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Review

Q1 Maternal Cannabis Use during Lactation and Potential Effects on

Q13 Human Milk Composition and Production: A Narrative Review

Q12 Irma Castro-Navarro 1,*

, Mark A McGuire 2

, Janet E Williams 2

, Elizabeth A Holdsworth 3

,

Courtney L Meehan 4

, Michelle K McGuire 1

1 Q2 University of Idaho, Margaret Ritchie School of Family and Consumer Sciences, Moscow, ID, United States; 2 Department of Animal, Veterinary,

and Food Sciences, University of Idaho, Moscow, ID, United States; 3 Department of Anthropology, the Ohio State University, Columbus, OH, United

States; 4 Department of Anthropology, Washington State University, Pullman, WA, United States

ABSTRACT

Cannabis use has increased sharply in the last 20 y among adults, including reproductive-aged women. Its recent widespread legalization is

associated with a decrease in risk perception of cannabis use during breastfeeding. However, the effect of cannabis use (if any) on milk

production and milk composition is not known. This narrative review summarizes current knowledge related to maternal cannabis use

during breastfeeding and provides an overview of possible pathways whereby cannabis might affect milk composition and production.

Several studies have demonstrated that cannabinoids and their metabolites are detectable in human milk produced by mothers who use

cannabis. Due to their physicochemical properties, cannabinoids are stored in adipose tissue, can easily reach the mammary gland, and can

be secreted in milk. Moreover, cannabinoid receptors are present in adipocytes and mammary epithelial cells. The activation of these re- ceptors directly modulates fatty acid metabolism, potentially causing changes in milk fatty acid profiles. Additionally, the endocannabinoid

system is intimately connected to the endocrine system. As such, it is probable that interactions of exogenous cannabinoids with the

endocannabinoid system might modify release of critical hormones (e.g., prolactin and dopamine) that regulate milk production and

secretion. Nonetheless, few studies have investigated effects of cannabis use (including on milk production and composition) in lactating

women. Additional research utilizing robust methodologies are needed to elucidate whether and how cannabis use affects human milk

production and composition.

Keywords: cannabis, breastfeeding, breastmilk, milk composition, cannabinoids, cannabinoid receptors, human milk, lactation, peroxisome

proliferator-activated receptors, prolactin

Statement of Significance

To our knowledge, no review has focused on the potential effects of maternal cannabis use on human milk composition and production. The

evidence provided here supports the possibility that, through several well documented pathways, cannabinoids might alter lipid metabolism in

the mammary gland, as well as milk production and secretion. Considering the recent increase in cannabis use among reproductive-aged women,

this narrative review highlights the need for well-designed, focused studies to address this question.

Abbreviations: 11-OH-THC, 11-hydroxy-tetrahydrocannabinol; AEA, N-arachidonoylethanolamide or anandamide; CBD, cannabidiol; CB1R, cannabinoid type 1

receptor; CB2R, cannabinoid type 2 receptor; CLA, conjugated linoleic acid; ECS, endocannabinoid system; FABP, fatty acid-binding protein; GH, growth hormone;

GPR, G protein-coupled receptor; MEC, mammary epithelial cell; NSDUH, National Survey on Drug Use and Health; PPAR, peroxisome proliferator-activated receptor;

PRL, prolactin; THC, Δ-9-tetrahydrocannabinol; THC-COOH, carboxy-tetrahydrocannabinol.

* Corresponding author. E-mail address: irma@uidaho.edu (I. Castro-Navarro).

journal homepage: https://advances.nutrition.org/

https://doi.org/10.1016/j.advnut.2024.100196

Received 18 December 2023; Received in revised form 20 February 2024; Accepted 22 February 2024; Available online xxxx

2161-8313/© 2024 The Author(s). Published by Elsevier Inc. on behalf of American Society for Nutrition. This is an open access article under the CC BY license

(http://creativecommons.org/licenses/by/4.0/).

Advances in Nutrition xxx (xxxx) xxx

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Methods

The research to write this narrative review was initially

performed using PubMed and Google Scholar databases. The

preliminary search included the terms “cannabis,” “marijuana,”

“lactation,” “human milk,” and “breastfeeding.” Additional

searches were conducted by looking for specific concepts

addressed in each section. Articles cited in the papers obtained

during the searches were also included. No restriction on the

time of publication was established.

Overall Trends in Cannabis Use

Cannabis (Cannabis sativa, Cannabis indica, and Cannabis

ruderalis; often referred to collectively as marijuana) is one of the

world’s most commonly used drugs, with >200 million people

using it in 2020 [1]. Cannabis use is increasingly legalized in

many regions around the globe, including numerous states in

United States. California became the first state in the United

States to allow medical use of cannabis in 1996. As of 2023, 21

states, 3 territories, and the District of Columbia have legalized

recreational cannabis use, and an additional 16 states have

regulated cannabis for medical use [2]. The use of this plant and

its derivatives among adults has spread in conjunction with its

legalization. In 2002, the Substance Abuse and Mental Health

Services Administration reported that 6.2% of the population in

United States used cannabis in the previous year [3]. Cannabis

use in the United States has nearly tripled since that time and was

reported to be 18.7% in 2021 with the greatest prevalence

(35.4%) among young adults aged 18– 25 y [3].

Not only has the prevalence of cannabis use increased, but

variation in cannabis products offered and the potency of those

products is greater than ever. Historically, smoking dried

cannabis flowers containing Δ-9-tetrahydrocannabinol (THC),

the major psychoactive cannabinoid, was the most common

method and product used. However, a notable variety of

cannabis products, developed from processed raw cannabis, are

now available (Table 1) [4–10], providing a wide diversity of

modes of use [11]. Data from Washington State’s cannabis

traceability system named Cannabis Central Reporting System

(https://lcb.wa.gov/ccrs) shows that, although cannabis flower

was still the most purchased product between 2014 and 2016

(accounting for two-thirds of expenditures), cannabis extracts

sales increased 145% in that period [6].

Potency of cannabis products, typically quantified as per- centage of THC per weight of product, has also increased in

recent decades. Several studies analyzing THC content in mari- juana dry flower in the United States reported an increased po- tency of >10% in the last decade [6,12–14]. This increase in THC

content may be a response to the rising demand for high-dose

THC products [14,15]. For example, the sale of high-dose THC

(>20% THC per weight) flower strains grew 50% between 2014

and 2016 in Washington State. An increase was also observed for

the sale of cannabis extracts, for which average THC potency is

triple that of products made from the cannabis flower [6]

(Table 1).

Cannabis Use by Reproductive-Aged Women

Although cannabis use is more prevalent among men than

women, this gender gap is narrowing; 42% of people who use

cannabis in North America are women, which is the highest

proportion worldwide [1]. This relatively high-usage rate among

North American women includes their reproductive years and

during pregnancy and lactation [16,17]. The National Survey on

Drug Use and Health (NSDUH) from 2002 through 2014

included surveys from of 200,510 women, 18–44 y of age. The

population was described as 61% White, 17.2% Hispanic, 13.7%

Black, and 8% other race/ethnicity; 59% had some college ed- ucation; and 55.9% had annual family incomes <$50,000.

Among the 10,587 pregnant women included in this survey,

prevalence of past-month use of cannabis increased 62.4% be- tween 2002 and 2014, although the frequency of use within this

population was low (<4%) [17]. Data collected in the NSDUH

also indicated that use rates during pregnancy increased sub- stantially from 3.4% to 7.0% between 2002 and 2017, with the

highest prevalence of daily marijuana use reported during the

first trimester [18]. The 2017 annual Pregnancy Risk Assessment

Monitoring System recorded information about the prevalence of

cannabis use during the postpartum period in 7 states (Alaska,

TABLE 1

Summary of cannabis products, routes, and modes of use; average Δ-9-tetrahydrocannabinol concentrations; and average amount of Δ-9-tetra- hydrocannabinol (mg) in a unit or package

Cannabis product1 Route of administration Mode of use THC concentration (THC % per weight of product)

or total THC in product (mg/unit or mg/package)

Flowers (i.e., bud, dried herb) Inhaled (smoked) Cigarettes, joints, blunts, pipes, bongs 22% [4]; 14%–18% [5]; 21% [6]; 20% [7]

Hash, resin, kief Inhaled (smoked) Cigarettes, joints, blunts, pipes, bongs 44%, 71%, and 34%, respectively [4];

hash/kief 41% [7]

Liquid concentrates

(oil, tinctures), dried herb

Inhaled (vaped) Cartridges, vape pens 59%–74% [4]; 69% [6]; 68% [7]

Solid or semisolid concentrates

(shatter, wax)

Inhaled

(flash vaporized)

Dabs, slang 75% [4]; 73% [7]

Concentrates infused Oral Edibles (candy, baked goods,

sublingual sprays, drinks, capsules)

2–8 mg/unit [4]; 0.01–99.1 mg/unit [8];

capsules 5–90 mg/unit; baked goods

8.4–50.6 mg/unit [9]; median through

products 1⁄4 10–25 mg/unit [10]

Concentrates infused Transdermal Lotions, balms, gels, patch 69 mg/unit [4]; 5 mg/unit [10]

Concentrates infused Rectal or vaginal Suppositories 240 mg/package [10]

1 Most popular cannabis products used by route/mode of administration; cannabis products can be adapted for use through different modes.

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Illinois, Maine, New Mexico, New York, Pennsylvania, and West

Virginia). They reported that overall prevalence of marijuana use

among 4604 postpartum participants was 5.5%, with 4.1% of

breastfeeding women reporting current use [19].

In contrast to overall usage trends, which are on the upswing,

the perception of the dangers of cannabis use among women of

reproductive age has declined [16,20–22]. In fact, cannabis

products are occasionally viewed as representing a less harmful,

more effective substance compared with over-the-counter and

prescription medications [23,24]. Indeed, cannabis and

cannabis-based products (containing THC) are often used

[24–26]—and some dispensaries are advising them—for treat- ment of pregnancy-related morning sickness [27]. During

breastfeeding, the main reasons reported by women for using

cannabis include the treatment of health problems such as anx- iety, depression, gastrointestinal problems (e.g., loss of appetite

and nausea), chronic pain, and posttraumatic stress disorder [28,

29].

Although very little is known about the potential effect of

maternal cannabis use during pregnancy and lactation on the

infant, THC has been detected in meconium of infants of mothers

who use cannabis [30–32] and in human milk [33–38], clearly

indicating that the infant can be exposed to this and other

compounds found in cannabis or metabolites thereof. Multiple

studies in the last decade have associated prenatal cannabis

exposure to negative newborn outcomes, such as low birth- weight, preterm birth, or higher neonatal intensive care unit

admission rates [32,39–43]. Longitudinal cohort studies have

also associated prenatal cannabis exposure with poorer perfor- mances in verbal activities, short-term memory, or attention in

infants and young adults [44–46]. However, inconsistent results

have been observed in academic achievement, and it has been

suggested that maternal/infant socioeconomic status might be

mediating some of the relationships reported with poorer per- formance [47,48]. Nonetheless, research will need to be con- ducted to rigorously evaluate different forms of cannabis use

(smoking, vaping, or ingesting) and to control for the amount of

cannabis used to elucidate if there is a dose–response effect of

prenatal cannabis exposure on infant outcomes.

There are even fewer studies evaluating the potential effects

of maternal cannabis use on the infant during breastfeeding, and

these studies have substantial limitations in that they include

low numbers of participants and the co-use of alcohol, tobacco,

and other drugs [49]. The scientific literature regarding the po- tential risks and benefits of cannabis use during breastfeeding is

extremely limited and does not provide clear guidance [50]. Due

to the limited evidence of effects of perinatal cannabis use, it is

unclear whether the benefits of breastfeeding outweigh the po- tential risks of exposure to THC or its metabolites via breast milk.

Organizations, such as the American Academy of Pediatrics,

American College of Obstetricians and Gynecologists, the Acad- emy of Breastfeeding Medicine, and the United States FDA

recommend reduction or cessation of cannabis use by pregnant

and breastfeeding women [49,51–53]. Nonetheless, it is clear

with the increasing cannabis use trends that these organizations’

recommendations are not being followed. Furthermore, these

recommendations are generally based on lack of evidence and

extreme caution (precautionary principle) rather than scientific

evidence of harm.

Pharmacokinetics of Cannabinoids and Their

Incorporation into Human Milk

Cannabinoids are grouped into 1 of 3 categories depending on

their origin. They are referred to as phytocannabinoids if derived

from the plant Cannabis sativa, endocannabinoids if produced in

the human body, and synthetic cannabinoids if they are manu- factured as “designer drugs” that bind to the cannabinoid re- ceptors. To date, 125 cannabinoids have been isolated from the

Cannabis sativa plant [54], among which THC and cannabidiol

(CBD) are the most abundant and well-studied. THC is the

compound in cannabis that produces many of its psychoactive

effects, whereas CBD is a nonpsychoactive cannabinoid reported

to have medicinal (e.g., analgesic, antispasmodic, and

anti-inflammatory) properties [55,56].

The timing of cannabinoid appearance in the circulatory

system after cannabis use varies widely and depends on the route

of administration. Peak plasma THC concentration is achieved

faster (within 3–10 min), and maximum concentrations in

plasma are higher when the cannabis is inhaled compared with

when it is ingested [56,57]. The amount of cannabinoids that can

reach the circulatory system after inhalation ranges from 10% to

50% of the total present in the product used, although there is

high interindividual variability related to depth of inhalation,

puff duration, and length of breath hold [58,59]. When cannabis

products are ingested, the appearance of THC in blood is slower,

typically resulting in maximal circulating concentrations after 1

h [9].

Approximately 90% of the THC in blood is partitioned into

the plasma compartment, where it is almost entirely found

bound to low-density lipoproteins [58]. Once in the blood,

cannabinoids rapidly redistribute into well-vascularized organs

and, due to their lipophilic nature, can easily be distributed to

adipose tissue (Figure 1). Indeed, adipose tissue may be the

major long-term accumulation depot, where fatty acid conju- gates of THC and 11-hydroxy-tetrahydrocannabinol

(11-OH-THC) may be formed, increasing their stability and

reaching adipose-to-plasma ratios of up to 104:1 [58,59].

Therefore, it is highly likely that the amount and distribution of

stored cannabinoids is affected by body composition [56], but

results from the few studies that have investigated this have not

been conclusive, as described below.

Ewell et al. [60] explored the potential association between

body composition and pharmacokinetics of circulating THC after

consumption of different edible marijuana products and found

that none of the body composition characteristics (including age,

height, bone mineral content, BMI, fat percentage and fat, and

lean and total mass) were consistently related to pharmacoki- netic parameters for any product. Wong et al. [61] assessed the

potential effect of exercise on plasma concentrations of THC in

people who regularly use cannabis and detected a positive cor- relation between BMI (generally used as an indirect indicator of

adiposity) and exercise-induced increased concentration of

plasma THC. Whereas higher BMI might represent greater adi- pose tissue mass (which could therefore store greater amounts of

lipophilic cannabinoids), high BMI can also reflect greater

muscle mass. Therefore, more studies are needed to describe

how body composition, as assessed by more sophisticated

methods such as dual x-ray absorptiometry, might influence

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cannabinoid pharmacokinetics and whether these relationships

are similar across the lifespan. Indeed, pregnancy and lactation

are stages of particular interest to this concern. The significant

changes in body fat mass that occur during pregnancy and

lactation may have different effects on THC circulation than

static body fat mass.

In addition to their high lipid-solubility, cannabinoids have a

small molecular weight (314.46 g/mol), allowing them to

transfer into and become concentrated within lipid-rich tissues,

such as the breast [34] (Figure 1). Indeed, several studies

[33–38,62,63] have demonstrated the presence of phytocanna- binoids and their metabolites in human milk (Table 2). Relative

incorporation of cannabinoids into milk appears to be different

depending on time postpartum. During the first days of lactation,

milk-producing mammary epithelial cells (MECs, sometimes

referred to as lactocytes) are small, and the spaces between them

are wide. These wide intercellular gaps allow leukocytes, Ig,

proteins, and drugs (including cannabinoids) to transfer easily

from the mother’s circulation into the milk [64]. Once the

intercellular gaps (sometimes referred to as leaky tight junctions)

are reduced in size, the transfer of drugs and other large mole- cules into the milk occurs by passive or facilitated diffusion down

their concentration gradients [65].

The passage of drugs into milk is affected by many additional

factors, such as acid–base dissociation constant (pKa) and pro- tein binding [64]. Due to its lipophilic nature and small molec- ular weight, THC transfers particularly readily into milk. A

pharmacokinetic study carried out by Baker et al. [33]

demonstrated that, after maternal cannabis inhalation, 2.5%

(range: 0.4%–8.7%) of the THC dose was secreted in the milk.

Once in milk, THC can be partially ionized because of its basic

pKa (10.6) and is therefore not able to pass back into maternal

plasma through passive diffusion even when its concentration is

greater in milk than in maternal plasma [65]. This phenomenon

leads to accumulation of THC in the milk, explaining the high

milk-to-plasma ratios (up to 8:1) reported previously [36,38].

Moreover, cannabis metabolites stored in adipose tissue may

have a slow release into the blood circulation and eventually

milk during lactation because these compounds can be detected

in milk from women who frequently use cannabis (>2 times/wk)

even after several weeks of abstention [38].

THC circulates through the body via the bloodstream, even- tually reaching the liver. Metabolism of THC includes hydrox- ylation in the liver through cytochrome P450, resulting in

11-OH-THC, which also has psychoactive effects. Plasma

concentrations of 11-OH-THC after oral ingestion are greater

than those observed in the plasma after smoking cannabis [58].

Degradation of THC by gastric secretions (e.g., hydrochloric

acid), combined with first-pass liver metabolism, reduces

bioavailability of THC to 6%–7% of the ingested dose

[58,59]. Further oxidation of 11-OH-THC produces

carboxy-tetrahydrocannabinol (THC-COOH), which is eventu- Q3

ally glucuronidated [58]. Most of the cannabinoids and their

metabolites are excreted in feces (65%–80%), with the

remainder in urine (20%–35%) [57]. The metabolites excreted

in feces—mainly in the form of nonconjugated metabolites—can

FIGURE 1. Absorption, transport, and metabolism of cannabinoids, including the most common routes of administration (inhaled and ingested) in

relation to their presence in milk. Abbreviations: 11-OH-THC, 11-hydroxy-tetrahydrocannabinol; THC-COOH, carboxy-tetrahydrocannabinol;

THC, Δ-9-tetrahydrocannabinol. Created with BioRender.com. Q11

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TABLE 2

Published research reporting concentrations of cannabinoids and their metabolites in milk produced by women who use cannabis.

Reference n Timing and

frequency of

cannabis use

Milk collection methodology Cannabinoids and

metabolites

concentrations in

milk, median (IQR) or

specified units

Time PP Excl. BF Collection

method

Collection

time

Full exp. Single/

both

breast

Perez-Reyes and

Wall, 1982 [36]

2 Subject 1: 1/d

Subject 2: 7/d

7–8 mo NR NR NR NR NR Subject 1: 105 ng/mL

THC; 11-OH-THC and

9-carboxy-THC were

not detected.

Subject 2: 340 and 4

ng/mL THC and 11-

OH-THC, respectively;

9-carboxy-THC not

detected.

Marchei et al.,

2011 [62]

1 NR NR NR NR NR NR NR 86 and 5 ng/mL THC

and 11-OH-THC,

respectively.

Baker et al., 2018

[33]

8 0.025–1 g/d

Abstained for 24 h

before using 0.1 g

of dry flower

3–5 mo Yes Pump 20 min and

1, 2, and 4

h after use

- Both Mean and maximum

(1 h after use) THC:

53.5 and 94 ng/mL,

respectively.

Bertrand et al.,

2018 [34]

50 88% of subjects

used at least daily

2/3 of

women

<1 y

NR NR NR Yes NR THC: 9.47 (IQR:

2.29–46.78) ng/mL (n

1⁄4 34)

11-OH-THC: 2.38

(IQR: 1.35–5.45) ng/

mL (n 1⁄4 5)

CBD: 4.99 (IQR:

2.92–5.97) ng/mL (n

1⁄4 5)

Moss et al., 2021

[35]

20 Used daily. Last

use <48 h before

sample collection

<2 mo NR NR 2 wk and 2

mo PP

No NR THC: 27.5 (IQR:

0.9–190.4) ng/mL (n

1⁄4 34)

11-OH-THC: 1.4 (IQR:

0.7–5.2) ng/mL (n 1⁄4

5)

THC-COOH: 1.9 (IQR:

0.5–16.6) ng/mL (n 1⁄4

18)

CBD: 1.2 (IQR:

0.5–17.0) ng/mL (n 1⁄4

13)

Sempio et al.,

2021 [37]

30 Used during

pregnancy;

frequency not

provided

NR NR NR NR NR NR THC: 8.08 (range:

0.84–130) ng/mL (n 1⁄4

30)

11-OH-THC: 1.94

(range: 1.66–2.42)

ng/mL (n 1⁄4 5)

THC-COOH: 1.30

(range: 2.05–2.98)

ng/mL (n 1⁄4 7)

Wymore et al.,

2021 [38]

25 Prenatal use >2

times/wk

1–6 wk NR NR Through

first 6 wk

PP

NR NR THC in all samples:

3.2 (IQR: 1.2, 6.8), 5.5

(IQR: 4.4, 16.0), and

1.9 (IQR: 1.1, 4.3) ng/

mL in 1, 2, and 6 wk,

respectively

Josan et al., 2022

[63]

13 Daily use during

pregnancy (n 1⁄4

12) and PP period

(n 1⁄4 8)

6–8 wk NR Pump From daily

or weekly

pumped

NR NR THC: 22 (range:

0.625–503) ng/mL (n

1⁄4 13)

11-OH-THC: 6 (range:

4–22) ng/mL (n 1⁄4 3)

THC-COOH: 2.6

(range: 1.6–5.9) ng/

mL (n 1⁄4 5)

Abbreviations: 11-OH-THC, 11-hydroxy-tetrahydrocannabinol; BF, breastfeeding; CBD, cannabidiol; excl., exclusively; exp., expression; IQR,

interquartile range; NR, not reported; PP, postpartum; THC, Δ-9-tetrahydrocannabinol; THC-COOH, carboxy-tetrahydrocannabinol.

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be detected for over a week after use [66–69]. Conversely,

metabolites in urine are mainly excreted in conjugated form,

and a single dose of THC may result in measurable metabolites

in urine for 12 d. Nevertheless, substantial differences can be

observed in the period of excretion depending on use frequency;

although cannabis cannabinoid metabolites can be detected in

urine for (on average) 8.5 d after use in people who occasionally

use cannabis, average time for excretion is 19 d in people who

frequently use cannabis [58].

Cannabinoid Receptors in Mammary Epithelial

Cells

The physiologic and psychoactive effects of cannabis use are a

result of the interaction of phytocannabinoids with the endo- cannabinoid system (ECS). This system is composed of canna- binoid receptors (detailed below), their endogenous ligands

(mainly anandamide [N-arachidonoylethanolamide [AEA]) and

2-arachidonoylglycerol) and the enzymes responsible for endo- cannabinoid synthesis, reuptake, and degradation (fatty acid

amide hydrolase and mono-acyl glycerol lipase) [70].

The main receptors in this system are G protein-coupled re- ceptors (GPRs) referred to as cannabinoid type 1 receptors

(CB1Rs) and cannabinoid type 2 receptors (CB2Rs), although

cannabinoids can also bind to GPR55, GPR18, GPR3, GPR6, and

GPR12. CB1R is particularly abundant in certain regions of the

central nervous system, such as the frontal cortex, hippocampus,

basal ganglia, and cerebellum. Decreased presence of CB1R in

the central nervous system is associated with disruption of its

many roles such as control of motor function, cognition and

memory, and analgesia [71]. Some studies also provide evidence

for presence of CB1R in peripheral tissues, such as adrenal

glands, pituitary gland, heart, lung, prostate, liver, uterus, ovary,

testis, bone marrow, thymus, and tonsils [72–74], as well as

adipose tissue, pancreas, and skeletal muscle [75]. Conversely,

CB2Rs are abundantly present in peripheral organs and cells with

immune function, including macrophages, the spleen, tonsils,

thymus, and leukocytes, as well as the lungs and testes [71].

The presence of CB1R and CB2R in MECs has been described

mostly in studies related to breast cancer, as CB2R is overex- pressed in some subtypes of mammary gland tumors [76]. Only a

limited number of studies, however, have reported the presence

(or absence) of cannabinoid receptors in MECs of healthy

women. Josan et al. [77] detected a higher expression of the

cannabinoid receptor 2 gene (CNR2) in differentiated HC11 cells

(a mouse MEC line) than in undifferentiated cells. Regarding

human cell lines, Caffarel et al. [78] evaluated expression of

CB1R and CB2R in healthy human MECs as well as in several

human breast cancer cell lines by real-time quantitative PCR and

confocal microscopy. Higher concentrations of CB1R mRNA

were detected in healthy MECs compared with cancerous breast

tissue, whereas the opposite was observed for CB2R mRNA.

Qamri et al. [79] also investigated the presence of CB1R and

CB2R in healthy human MECs and several breast cancer cell lines

using tissue microarray. Expression of both receptors was

detected in all cancer cell lines assessed as well as in healthy MEC

samples. However, they reported a higher percentage of CB1R

and CB2R staining in breast cancer cell lines (28% and 35%,

respectively) than in healthy MECs (3% and 5%, respectively).

The expression of the cannabinoid receptor genes CNR1 and

CNR2 in lactating human MECs has been proved in a limited

number of studies [80,81]. Lemay et al. [81] sequenced mRNA

found in the milk fat layer from 3 colostrum, 5 transitional, and 8

mature milk samples. CNR1 and CNR2 genes were expressed in 1

colostrum sample and 1 mature milk sample, respectively. Twig- ger et al. [80] analyzed mammary cells isolated from human milk

(n 1⁄4 8) and nonlactating mammary tissue (n 1⁄4 7) using single-cell

transcriptomic methodology. Although the expression of CNR1

was low overall, higher expression was observed in nonlactating

mammary tissue samples than in human milk samples. Expression

of CNR2 was low and similar in both groups of samples [80].

Further research with a larger number of samples is necessary to

disclose if and how the expression of CNR1 and CNR2 might be

affected by the lactation process.

Cannabinoids can also bind to peroxisome proliferator- activated receptors (PPARs) [57,82], a family of nuclear hor- mone receptors (including isoforms α, β/δ, and γ) that can bind

to DNA sequences, leading to changes in the transcription of

target genes. Although PPARs are primarily activated by unsat- urated fatty acids [83], it has been suggested that cannabinoids

can also activate PPAR in different ways. For example, canna- binoids can 1) be transported intracellularly by fatty

acid-binding proteins (FABP) and activate PPAR directly; 2)

activate surface cannabinoid receptors causing intracellular

signaling cascades that lead to the activation of PPAR indirectly;

and 3) be metabolized into cannabinoid metabolites, which can

activate PPAR [84–86].

PPARs have been detected mainly in adipose tissue and, to a

lesser extent, in mammary tissue of several species. Studies in

cattle have demonstrated that the gene peroxisome proliferator- activated receptor γ (PPARG) is highly expressed in adipose tis- sue and moderately expressed in mammary tissue and in a

mammary epithelial cell line (MAC-T) [87,88]. Moreover,

expression of PPARG in the mammary gland increases during

pregnancy and lactation [88,89]. The PPARG gene has been Q4

found to be expressed also (in low-to-moderate amounts) in

lungs, spleen, ovaries and, at very low concentrations, in liver,

kidneys, leukocytes, and small intestine [87,90,91]. In mono- gastrics such as mice and humans, PPARG is also highly

expressed in adipose tissue [92–95].

The expression of the gene peroxisome proliferator-activated

receptor α (PPARA) is more widespread among tissues and cells

than that of PPARG. The highest expression of PPARA has been

described in the kidney and liver, followed by adipose tissue,

small intestine, and semitendinosus muscle in dairy cattle.

Mammary glands of cattle have a relatively modest expression of

PPARA [90]. PPARβ/δ is the least studied PPAR isotype. Bionaz

et al. [90] observed similar expression of the gene peroxisome

proliferator-activated receptor δ (PPARD) in all bovine tissues

and cells assessed (including adipose tissue, rumen, jejunum,

liver, kidney, muscle, hoof, lung, mammary gland, and placenta).

Expression of PPARD in bovine mammary cells has also been

demonstrated by others [96].

As mentioned above, cannabinoids can be transported

intracellularly bound to FABPs, proteins that mainly mediate

the cytosolic movement of lipids [86]. FABPs are found in

numerous cell types of mammalian tissues involved in the up- take and/or utilization of fatty acids [97]. Indeed, high

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concentrations of FABPs have been found in rat [98,99] and

bovine [100] mammary tissue.

In addition, transient receptor potential channels are highly

selective epithelial calcium (Ca2þ) channels involved in ionic

homeostasis and cellular signaling [101]. Cannabinoids can bind

to members of the transient receptor potential vanilloid channel

subfamily expressed in healthy human breast tissues [102].

Cannabinoids can also bind to monoamine transporters, adeno- sine equilibrative nucleoside transporters, and glycine receptors

[57,82] whose possible effects on lactogenesis and milk syn- thesis are currently unknown.

As previously discussed, there are several pathways through

which cannabinoids might interfere with MEC function. How- ever, the mammary gland is a complex matrix made up of MECs,

stroma cells, adipose tissue, blood and lymphatic vessels, and

nerve tissue [103]. Consequently, studying the effects of can- nabinoids in isolated MECs does not fully replicate the envi- ronment of the human mammary gland. Indeed, use of a more

naturalistic and complex tissue matrix that includes adipose cells

would be more translatable. The use of organoids, for example, is

an important model for human mammary gland research [104]

because 3-dimensional mammary organoid models reproduce

extracellular conditions, maintain spatial morphology, and could

be cocultured with adipocytes and other stromal components

[104]. Moreover, organoids can be maintained in controlled

medium, thus inducing the lactating conditions and in turn

making it possible to understand the effects of cannabinoids on

the full scope of the lactating mammary gland [105,106].

Effects of Cannabinoids on Milk Composition

Roles of the ECS include regulating several physiologic pro- cesses such as homeostasis and energy balance, as well as mod- ulation of numerous neuro-processes, including anxiety, feeding

behavior/appetite, emotional behavior, depression, neuro- genesis, neuroprotection, reward, cognition, learning, memory,

and pain sensation [55,107]. Regarding the possible relationship

of the ECS with milk composition, one of the most closely linked

potential roles of the ECS is its likely modulation of lipid

metabolism. This is because modulation of lipid metabolism is

carried out in part through direct activation of PPARs or through

the activation of cannabinoid receptors (Figure 2), which in turn

triggers a cascade of reactions that ultimately activate PPARs

(108). PPARs activated by cannabinoid form a heterodimer with

the retinoid X receptor (RXR). This PPAR/RXR complex can bind

to specific response elements in the DNA, in turn regulating

expression of target genes involved in lipid metabolism and cell

differentiation [109]. PPARγ is upregulated in mammary tissue

during lactation, suggesting an essential role in regulation of

milk fat synthesis [110].

In addition, the endocannabinoid AEA acts as an agonist of

both CB1R and PPARγ, causing adipocyte differentiation and

lipid accumulation [111,112]. Treatment of mouse 3T3-F442A

preadipocytes with the CB1R receptor agonist HU210—a syn- thetic cannabinoid—increased the concentration of PPARγ and

the accumulation of lipid droplets [113]. The same effect was

observed after treating mouse adipocytes with AEA; increased

PPARG2 gene expression and CB1R protein content were

observed compared with untreated cells [112]. Moreover, acti- vation of adipocyte CB1Rs in mice stimulates lipoprotein lipase

activity [114]. This enzyme plays an important role in milk fat

synthesis as it regulates the hydrolysis of circulating triglyceride

and the uptake of fatty acids in the mammary gland [115].

Accordingly, blocking CB1R binding in adipose tissue increases

lipolysis, decreases lipogenesis, and increases the oxidation of

fatty acids inside the adipocyte [108].

In addition to endocannabinoids, some polyunsaturated fatty

acids such as some isomers of conjugated linoleic acid (CLA) can

act as natural PPARγ ligands. Indeed, the effect of t10c12-CLA on

lipid milk composition—both in animals and humans—has been

described previously. More specifically, treatment with PPARγ

ligand t10c12-CLA has a clear negative effect on lipogenic net- works in several species such as cattle [91,116], mice [117],

goats [118], and humans [119].

Whether cannabinoids have the same effect is currently un- known, but as described above, cannabinoids might modulate

milk macronutrient composition, especially lipid and fatty acid

content, by activating cannabinoid receptors and/or PPARγ.

FIGURE 2. Putative effects of cannabinoids in mammary epithelial cells and secretion of cannabinoids in milk. Abbreviations: CBR, cannabinoid

receptor; FA, fatty acid; FABP, fatty acid-binding protein; PPAR, peroxisome proliferator-activated receptor; RXR, retinol X receptor; TRPV,

transient receptor potential vanilloid. Created with BioRender.com.

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However, only a limited number of studies have addressed the

direct effect of phytocannabinoids on milk composition, and

additional rigorous research is warranted.

In a recent in vitro study, the effect of THC and CBD on milk

production was investigated using HC11 cells (a MEC line iso- lated from mice). After treating HC11 cells with different

amounts of either THC or CBD, reduced transcription (lower

mRNA concentrations) of the protein synthetic genes casein β

(CSN2) and whey acidic protein was observed for both canna- binoids. THC and CBD treatments also decreased expression of

several genes related to lipid metabolism (fatty acid synthase

[FASN], fatty acid-binding protein 4 [FABP4], glucose trans- porter 1 [GLUT1], hexokinase 2 [HK2], perilipin 2 [PLIN2], and

lipoprotein lipase [LPL]) and reduced overall lipid concentra- tions [77]. These results suggest that cannabinoids may affect

human milk macronutrient composition. However, the effect of

cannabis or its metabolites on the lactating mammary gland

needs to be confirmed with in vivo and clinical studies.

In humans, only one study has investigated the association

between cannabis use and milk composition. In the study con- ducted by Josan et al. [63], a single milk sample was collected

from 19 breastfeeding women who used cannabis and 17

breastfeeding women who did not use cannabis over 6–8 wk

postpartum. The participants provided 2 ounces of milk from

their daily or weekly expression, using either manual or electric

pumps. Milk samples were analyzed for several cannabinoids by

HPLC-mass spectrometry; lactose using an ELISA kit; and lipids,

total carbohydrates (as sum of lactose and oligosaccharides), and

crude protein (including nonprotein nitrogen and true protein)

from nitrogen content using a Miris Human Milk Analyzer. No

differences were observed in concentrations of lipids, total car- bohydrates, crude protein, or true protein in milk produced by

women who used compared with those who did not use

cannabis. However, lactose concentrations were higher in the

milk produced by women who used only cannabis (not mixed

with tobacco) compared with those of women who did not use.

When controlling for cooccurrence of tobacco use, milk pro- duced by women who used cannabis and tobacco had lower

concentrations of total carbohydrates and higher concentrations

of crude and true protein [63]. Because sampling details were

not provided (unknown amount of foremilk and hindmilk) and

timing of sampling was not controlled for a variety of important

factors (e.g., time of day and time since last feed) related to

variation in milk composition (e.g., lipid content), these data

should be interpreted with caution. In addition, time since last

cannabis exposure was not recorded. Clearly, additional

well-controlled studies are needed to understand the potential

effects of maternal cannabis use on milk composition.

Maternal Cannabis Use and Milk Production

The endocrine system is responsible for regulating lactation,

including mammogenesis (development of the mammary gland),

lactogenesis (establishment of lactation), and galactopoiesis

(maintenance of milk secretion). Milk production is controlled by

prolactin (PRL) and growth hormone (GH), although regulation of

milk production is slightly different depending on the species. GH

is dominant in ruminants, whereas PRL is dominant in rodents and

humans [120,121]. In humans, lactogenesis starts in mid- pregnancy with the differentiation of the mammary gland to

secrete small quantities of specific milk components through a

combination of high concentrations of estrogen and progesterone.

However, secretion of milk is inhibited by progesterone at this

point. The second step in lactogenesis occurs around parturition;

after a rapid decrease of progesterone concentrations, inhibition

of PRL release ends and milk production and secretion start. The

suckling action of the infant at the breast (or pumping) causes

FIGURE 3. Feasible effects of cannabinoids on the hypothalamus–pituitary axis related to lactation. Created with BioRender.com.

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release of oxytocin in the hypothalamus that stimulates milk

ejection in the mammary gland and the release of PRL by the

anterior pituitary gland (Figure 3). Conversely, secretion of

dopamine and/or the lack of suckling stimuli (or pumping) inhibit

PRL release, and consequently, milk production [120,122].

Cannabinoids such as THC and CBD are known to interact

with the dopaminergic system [123,124], leading to possible

effects on milk synthesis. However, studies to determine how

cannabinoids interact with the dopaminergic system [125–128]

have yielded inconclusive results (described below), and more

research is warranted.

Effects of cannabinoids on PRL

The inhibitory effect of endocannabinoids AEA and 2-arachi- donoylglycerol on PRL has been demonstrated in mice [74,129,

130], and a similar effect was observed after THC administration

[131,132]. Rodríguez de Fonseca et al. [125] observed a brief

rise in plasma PRL before a prolonged decrease after THC

administration in rats. Pagotto et al. [126] proposed a biphasic

action of cannabinoids on PRL secretion; first an increase of PRL

secretion by activation of CB1R in the pituitary, followed by an

inhibitory effect through the activation of dopamine release.

However, studies in monkeys have shown both a reduction of

circulating PRL concentrations [127] and no clear trends [128]

after THC administration.

The specific effect of THC on PRL was addressed in 2 studies

on rats carried out in the 1980s. In the first study, THC was

injected to ovariectomized rats, and serum PRL concentrations

were assessed before and after treatment. The research reported

that THC suppressed serum PRL concentrations 10 min after the

treatment, an effect that lasted for 1 h [133].

In the second study, THC or vehicle was injected into lactating

rats before initiating suckling or once suckling was established

[134]. After treatment with vehicle, serum PRL concentrations

increased from 14 to 215 ng/mL during suckling and decreased

to 74 ng/mL 1 h after suckling ceased. Conversely, in the THC

group, PRL concentration did not change during suckling,

reaching the highest concentration at 53 ng/mL. When testing

the THC effect once suckling was established, they observed that

serum PRL concentration declined following treatment, and

concentrations remained lower even though the suckling

continued. Whether the THC effects on serum PRL concentra- tions observed in lactating rats also occur in lactating women has

not been explored.

The effect of THC on human serum PRL concentrations in

nonlactating women using cannabis has been studied, but results

are conflicting. Some studies have concluded that THC does not

affect serum PRL concentration after acute exposition

[135–137]. However, D’Souza et al. [136] observed that plasma

PRL in a group of people who frequently used cannabis (>10

exposures over last month) was lower than in people who did not

use. On the contrary, Lee et al. [138] quantified PRL in the serum

of 6 people who chronically and heavily used cannabis (used for

5 y, and between 25 and 30 d of use within the last months)

and reported that half had elevated PRL concentrations beyond

the reference range.

The association of cannabis use and milk production was

considered in one study carried out by Josan et al. [63].

Lactating women over 6–8 wk postpartum who used cannabis

(n 1⁄4 22) and others who did not use cannabis (n 1⁄4 18)

completed a survey about breastfeeding practices and usage

patterns of cannabis. The 66.7% of the women who used

cannabis during pregnancy used it daily, mostly via smoking

(94%). Postpartum use was reported by 55%, following similar

patterns; 66.7% used cannabis daily, and most (83%) smoked

[63]. In this study, the group of women who used cannabis

self-reported lower concentrations of milk production (average

amount of milk pumped at one time) during the first 6 wk

postpartum. It is important to note that, 41% and 36.4% of the

participants who used cannabis reported cigarette use during

and after pregnancy, respectively, and reduced production of

milk among tobacco-smoking women has been reported [139].

Therefore, it is still unknown whether cannabis use itself does

indeed influence milk production.

The possible reduction in milk production caused by canna- binoids’ effects on PRL concentrations could be a factor affecting

the establishment of breastfeeding. Indeed, concerns about milk

supply is one of the main reasons why women stop breastfeeding

completely before 6 mo [140,141]. Although a shorter duration

of breastfeeding was observed in women who used cannabis than

in those who did not use [142], the association of this shorter

breastfeeding duration with lower milk production was not

addressed in the study.

To evaluate the possible effect of cannabinoids on milk pro- duction, accurate methods to measure milk production must be

used to achieve reliable results. Factors influencing variability in

milk production, such as time postpartum, time of the day, time

since last breastfeeding session, and maternal factors (e.g.,

adiposity and medications) must be controlled for or at least

detailed. Likewise, an accurate analytical method for measuring

milk production, such as deuterium dilution or test-weighing,

needs to be used to fully understand the physiology and out- comes that might be associated with cannabis use during

breastfeeding [143]. Thus, studies designed to determine the

specific effect of cannabis (and not other products such as to- bacco) on milk production should be pursued.

Effects of cannabinoids on dopamine and oxytocin

Increased dopamine release caused by cannabinoids has been

observed in studies using murine models [144,145]. Moreover, it

has been suggested that this cannabis-induced release of dopa- mine is caused by the activation of CB1R in the hypothalamus

[146,147]. Higher dopamine concentrations might inhibit PRL

release from the pituitary, affecting regulation of milk synthesis

and secretion [148].

The effect of cannabinoids on oxytocin during lactation was

assessed in an animal model study. Intravenous THC or vehicle

was injected into lactating rats and the stretch response of the

pups—a signal of milk ejection—was recorded [149]. Milk

ejection is caused by an increase in the mammary pressure

provoked by the release of oxytocin. The intervals between milk

ejections before THC or vehicle injection were 7 and 6.5 min,

respectively. After injection of vehicle in the control group,

intervals between milk ejections remained similar to those

before treatment. However, after injection of THC, there was a

latency period of 59 min before the next milk ejection was

observed; even after resuming milk ejections, intervals were

lengthened (between 15 and 16 min).

In addition to regulating lactogenesis, oxytocin and dopamine

play key roles in establishment of the mother–infant bond. In

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animal models, higher oxytocin receptor concentrations have

been observed in rats that showed more attachment to the pups.

The same effect has been observed with dopamine; decreased

dopamine transporters are associated with weakened maternal

behavior [150]. A recent study demonstrated that the ECS is

involved in the oxytocin-dependent formation of pair bonds. The

administration of an endocannabinoid antagonist to female

paired prairie voles inhibited the oxytocin-bonding effect and

even increased “rejection-like” behaviors toward their partners

[151]. The possible effect of cannabis use on mother–infant

bonding has yet to be explored.

Summary

Prevalence of cannabis use among the United States popula- tion has increased over the last 20 y with a notable proportion of

pregnant and breastfeeding women reporting use. At the same

time, perceived risk of cannabis has decreased within this pop- ulation. It is widely demonstrated that phytocannabinoids can be

found in milk produced by women who use cannabis during

pregnancy and/or breastfeeding. Although empirical support in

human is lacking, results from animal studies and human studies

focused on nonpregnant, nonlactating individuals suggests the

possibility that long-term accumulation of cannabinoids in

mammary adipose tissue might interfere with the process of

lactogenesis by directly activating cannabinoid receptors.

Furthermore, phytocannabinoids may affect milk output and

composition, especially lipid and fatty acid profiles, by modu- lating the expression of genes involved in fatty acid synthesis.

Regulation of synthesis and secretion of milk might also be

affected by cannabinoids via their interactions with the endo- crine system. However, substantial research is needed utilizing

rigorous methods for milk collection and production to demon- strate any of these potential effects.

Author contributions

The authors’ responsibilities were as follows – ICN, MKM,

MAM: conceptualized and designed this review; ICN: researched,

analyzed the background literature, and drafted the manuscript;

MKM, MAM, JEW, EAH, CLM: provided critical review, com- mentary, and revisions to the manuscript; and all authors: read

and approved the final manuscript.

Q5 Conflict of interest

The authors report no conflict of interest.

Q6 Funding

Q7 The authors reported no funding received for this study.

Q8 References

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36

37

38

39

40

41

42

43

44

45

46

47

48

49

50

51

52

53

54

55

56

57

58

59

60

61

62

63

64

65

66

14