased

[208,212]. This may change the levels of leukaemia inhibitory factor,

which is known to be essential for successful invasion and migration

during placental development [213,214].

Taken together these data suggest that endocannabinoids have a

key role, not only on the cells and tissues of the fetal–maternal

interface but also on their interaction with the innate and adaptive

immune system. This under-explored area of possible interaction

between the immunocannabinoid system [187] and reproduction is

likely to be a focus of intense research in the near future.

10. Conclusions

The endocannabinoid system (ECS) is involved in various aspects

of human reproduction. It appears to be an important cog in the

complex mechanisms (wheel) of gametogenesis. With respect to

spermatogenesis, 2-AG appears to promote meiotic progression in the

germ cell by activating type-2 cannabinoid receptors [126]. Levels of

AEA also appear to be related to follicular size and quality of the ova

produced during oogenesis. This system is involved in the regulation

of fertilization through actions that result in spermatozoa activation

and thereafter inﬂuence hatching of the embryo, blastocyst matura-

tion, oviductal transport, implantation and early pregnancy mainte-

nance. Changes in plasma levels of some of the cannabinoid ligands

(e.g. anandamide) provide evidence for a tight regulation of early

pregnancy by this group of compounds. Changes in pregnancy and

labour also suggest an involvement in labour onset and maintenance.

Although this review has highlighted areas where the evidence is

coherent and strong, so many questions remain unanswered and only

through collaborative and international studies will these be

adequately addressed. Such collaboration may initially focus on the

changes of the cannabinoid receptors, FAAH, NAPE-PLD, and AEA

which have been thoroughly investigated in animals and partly in

humans, to determine the translational potential of the ECS in

establishing and maintaining a healthy pregnancy.

Conﬂicts of interest

The authors afﬁrm that there are no conﬂicts of interest.

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The Rise of High-THC Cannabis Health Implications and Mental Health Risks

Negative Results

Full-text available

Jul 2024

Certain genetic factors, like variations in the COMT and AKT1 genes, may increase an individual’s vulnerability to cannabis-induced psychosis. Cannabis is a complex plant containing over 400 chemical compounds, including key cannabinoids such as delta-9-tetrahydrocannabinol (THC) and cannabidiol (CBD), which exert opposing effects. The identification of these compounds has led to the exploration of the endocannabinoid system, a crucial neurotransmitter system widespread in the brain and body, responsible for various significant physiological functions. Recently, there has been a global increase in cannabis potency, raising health concerns. Epidemiological studies indicate a link between dose-dependent cannabis use and an elevated risk of persistent psychotic disorders. However, not all users experience adverse effects equally. The factors that contribute to individual susceptibility remain unclear, although emerging research suggests that genetics and personality traits may play a role. This article first examines the biochemical basis of cannabis and its two primary compounds, followed by a review of the factors that may explain the variability in individual responses to cannabis.

Schizophrenia and Cannabis Use How Susceptibility Genes Affect Outcomes

Method

Full-text available

Jun 2024

A small percentage of users may develop schizophrenia or bipolar disorder, while many experience transient psychotic symptoms, such as paranoia and hallucinations. Cannabis is a complex plant containing over 400 chemical compounds, including key cannabinoids such as delta-9-tetrahydrocannabinol (THC) and cannabidiol (CBD), which exert opposing effects. The identification of these compounds has led to the exploration of the endocannabinoid system, a crucial neurotransmitter system widespread in the brain and body, responsible for various significant physiological functions. Recently, there has been a global increase in cannabis potency, raising health concerns. Epidemiological studies indicate a link between dose-dependent cannabis use and an elevated risk of persistent psychotic disorders. However, not all users experience adverse effects equally. The factors that contribute to individual susceptibility remain unclear, although emerging research suggests that genetics and personality traits may play a role. This article first examines the biochemical basis of cannabis and its two primary compounds, followed by a review of the factors that may explain the variability in individual responses to cannabis.

Cannabis Use in Adolescence Links to Schizophrenia and Other Psychoses

Technical Report

Full-text available

May 2024

The increasing use of high-THC cannabis, especially among young people, has raised public health concerns about long-term mental health impacts. Cannabis is a complex plant containing over 400 chemical compounds, including key cannabinoids such as delta-9-tetrahydrocannabinol (THC) and cannabidiol (CBD), which exert opposing effects. The identification of these compounds has led to the exploration of the endocannabinoid system, a crucial neurotransmitter system widespread in the brain and body, responsible for various significant physiological functions. Recently, there has been a global increase in cannabis potency, raising health concerns. Epidemiological studies indicate a link between dose-dependent cannabis use and an elevated risk of persistent psychotic disorders. However, not all users experience adverse effects equally. The factors that contribute to individual susceptibility remain unclear, although emerging research suggests that genetics and personality traits may play a role. This article first examines the biochemical basis of cannabis and its two primary compounds, followed by a review of the factors that may explain the variability in individual responses to cannabis.

Cannabis Use and Schizophrenia Exploring the Path from Use to Illness

Research Proposal

Full-text available

Apr 2024

Identifying vulnerable individuals (e.g., those with family history or schizotypal traits) can help implement early prevention and treatment strategies to mitigate the effects of cannabis on mental health. Cannabis is a complex plant containing over 400 chemical compounds, including key cannabinoids such as delta-9-tetrahydrocannabinol (THC) and cannabidiol (CBD), which exert opposing effects. The identification of these compounds has led to the exploration of the endocannabinoid system, a crucial neurotransmitter system widespread in the brain and body, responsible for various significant physiological functions. Recently, there has been a global increase in cannabis potency, raising health concerns. Epidemiological studies indicate a link between dose-dependent cannabis use and an elevated risk of persistent psychotic disorders. However, not all users experience adverse effects equally. The factors that contribute to individual susceptibility remain unclear, although emerging research suggests that genetics and personality traits may play a role. This article first examines the biochemical basis of cannabis and its two primary compounds, followed by a review of the factors that may explain the variability in individual responses to cannabis.

Cannabis and Mental Health Identifying At-Risk Populations for Psychotic Disorders

Presentation

Full-text available

Feb 2024

Not everyone who uses cannabis develops mental health problems. Some may only experience short-term effects like anxiety or paranoia, while others may develop long-term disorders. Cannabis is a complex plant containing over 400 chemical compounds, including key cannabinoids such as delta-9-tetrahydrocannabinol (THC) and cannabidiol (CBD), which exert opposing effects. The identification of these compounds has led to the exploration of the endocannabinoid system, a crucial neurotransmitter system widespread in the brain and body, responsible for various significant physiological functions. Recently, there has been a global increase in cannabis potency, raising health concerns. Epidemiological studies indicate a link between dose-dependent cannabis use and an elevated risk of persistent psychotic disorders. However, not all users experience adverse effects equally. The factors that contribute to individual susceptibility remain unclear, although emerging research suggests that genetics and personality traits may play a role. This article first examines the biochemical basis of cannabis and its two primary compounds, followed by a review of the factors that may explain the variability in individual responses to cannabis.

Understanding Cannabis-Induced Psychosis Risk Factors and Preventive Strategies

Preprint

Full-text available

Jan 2024

The endocannabinoid system, involved in regulating mood, cognition, and perception, interacts with other neurotransmitters like dopamine, GABA, and glutamate—systems that play a role in psychotic illnesses like schizophrenia. Cannabis is a complex plant containing over 400 chemical compounds, including key cannabinoids such as delta-9-tetrahydrocannabinol (THC) and cannabidiol (CBD), which exert opposing effects. The identification of these compounds has led to the exploration of the endocannabinoid system, a crucial neurotransmitter system widespread in the brain and body, responsible for various significant physiological functions. Recently, there has been a global increase in cannabis potency, raising health concerns. Epidemiological studies indicate a link between dose-dependent cannabis use and an elevated risk of persistent psychotic disorders. However, not all users experience adverse effects equally. The factors that contribute to individual susceptibility remain unclear, although emerging research suggests that genetics and personality traits may play a role. This article first examines the biochemical basis of cannabis and its two primary compounds, followed by a review of the factors that may explain the variability in individual responses to cannabis.

Endocannabinoids, Dopamine, and Psychosis Unraveling the Connection

Chapter

Full-text available

Aug 2024

Cannabis is a complex plant containing over 400 chemical compounds, including key cannabinoids such as delta-9-tetrahydrocannabinol (THC) and cannabidiol (CBD), which exert opposing effects. The identification of these compounds has led to the exploration of the endocannabinoid system, a crucial neurotransmitter system widespread in the brain and body, responsible for various significant physiological functions. Recently, there has been a global increase in cannabis potency, raising health concerns. Epidemiological studies indicate a link between dose-dependent cannabis use and an elevated risk of persistent psychotic disorders. However, not all users experience adverse effects equally. The factors that contribute to individual susceptibility remain unclear, although emerging research suggests that genetics and personality traits may play a role. This article first examines the biochemical basis of cannabis and its two primary compounds, followed by a review of the factors that may explain the variability in individual responses to cannabis.

Endocannabinoid System and Psychosis A Neurochemical Overview

Book

Full-text available

Jul 2024

Over the past 15 years, street cannabis strains with higher THC content have become more common, especially variants like “skunk” or “sinsemilla.” Cannabis is a complex plant containing over 400 chemical compounds, including key cannabinoids such as delta-9-tetrahydrocannabinol (THC) and cannabidiol (CBD), which exert opposing effects. The identification of these compounds has led to the exploration of the endocannabinoid system, a crucial neurotransmitter system widespread in the brain and body, responsible for various significant physiological functions. Recently, there has been a global increase in cannabis potency, raising health concerns. Epidemiological studies indicate a link between dose-dependent cannabis use and an elevated risk of persistent psychotic disorders. However, not all users experience adverse effects equally. The factors that contribute to individual susceptibility remain unclear, although emerging research suggests that genetics and personality traits may play a role. This article first examines the biochemical basis of cannabis and its two primary compounds, followed by a review of the factors that may explain the variability in individual responses to cannabis.

Psychotic Reactions to Cannabis Schizotypal Personality and Mental Health Outcomes

Experiment Findings

Full-text available

May 2024

The risk of psychosis increases in a dose-dependent manner—the more cannabis someone uses, the higher their risk of psychosis. Cannabis is a complex plant containing over 400 chemical compounds, including key cannabinoids such as delta-9-tetrahydrocannabinol (THC) and cannabidiol (CBD), which exert opposing effects. The identification of these compounds has led to the exploration of the endocannabinoid system, a crucial neurotransmitter system widespread in the brain and body, responsible for various significant physiological functions. Recently, there has been a global increase in cannabis potency, raising health concerns. Epidemiological studies indicate a link between dose-dependent cannabis use and an elevated risk of persistent psychotic disorders. However, not all users experience adverse effects equally. The factors that contribute to individual susceptibility remain unclear, although emerging research suggests that genetics and personality traits may play a role. This article first examines the biochemical basis of cannabis and its two primary compounds, followed by a review of the factors that may explain the variability in individual responses to cannabis.

From THC to Psychosis Neurotransmitters and the Endocannabinoid System's Role

Conference Paper

Full-text available

Feb 2024

High-THC cannabis use is linked to increased risks of mental health problems, particularly in vulnerable individuals. Cannabis is a complex plant containing over 400 chemical compounds, including key cannabinoids such as delta-9-tetrahydrocannabinol (THC) and cannabidiol (CBD), which exert opposing effects. The identification of these compounds has led to the exploration of the endocannabinoid system, a crucial neurotransmitter system widespread in the brain and body, responsible for various significant physiological functions. Recently, there has been a global increase in cannabis potency, raising health concerns. Epidemiological studies indicate a link between dose-dependent cannabis use and an elevated risk of persistent psychotic disorders. However, not all users experience adverse effects equally. The factors that contribute to individual susceptibility remain unclear, although emerging research suggests that genetics and personality traits may play a role. This article first examines the biochemical basis of cannabis and its two primary compounds, followed by a review of the factors that may explain the variability in individual responses to cannabis.

Pharmacology of Cannabinoid Receptor Ligands

Article

Aug 1999

Roger G Pertwee

Mammalian tissues contain at least two types of cannabinoid receptor, CB₁ and CB₂ , both coupled to G proteins. CB₁ receptors are expressed mainly by neurones of the central and peripheral nervous system whereas CB₂ receptors occur in certain non-neuronal tissues, particularly in immune cells. The existence of endogenous ligands for cannabinoid receptors has also been demonstrated. The discovery of this 'endogenous cannabinoid system' has been paralleled by a renewed interest in possible therapeutic applications of cannabinoids, for example in the management of pain and in the suppression of muscle spasticity/spasm associated with multiple sclerosis or spinal cord injury. It has also prompted the development of a range of novel cannabinoid receptor ligands, including several that show marked selectivity for CB₁ or CB₂ receptors. This review summarizes current knowledge about the in vitro pharmacological properties of important CB₁ and CB₂ receptor ligands. Particular attention is paid to the binding properties of these ligands, to the efficacies of cannabinoid receptor agonists, as determined using cyclic AMP or [³⁵S]GTPγS binding assays, and to selected examples of how these pharmacological properties can be influenced by chemical structure. The in vitro pharmacological properties of ligands that can potently and selectively oppose the actions of CB₁ or CB₂ receptor agonists are also described. When administered by themselves, some of these ligands produce effects in certain tissue preparations that are opposite in direction to those produced by cannabinoid receptor agonists and the possibility that the ligands producing such 'inverse cannabimimetic effects' are inverse agonists rather than pure antagonists is discussed.

Effects of Maternal Marijuana and Cocaine Use on Fetal Growth

Article

Oct 1989
Obstet Anesth Digest

EFFECT OF MARIJUANA USE IN PREGNANCY ON FETAL GROWTH

Article

Dec 1986
AM J EPIDEMIOL

In a prospective study of 3,857 pregnancies ending in singleton live births at Yale-New Haven Hospital, New Haven, Connecticut, in 1980–1982,9.5% of mothers reported using marijuana (4.1% occasionally and 5.4% at least 2–3 times monthly). Among whtte women, regular use was associated with an increased risk of delivering a low birth weight (<2,500 gm) infant (odds ratio (OR) = 2.6, 95% confidence interval (CI) = 1.1–6.2) and small for gestational age infant (OR = 2.3, 95% CI = 1.3–4.1) after adjustment for other risk factors. Nonwhite marijuana users were not at further increased risk for delivering a low birth weight or small for gestational age infant beyond the elevated rates of these conditions already experienced by nonwhites in general. Marijuana use was also related to preterm delivery (gestational age <37 weeks from last menstrual period) in white women (OR = 1.9, 95% CI = 1.0–3.9) but not nonwhtte women. Occasional use was unrelated to the risk of low birth weight, small for gestational age, or preterm delivery.

Effect of Tetrahydrocannabinol on the Hypothalamic-Pituitary Axis in the Ovariectomized Rhesus Monkey**Supported by National Institute on Drug Abuse Grant 1-R01-DA1346-02.

Article

Mar 1979
FERTIL STERIL

Single doses of ∆ 9 -tetrahydrocannabinol (THC) (5.0, 2.5, 1.25, or 0.625 mg/kg) can decrease the levels of both luteinizing hormone (LH) and follicle-stimulating hormone (FSH) in the ovariectomized rhesus monkey. The inhibition of gonadotropins (50% to 88%) lasts for 6 to 24 hours depending upon the dose of THC. There are no great differences in the responses of the two gonadotropins to THC. The inhibition of gonadotropin levels by THC appears to be at the level of the hypothalamus, since both LH and FSH are released from the pituitary gland in response to LH-releasing factor in the presence of THC.

Islet G protein-coupled receptors as potential targets for treatment of type 2 diabetes (vol 8, pg 369, 2009)

Article

Aug 2009

Bo Ahren

Islet G protein-coupled receptors as potential targets for treatment of type 2 diabetes

Article

Jan 2009

B. Ahrén

Morphological changes of spermatozoa during marihuana induced depression of human spermatogenesis

Article

Jan 1978

Langman's Medical Embryology

Article

Jan 1995

Effect of tetrahydrocannabinol on the hypothalamic pituitary axis in the ovarectimised rhesus monkey

Article

Jan 1979
FERTIL STERIL

Platelet and Leukocyte Counts in Pregnancy

Article

Dec 1979
J Am Med Assoc

Roy M. Pitkin

Platelets and leukocytes in venous blood were counted with automated methodology in 23 women studied longitudinally throughout pregnancy and at six weeks after delivery. The average platelet count declined monotonically in a manner consistent with the gestational increase in blood volume. Total leukocyte count rose early in gestation and remained elevated, with neutrophils accounting for the changes. Absolute neutrophil counts during gestation were nearly twice those of the same women postpartum (5.76 vs 3.13çu mm ×10-3.) The monocyte count also tended to increase, whereas lymphocytes, eosinophils, and basophils declined in number. (JAMA 242:2696-2698, 1979)