The Effect of Cannabis on Prolactin: A Scoping Review of Endocrine Implications for Maternal and Fetal Health

The Effect of Cannabis on Prolactin: A Scoping Review of Endocrine Implications for Maternal and Fetal Health | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Systematic Review The Effect of Cannabis on Prolactin: A Scoping Review of Endocrine Implications for Maternal and Fetal Health Nataly Ayoub, Abjot Basra, Leticia Galan, Alison Shea This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-7403198/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Background: Cannabis use is increasing among women of reproductive age, yet its effects on prolactin (PRL), a hormone critical to lactation and maternal health, are poorly understood, especially in pregnancy and lactation contexts. Objectives: A scoping review exploring cannabis and prolactin levels in reproductive states was conducted to map the evidence and identify gaps for future research. Method: English peer-reviewed studies investigating the effect of cannabis or cannabinoids on prolactin in female or maternal models, either animal or human, were included. Medline, Scopus, and Embase were searched. Two reviewers screened data on study design, population, cannabis exposure, prolactin measures, and outcomes. Results: Thirty studies were included. In animals, tetrahydrocannabinol exposure often suppressed prolactin, especially during key reproductive stages. Human studies were inconsistent, with limited data on pregnancy or lactation. Conclusions: Cannabis impacts prolactin in a species- and context-specific manner. More rigorous human studies are urgently needed to guide perinatal care. Drug Discovery, Design, & Development Pregnancy Lactation Reproduction Cannabinoids Perinatal Care Figures Figure 1 INTRODUCTION Background Cannabis is the most cultivated, traded, and used illicit drug worldwide ( World Health Organization , 2025). Around 147 million people, or 2.5% of the global population, used cannabis in 2024 ( World Health Organization , 2025). Canada has seen a significant increase in cannabis use since its legalization through the Cannabis Act in October 2018. In 2024, more than 26% of Canadians had used cannabis in the past year, among whom 6% consumed cannabis nearly daily ( Health Canada, 2023). The information presented above represents the increasing acceptance of cannabis as well as global trends in cannabis opinions. Although cannabis use has its effects on various groups, normalization can be especially alarming among vulnerable populations, such as women of childbearing age, pregnant and lactating women. Until 2018, it was estimated that 47.6% of women of childbearing age (15-44 years) had used cannabis ( Statistics Canada, 2019 ). In 2020, among the age group 20-24, the prevalence of cannabis use in the previous 12 months was 20% ( Health Canada, 2021 ). Prevalence rates reported among pregnant women in Canada have ranged from 2.6-11%. An anonymous questionnaire-based study in a large urban center in Ontario found 11.3% of respondents used cannabis at any point of pregnancy, 4.2% were continuing cannabis use, and 4.8% had plans to use cannabis while breastfeeding ( Kaarid et al. , 2020). A Canadian maternal health survey of 7111 women also recently reported cannabis use during pregnancy at 3.1% and during breastfeeding at 2.6% Grywacheski et al. , 2021 ). Comparable rates were also reported in regional studies such as the BORN Ontario database, which demonstrated a 61% rise in cannabis use during pregnancy, from 1.2% in 2012 to 1.8% in 2017 ( Corsi et al. , 2019 ). Cannabis use during pregnancy has been associated with poor birth outcomes but there is a paucity of information on how cannabis may affect lactation, and the hormones involved (Luke et al., 2019; Kim, 2020 ). Prolactin (PRL) plays a critical role in lactation during pregnancy and milk synthesis in the postpartum period as it participates in lactogenesis, enabling the production of essential ingredients in human milk for infant growth and immune maturation ( Kim, 2020 ). In stage II lactogenesis, which commences after parturition, lactogenesis is coupled with a rise in the secretion of PRL and metabolic adaptation necessary for milk secretion, while stage I lactogenesis takes place several weeks prior to parturition when PRL accumulation of milk substrate (Hartmann, 1973). Peak PRL levels during stage III lactogenesis further regulate milk composition, promoting the synthesis of proteins like β-casein (Kobayashi et al., 2016; Vorherr H, 1979). In addition to its lactation function, PRL is synthesized in various sites other than the pituitary, such as the brain and placenta, where it plays an important role in neuroendocrine and immune system development during fetal growth (Lawrence & Lawrence, 2011, p. 69). Low PRL levels in mothers are related to negative infant birth and developmental outcomes. Compared to newborns exposed to normal range PRL levels, the birth weight Z-scores decreased by 0.169 units for newborns of mothers with low PRL levels ( Wang et al. , 2022 ). Apart from birth weight, maternal PRL levels also seem to have an impact on postnatal growth and neurodevelopment. Higher PRL levels were positively correlated with elevated insulin-like growth factor 1 (IGF-1), a growth promoting hormone, of the offspring, but with no statistically significant relationship with placental growth hormone ( Wang et al. , 2022 ). Alongside prolactin’s role in lactation, downstream effects on cognitive development through breastfeeding are also evident. Breastfeeding has been previously demonstrated to promote brain structure, white matter growth and cognitive abilities (Chade et al., 2024). However, little is known about how cannabis may affect PRL in pregnancy and lactating individuals. Objective The objective of this scoping review is to systematically map what is known regarding the association between cannabis exposure and PRL levels in females, particularly when considering pregnant and lactating individuals. This article aims to summarize existing literature on the acute and chronic effects of cannabis use on PRL, to explore methodological patterns and constraints, and to discuss the relevance for maternal and infant health. Informed by the Population–Concept–Context framework, the following research question is addressed: What is the effect of cannabis use on PRL levels in female participants, particularly in the context of maternal and fetal health? Population: Female subjects, with an emphasis on pregnant and lactating individuals (including human and animal studies) Concept: Exposure to cannabis or cannabinoids and their effects on PRL levels Context: Clinical, preclinical, and epidemiological settings involving reproductive and endocrine health METHODS Scoping Review Protocol: There was no registered protocol for this scoping review. The approach was designed based on Arksey and O’Malley’s model and the PRISMA-ScR extension criteria. Search Strategy To obtain a comprehensive review of existing literature, a search was performed on OVID Medline, Scope and Embase between September and December 24th, 2024. A comprehensive and structured search strategy was used to search for the concept of the review using various search terms (Appendix A). The PICOS framework was used to select the studies with the population of interest being females who were pregnant or non-pregnant. The exposure was cannabis, and the outcome of interest was PRL. Eligible studies could or could not have been with control; and included study designs could be experimental (e.g. randomized controlled trials, preclinical animal studies) or observational studies (e.g. cohort, case-control, cross-sectional). Papers were excluded if they focused on topics unrelated to PRL regulation or lactation (i.e., schizophrenia, Parkinson’s Disease), analyzing the effect of other substances (e.g., alcohol, amphetamines) with cannabis interaction in PRL regulation. Data Extraction To present the key findings of studies included in this scoping review, a data extraction form was developed. Major headings, such as authors, publication year, study design, population descriptions, intervention, control, outcome, period and duration of exposure are captured. It also included methods of cannabis administration and dosage. The main results of each study were also reported, with particular emphasis on the impact of cannabis in women, either in the general population or during pregnancy, regarding PRL levels. The screening was independently conducted by two reviewers, which contributed to the accuracy and consistency of the information collected. Data Analysis To enable an efficient synthesis of the evidence, the extracted data were charted based on several study characteristics including study design, type of cannabis, and outcome measures. A narrative synthesis methodology was then used to describe the literature. Critical Appraisal of Individual Sources of Evidence As per the objectives of a scoping review, no formal critical appraisal or risk of bias assessment was conducted. The focus was on the mapping of the current literature and not on the quality or strength of the evidence. RESULTS Flow Diagram The study selection is shown in a flowchart that presents the progress of the articles from the search to the exclusion steps (Figure 1). First, a total of 596 studies were found, and 203 duplicates were removed, resulting in 393 unique studies for screening. 269 studies were excluded after the screening phase due to failure to meet the exclusion criteria. Of these, 94 articles were excluded following the full text review as they were not consistent with the prespecified eligibility criteria (Appendix B). A total of 30 studies were finally included in the review. Source of Evidence Characteristics Of the 30 studies included in our review, most had been published before 2000, that is: 24 (80.0%) in the pre-2000 period, 4 (13.3%) in the 2000‒2010 period, 1 (3.3%) in the 2010‒2020 period, and 1 (3.3%) in the 2020‒2025 period (Appendix C ) . Most of the studies were experimental studies in animals (n=23/76.7%) followed by observational human studies (n=7/23.3%). All studies incorporated female populations as the primary aim, where 22 (73.3%) included non-pregnant populations, 7 (23.3%) pregnant populations and 1 study (3.3%) both non-pregnant and pregnant populations. Among the 23 experimental animal studies included, 9 studies (39.1%) were carried out in ovariectomized (OVX) animals, to mimic the absence of hormones. Rats were the animal model in 17 (73.9%) studies where 3 (13.0%) utilized monkeys and 3 (13.0%) contained unspecified mice or rodent strains. Pregnancy-related models were used in 7 studies (30.4%), employing naturally pregnant, pseudopregnant, or postpartum rats and mice. Few studies (n=1, 4.3%) among these 7 animal studies combined pregnant and non-pregnant groups. Sample sizes among studies were quite variable, with as few as 3 animals per group to 20 animals per group, with the majority of studies making use of 8-10 animals per group as a standard for hormones. Of the seven studies examined in humans, age was only indicated in 6, and 5 studies reported both mean and SD. Age was reported inconsistently even among these five studies: some studies averaged ages across the entire sample (e.g., users and controls grouped together); others reported separate user subgroup means. The age of all females was between 18 to 55 years; and the mean ages of participants in each of the reviewed studies were between 23 and 29 years. A summary of reported mean ages results in an average age of 25.3 years, describing young to early middle-aged adult females as the main population studied for cannabis and PRL modulation. Study designs differed in classification of cannabis exposure: frequent users were often defined as using cannabis ≥10 times monthly or ≥100 times ever, and this was confirmed by a positive urine drug screen. Several studies classified users into types based on frequency (e.g., frequent, moderate, infrequent); one study requested only a minimum of one year of history of use with abstinence before testing. Three of these studies applied acute administration paradigms (e.g., vaporized or IV Δ⁹- tetrahydrocannabinol (THC)), the remaining ones medicated chronic or combined chronic-acute exposure profiles, three of them testing PRL response to THC in regular consumers. Duration of exposure was also different, with most studies reporting findings based on chronic use (repeated or habitual use over weeks to years), and three studies of acute administration of THC, whether IV or inhalation, respectively. In terms of the impact of cannabis on PRL levels in all 30 studies, 14 (46.7%) reported a decrease in PRL, 10 (33.3%) had mixed effects, and 6 (20.0%) reported no effect. Within the 23 animal in vivo studies, 11 (47.8%) saw a reduction, 9 (39.1%) showed inconsistent effects, and 3 (13.0%) found no effect. Of the 7 human in vivo studies, similar heterogeneity existed: 3 (42.9%) reported a reduction in PRL, 1 (14.3%) reported mixed results, and 3 (42.9%) reported no effect. Regarding the classes of cannabis compounds tested in vivo animal studies, Δ 9-THC was the most common compound that was researched (n = 19, 82.6%), and was followed by anandamide (ANA, n = 2, 8.7%), a combination of Δ 9-THC and ANA (n = 1, 4.3%) and HU-210 (n = 1, 4.3%). In general, much of the evidence consists of older animal studies reports. The small number of recent human studies, particularly amongst pregnant populations, highlights an important gap of knowledge. Findings See Appendix D for an overview of the included studies. Animal Studies (Pregnancy): Several significant findings are considered based on experimental animal studies. Wenger et al. ( 1997 ) examined the effects of ANA, an endogenous cannabinoid, on pregnant rats, compared to the exogenous cannabinoid THC, the principal psychoactive agent in marijuana. Daily intraperitoneal injections of ANA and THC (0.02 mg/kg) were given between the third week of pregnancy (a developmental time point similar to the final stage of pregnancy in humans). Hormonally, ANA and THC decreased luteinizing hormone (LH) and serum PRL, whereas ANA also inhibited pituitary PRL and serum growth hormone. Furthermore, Wenger and his colleagues ( 1999 ) also studied the effect of cannabinoids on reproduction where a single injection of ANA was given. Two additional groups of female rats were treated with ANA by intraperitoneal administration at a dose of 0.02 mg/kg daily in acute-sub chronic exposure lasting days during the third week of pregnancy. They demonstrated that ANA exposure at this sensitive time led to maternal hyperprolactinemia, a lower LH and PRL level, prolonged pregnancy, and a higher rate of stillbirth. Bromley et al. ( 1978 ) studied the immediate effects of THC on PRL release in lactating rats and found that suckling-induced PRL levels were significantly inhibited, accompanied by impaired maternal behaviors specifically involving pup retrieval and crouching. Lactating rats were trained to nurse their pups and then were administered either intravenous THC (1.25 or 4.0 mg/kg) or a vehicle on the training day. This brief time interval (30 min-2 h post-treatment) corresponds to an acute exposure study. However, the single THC injection was enough to disturb the hormonal responses, suppressing suckling-induced PRL rise within 30 min and lasting 2 hrs. It indicates THC's ability to disrupt maternal behaviors during lactation, possibly mediated through centralized hormone action. Hughes Jr. et al. ( 1982 ) also investigated THC’s influence on releasing PRL in pseudopregnant rats, a condition similar to normal pregnancy observed in female rats, where the animals basal blood levels of hormones resemble those found in pregnant animals even in absence of embryo implantation achieved through stimulation of the cervix. The use of this model isolated maternal hormone regulation. THC was given briefly as dosing occurred acutely, but repeatedly (hourly × 1.0 mg/kg body weight) for roughly 17h of exposure. This acute, time-restricted exposure was designed to interfere with the nocturnal surge of PRL which drives early pseudopregnancy. This study demonstrated that THC effectively inhibits the secretion of PRL until 6:00 a.m. on Day 2, after which levels returned to control levels. Despite this short-term disruption, the length of pseudopregnancy was unaffected, indicating that short-term THC exposure can cause temporary disruption to hormonal control without the potential for broader reproductive impacts. All previous studies showed how PRL levels can be suppressed to some extent by using pregnant animals in experiments, but the research below shows nuanced results. García-Gil et al. ( 1997 ) evaluated the consequences of chronic perinatal exposure to Δ9-THC in Wistar rats, with the administration of daily oral doses of 5 mg/kg from gestational day 5 to postnatal day 24, which cuts across a significant period of development including those of the late gestation and lactation. The extended exposure potentially evoked greater adaptive neuroendocrine responses that would have maintained regulation of basal PRL levels, while avoiding the decreases in acute models observed. Moreover, Raine et al. ( 1978 ) studied the impact of Δ1-THC on plasma PRL concentrations, and on the development of the mammary gland of the mouse in late pregnancy and of the lactating gland. The study included chronic exposure in which animals were monitored from late pregnancy (approximately day 17) to early (day 2) and maximum lactation (day 12) with their pup. They found that high lipoprotein lipase activity, which occurs normally in the mammary gland at parturition, was greatly reduced by THC. Furthermore, the elevation of plasma PRL to peak levels was advanced in the control group compared with THC treated mice suggesting that THC delayed the PRL surge during lactation. This late PRL peak may hold responsibility for impaired mammary gland development and the delayed onset of a peak lipoprotein lipase activity necessary for lactation. Wenger et al. ( 1997 ) administered daily THC injections from gestational day 14 until delivery (equivalent to the third week of pregnancy), and found that the effects on PRL were time-dependent: pituitary PRL initially decreased on days 0 and 5 but rebounded by day 10, while serum PRL declined in both sexes on day 0 and remained suppressed in females through day 10. Collectively, this series of studies underscore the complex effects of cannabinoids on pregnancy and lactation, with a focus on effects at the level of hormone control, maternal behavior and offspring development. Animal Studies Variability of the cannabinoid-regulated PRL secretion in female experimental animals depends on various parameters, such as the phase of the estrous or the reproductive cycle, cannabinoid dose, treatment duration and hormonal status. The results of the acute and chronic cannabinoid treatment on PRL vary from inhibition to no changes and on occasions also biphasic effects in the 16 studies, indicating dynamic neuroendocrine interactions. Early studies of acute effects of cannabinoids displayed mixed results. Asch et al. ( 1981 ) gave one-time doses of THC (2.5 mg/kg) to sexually mature female rhesus monkeys in the follicular phase and found no significant changes in PRL levels. It remains unclear whether the results were due to confounding factors, such as sampling that did not align with natural estrogen fluctuations, or if it reflects a true null result, suggesting that the endogenous PRL response may not be particularly sensitive to THC exposure. In contrast, Field et al. ( 1986 ) have shown in prepubertal female rats that acute THC 10 mg-1 kg decreased PRL significantly, noting that it blocked the late afternoon surge of PRL in proestrus rats, an effect which diminished with repeated exposures to the drug. More subtle inferences could be drawn from observed effects of reproductive cycle stages. In a more elaborate approach, Bonnin et al. ( 1993 ) examined THC-induced changes in PRL and dopaminergic mechanisms in female rhesus monkeys in relation to the phases of the cycle. They observed that THC also enhanced PRL during the afternoon on the day of estrus, and this change was associated with a decrease in anterior pituitary D2 dopamine receptor density, a receptor through which inhibitory dopaminergic control of PRL is mediated. Acute high-dose THC also reduced PRL on the day of estrus in adult females rats (Chakravarty et al., 1975 ). Consistent with these findings, Martin-Calderon et al. ( 1998 ) studied the effects of HU-210, a cannabinoid synthetic analogue, on PRL in female rats, showing a biphasic response. Low doses of HU-210 (4 μg/kg) induced PRL secretion, whereas higher doses (20 and 100 μg/kg) were associated with a marked inhibition of PRL release. Wenger et al. ( 1995 ) demonstrated that THC and ANA (both at 0.02 mg /kg) produced a decrease in serum PRL and LH (but not FSH) in OVX. These findings raise the possibility that cannabinoids, in the absence of ovarian hormones, modulate pituitary hormone secretion directly via a neuroendocrine mechanism rather through the integrated hormonal pathways that are functioning during pregnancy. Consistent with this, Steger et al. ( 1983 ) observed that in estrogen-primed OVX rats THC inhibited PRL surges provoked by progesterone, a result confirmed later by Hughes et al. ( 1981 ) which showed that the reduction of PRL by THC occurred centrally and not directly in the pituitary, since the effect was absent in hypophysectomized rats or isolated pituitary tissue. Similarly, Asch et al. ( 1979 ) reported that acute THC treatment decreased PRL levels in oophorectomized female rhesus monkeys. However, the suppressive effect of THC on PRL secretion was reversed by TRH (thyrotropin-releasing hormone) administration. This indicates that the suppression of response to TRH by THC is at the hypothalamic level involving estrogen release, rather than at the level of the pituitary. Although these acute effects are important to consider, we must also explore more chronic exposure as may be the case for pregnant and lactating individuals. Our investigation has suggested that chronic cannabinoid exposure is complicated, but the effects appear to be similar. Chakravarty et al. ( 1979) described long-term decreases in serum PRL levels, and disruption of the estrous cycle of rats treated for 10 days with THC. Murphy et al. ( 1991) demonstrated that THC reduced levels of estradiol-induced PRL surges in immature female rats only at certain times of day, without affecting dopaminergic function (indicating estrogen-cannabinoid interactions that are not mediated via the classical dopaminergic pathways). Hormonal influences over the cannabinoid effects were experimented by Scorticati et al. ( 2003) , which reported that ANA by itself did not have a significant effect on PRL, however, these effects were modulated by estrogen presence, indicating that cannabinoid responsiveness is hormone dependent. Tyrey ( 1986) also evaluated THC in ovariectomized female rats and reported that it reduced plasma levels of PRL; yet the medial basal hypothalamus of the brain was removed, THC no longer produced decreases in PRL levels, suggesting that this region of the brain is crucial to THC’s effect on PRL. More recently, Ryan et al. ( 2021) treated female rhesus monkeys with THC 1 mg/kg s.c. for 4 months and reported no alterations to PRL. Even with chronic use in a primate model, PRL levels remained steady. Nonetheless, tolerance may be evident after chronic exposure, and cannabinoid effects may depend on the administration time as well as the hormonal status of the animal. Only one study was located that examined perinatal THC administration and this produced long-term PRL suppression in adult female offspring (Murphy et al., 1995) . Human Studies (Pregnancy & General Women): The effect of cannabis on PRL in humans studies are inconsistent, with some indicating no effect and others observing reductions. A comprehensive investigation was carried out by Block et al. ( 1991 ), long-term use of cannabis, defined as using marijuana on more than a weekly basis in the last two years, was not linked to a change in serum PRL levels in comparison with non-users. There were 149 participants, aged 18–42 (mean age was 23.5), with frequent users categorized as consuming cannabis at least seven days per week. The research did not, however, detail what type of cannabis had been used, and the results could be different with higher-potency products or another length of exposure. Ranganathan et al. ( 2009 ) reported significantly reduced baseline PRL in frequent cannabis users (defined as having used cannabis 10+ times the month prior to recruitment: all with positive (Δ9-THC concentration >50 ng/mL) urine toxicology compared to non-cannabis users. Schander et al. ( 2008 ) had the same methodology but reported decreased change in PRL post-administration. D’Souza et al. ( 2008 ) also observed decreased baseline PRL secretion in frequent female cannabis users. The study involved 28 participants (17 healthy controls and 11 frequent cannabis users) who received a placebo and an active challenge with haloperidol (0.057 mg/kg) on two separate test days, each preceded by placebo/active Δ-9-THC (0.0286 mg/kg) intravenously. Heavier users were determined by 100+ lifetime uses, use in the last week, or diagnosis of cannabis abuse disorder. They were exposed not chronically, but with THC, 90- and 215-minutes following haloperidol. The lower baseline PRL levels of frequent users indicated chronic cannabis use could alter long-term, but not short-term, dopaminergic activity, particularly in the tuberoinfundibular pathway, responsible for the regulation of PRL release. By contrast, other studies have described initial suppression of PRL after THC. In a study by Klumpers et al. ( 2012 ), THC inhalation resulted in a 21% reduction in PRL levels compared to placebo, among women of reproductive age (18-45 years) particularly after repeated doses (2-, 6-, and 6 mg) or placebo via inhalation with 1.5 h intervals. Similarly, Mendelson et al. ( 1985 ) reported that PRL decreased significantly over time after smoking a marijuana cigarette containing 1.8% Δ-9-THC on the day of ovulation in the woman's menstrual cycle. Eight healthy adult females aged 21–33 years (mean age 26 years), who regularly used cannabis (14 occasions per month) were enrolled. This was an acute exposure trial in which each participant smoked one marijuana cigarette weighing 1 gram over approximately 12 minutes. Estradiol and progesterone remained unchanged, whereas LH and PRL revealed modest but significant pulses of ∼45-minute duration indicating that there are acute yet tangible endocrine shifts due to THC. With respect to pregnancy, only one study could be located with this population of female humans. Braunstein et al. ( 1983 ) compared 13 pregnant participants who were cannabis users, all at different trimesters to a matched group of 13 non-users. Cannabis use was verified via tests for THC in blood serum, varying from 3.2 to 70.6 ng/ml (suggesting recent use during 2–4 h before testing). Hormone levels were measured, and they found no difference in the secretion of PRL and other hormones among users and non-users. DISCUSSION Interpretation of Findings Through this scoping review, we found that the relationship between cannabis and PRL concentrations among females is complex, and the literature are heterogeneous. In animal studies, particularly in rats, cannabinoids have a general inhibitory impact on PRL secretion. These effects are most pronounced in acute exposure. THC has been shown to reduce pituitary and serum PRL levels in pregnant rats, to inhibit suckling-induced PRL release in lactating rats, and to interfere with maternal behavior, possibly impairing reproductive and maternal functioning. Furthermore, THC delayed nocturnal PRL surge in pseudopregnant rats, and inhibited PRL release depending on the time of administration during the estrous cycle, with suppression observed in the morning of estrus but stimulation noted in the afternoon. Such data emphasizes the circadian control of PRL. Because PRL peaks nocturnally, during the hours breastfeeding infants typically nurse, cannabis use by a lactating mother, especially early in the morning, could affect this circadian surge, alongside declining milk production. The consumption of cannabis among women, could interfere with the natural hormonal surge with potential negative ramifications on their milk quantity. This is particularly important in neonates who require regular night feeds for growth, development, and immune function. The failure to control for circadian variations, particularly for its nocturnal and early morning peaks may explain the heterogeneity in the effects of cannabis observed in human studies. ANA-induced inhibition of PRL was also demonstrated in ovariectomized rats, and estrogen was found to modulate the response of PRL. In terms of mechanisms, these inhibitory effects may be located centrally, presumably involving THC-induced stimulation of hypothalamic dopamine activity and subsequent PRL suppression via dopaminergic blockade of the pituitary. Species-dependent effects, differences in doses, hormonal status, and experimental design (e.g., timing of the sampling and using single time-point measurement of PRL) contribute to the difficulty of comparing results across studies. The currently available human studies display mixed findings. Some have observed a decrease in serum PRL, particularly in the luteal phases of nonpregnant women, while others have no effect or rather an elevation in PRL levels. Considering the length and nature of exposure, acute exposure may lead to temporary PRL suppression, but with chronic exposure, there may be compensatory action through a new homeostasis. In pregnant human users, a single study that was located indicated that cannabis intake did not affect placental hormones or PRL levels, yet functional lactation success is less frequently evaluated. Clearly, we need more studies investigating this possible association (or lack thereof). From a clinical perspective, these results highlight the importance of early detection and counseling in reproductive care. Providers should not only inquire about cannabis use, but the timing, frequency, and route of administration. Providing evidence-based information on the hormonal effects of cannabis to patients is critical, especially when cannabis is a common choice for anxiety or nausea management, to facilitate empowered decision-making. From a healthcare practice management perspective, childcare providers need to consider cannabis use as a possible factor when assessing concerns about breastfeeding, such as low milk production or abrupt end to lactation. Long-term management may involve breastfeeding support, monitoring of PRL as indicated, and individualized support to address patients’ inability to cease treatment. Pediatric Nurse Practitioners and pediatric oriented Family Nurse Practitioners are ideally placed to recognize early signs of cannabis-induced hormonal disruptions, particularly in the postpartum period. Nurse practitioners should incorporate these findings in anticipatory guidance, lactation consultations, and care plans, to advance maternal-child outcomes with routine screening and patient-centered education. Strengths & Limitations This review has a particular strength in its incorporation of animal and human studies, examining the interactions of cannabinoids, including THC, anandamide, and synthetic analogs, on PRL control over distinct reproductive states. This cross-species, cross-context process makes it possible to elaborate mechanisms by which cannabinoid exposure in specific “critical periods”, including pregnancy, lactation, estrous or menstrual cycle phases, may lead to various endocrine changes. The review provides a holistic, yet in-depth view of cannabinoid-PRL interactions through interpretation of experimental models and real-life human data. However, some limitations hinder interpretability and generalizability of the results. A large percentage of this information comes from rodent models, which provide useful mechanistic insights but are too simplistic to model the complexities of human hormonal control. In addition, a minority of studies included non-human primates or a pregnancy intervention, limiting their relevance to specific populations, including pregnant and lactating persons. The sizes of samples in both animal and human studies were often small, underpowering the detection of subtle or long-lasting effects. Human studies exhibited heterogeneity in the definitions of cannabis exposure such as frequency, dose, route of administration, and cannabinoid composition. Critically, limitations are also inherent in the nature of the scoping review method. As opposed to systematic reviews or meta-analyses, the goal of scoping reviews is to map the unindexed literature and determine knowledge gaps rather than critique the quality of studies or combine effect sizes. The inclusion criteria were thus deliberately broad, and there is heterogeneity in the quality of studies and method used. In addition, the lack of formal risk-of-bias does not allow presented findings to be weighted to their confidence in their rigor of study. CONCLUSION Summary This scoping review aimed to explore the effects of cannabis on PRL secretion in relation to the reproductive stages among both animals and humans. In animal models, exposure to cannabis (acute or chronic) predominantly inhibits PRL. This action was evident across various reproductive contexts (pregnant, lactating, pseudopregnant, and estrous cycling), and seems to be a centrally mediated event, likely through the hypothalamic dopaminergic pathways. Some studies demonstrated biphasic responses depending on dosage, timing, and hormonal context. During pregnancy, PRL suppression did not always equate with obvious reproductive dysfunction, but aberrations in rhythms and lactational signaling were observed. Findings from human studies were less consistent. Some studies reported reduced PRL after acute THC exposure, especially in nonpregnant women, whereas other studies found no change or even increases according to hormonal phase and tolerance. Pregnancy-specific data in human studies is extremely limited. Future Directions Well-designed human studies are needed to explain the effects of cannabis on PRL in distinct populations and levels of use with longitudinal studies, as well as definite studies during pregnancy and lactation. More detailed studies of biphasic reactions and the underlying mechanisms, with standardized protocols considering different cannabinoid profiles, are also urgently necessary. Abbreviations THC Tetrahydrocannabinol PRL Prolactin Declarations Ethics approval and consent to participate Not applicable. Consent for publication Not applicable. Availability of data and materials All data generated or analyzed during this study are included in this manuscript. Competing interests The authors declare that they have no competing interests. Funding This research received no external funding. Authors' contributions A.S. supervised the project and, together with L.G., contributed to the interpretation of the data and revision of the manuscript. A.B. served as a second reviewer during data screening and contributed to editing the scoping review. N.A. participated in data screening, conducted analysis and interpretation of results, drafted the manuscript, prepared the figures and appendix, edited content, and implemented feedback during revision. All authors approved the submitted version of the manuscript and agree to be personally accountable for their own contributions as well as to ensure the integrity and accuracy of the work as a whole. Acknowledgements The authors would like to thank the Faculty of Health Sciences at McMaster University for providing institutional support for this research. References Asch RH, Smith CG, Siler-Khodr TM, Pauerstein CJ (1979) Acute Decreases in Serum Prolactin Concentrations Caused by ∆9-Tetrahydrocannabinol in Nonhuman Primates*†. 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Adv Nutr 15(4):100196. https://doi.org/10.1016/j.advnut.2024.100196 Chade ES, Júnior OR, Souza NMP, da Silva AJ, de Ferreira OK, Reolon LM, Bonini JB, Rego JS, F. G., Sari MHM (2024) The Influence of Nutritional Status on Brain Development: Benefits of Exclusive Breastfeeding. Pediatr Rep 16(3) Article 3. https://doi.org/10.3390/pediatric16030061 Chakravarty I, Shah PG, Sheth AR, Ghosh JJ (1979) Mode of action of delta-9-tetrahydrocannabinol on hypothalamo—Pituitary function in adult female rats . https://doi.org/10.1530/jrf.0.0570113 Chakravarty I, Sheth AR, Ghosh JJ (1975) Effect of acute delta9-tetrahydrocannabinol treatment on serum luteinizing hormone and prolactin levels in adult female rats. Fertil Steril 26(9):947–948. https://doi.org/10.1016/s0015-0282(16)41364-6 Corsi DJ, Hsu H, Weiss D, Fell DB, Walker M (2019) Trends and correlates of cannabis use in pregnancy: A population-based study in Ontario, Canada from 2012 to 2017. Can J Public Health 110(1):76–84. https://doi.org/10.17269/s41997-018-0148-0 D’Souza DC, Braley G, Blaise R, Vendetti M, Oliver S, Pittman B, Ranganathan M, Bhakta S, Zimolo Z, Cooper T, Perry E (2008) Effects of haloperidol on the behavioral, subjective, cognitive, motor, and neuroendocrine effects of ∆-9-tetrahydrocannabinol in humans. Psychopharmacology 198(4):587–603. https://doi.org/10.1007/s00213-007-1042-2 D’Souza DC, Ranganathan M, Braley G, Gueorguieva R, Zimolo Z, Cooper T, Perry E, Krystal J (2008) Blunted Psychotomimetic and Amnestic Effects of ∆-9-Tetrahydrocannabinol in Frequent Users of Cannabis. Neuropsychopharmacology 33(10):2505–2516. https://doi.org/10.1038/sj.npp.1301643 García-Gil L, De Miguel R, Muñoz RM, Cebeira M, Villanua MA, Ramos JA, Fernández-Ruiz JJ (1997) Perinatal ∆9-Tetrahydrocannabinol Exposure Alters the Responsiveness of Hypothalamic Dopaminergic Neurons to Dopamine-Acting Drugs in Adult Rats. Neurotoxicol Teratol 19(6):477–487. https://doi.org/10.1016/S0892-0362(97)00048-2 Grywacheski V, Ali J, Baker MM, Gheorghe M, Wong SL, Orpana HM (2021) Opioid and Cannabis Use During Pregnancy and Breastfeeding in Relation to Sociodemographics and Mental Health Status: A Descriptive Study. Journal of Obstetrics and Gynaecology Canada: JOGC = Journal d’obstetrique et Gynecologie Du Canada: JOGC , 43 (3), 329–336. https://doi.org/10.1016/j.jogc.2020.09.017 Hartmann PE (1973) Changes in the composition and yield of the mammary secretion of cows during the initiation of lactation. J Endocrinol 59(2):231–247. https://doi.org/10.1677/joe.0.0590231 Hughes CL,and, Tyrey L (1982) Effects of (-)-Trans-∆9-Tetrahydrocannabinol on Serum Prolactin in the Pseudopregnant Rat. Endocr Res Commun 9(1):25–36. https://doi.org/10.1080/07435808209045750 Kaija Kaarid; Nancy Vu; Katelyn Bartlett Tejal Patel; Sapna Sharma ; Richard Honor ; Alison Shea. Prevalence and correlates of cannabis use in pregnancy and while breastfeeding: A survey-based study. J Obstet Gynecol Can, 42, Issue 5, 677–678 Kim YJ (2020) Pivotal roles of prolactin and other hormones in lactogenesis and the nutritional composition of human milk. Clin Experimental Pediatr 63(8):312–313. https://doi.org/10.3345/cep.2020.00311 Klumpers LE, Cole DM, Khalili-Mahani N, Soeter RP, te, Beek ET, Rombouts SARB, van Gerven JM (2012) A. Manipulating brain connectivity with δ9-tetrahydrocannabinol: A pharmacological resting state FMRI study. NeuroImage , 63 (3), 1701–1711. https://doi.org/10.1016/j.neuroimage.2012.07.051 Kobayashi K, Oyama S, Kuki C, Tsugami Y, Matsunaga K, Suzuki T, Nishimura T (2016) Distinct roles of prolactin, epidermal growth factor, and glucocorticoids in β-casein secretion pathway in lactating mammary epithelial cells. Mol Cell Endocrinol 440:16–24. https://doi.org/10.1016/j.mce.2016.11.006 Lawrence RA, Lawrence RM (2011) Breastfeeding: A Guide for the Medical Professional, 7th edn. Mosby, p 69 Luke S, Hutcheon J, Kendall T (2019) Cannabis Use in Pregnancy in British Columbia and Selected Birth Outcomes. J Obstet Gynecol Can 41(9):1311–1317. https://doi.org/10.1016/j.jogc.2018.11.014 Martı́n-Calderón JL, Muñoz RM, Villanúa MA, del Arco I, Moreno JL, de Fonseca FR, Navarro M (1998) Characterization of the acute endocrine actions of (–)-11-hydroxy-∆8-tetrahydrocannabinol-dimethylheptyl (HU-210), a potent synthetic cannabinoid in rats. Eur J Pharmacol 344(1):77–86. https://doi.org/10.1016/S0014-2999(97)01560-4 Mokler DJ, Robinson SE, Johnson JH, Hong JS, Rosecrans JA (1987) Neonatal administration of delta-9-tetrahydrocannabinol (THC) alters the neurochemical response to stress in the adult Fischer-344 rat. Neurotoxicol Teratol 9(4):321–327. https://doi.org/10.1016/0892-0362(87)90023-7 Murphy LL, Gher J, Szary A (1995) Effects of prenatal exposure to delta-9-tetrahydrocannabinol on reproductive, endocrine and immune parameters of male and female rat offspring. Endocrine 3(12):875–879. https://doi.org/10.1007/BF02738892 Murphy LL, de Fonseca R, F., Steger RW (1991) Delta 9-Tetrahydrocannabinol antagonism of the anterior pituitary response to estradiol in immature female rats. Steroids 56(2):97–102. https://doi.org/10.1016/0039-128x(91)90131-e Raine JM, Wing DR, Paton WDM (1978) The effects of ∆1-tetrahydrocannabinol on mammary gland growth, enzyme activity and plasma prolactin levels in the mouse. Eur J Pharmacol 51(1):11–17. https://doi.org/10.1016/0014-2999(78)90056-0 Ranganathan M, Braley G, Pittman B, Cooper T, Perry E, Krystal J, D’Souza DC (2009) The effects of cannabinoids on serum cortisol and prolactin in humans. Psychopharmacology 203(4):737–744. https://doi.org/10.1007/s00213-008-1422-2 Reece AS, Hulse GK (2020) Canadian Cannabis Consumption and Patterns of Congenital Anomalies: An Ecological Geospatial Analysis. J Addict Med 14(5):e195. https://doi.org/10.1097/ADM.0000000000000638 Ryan KS, Bash JC, Hanna CB, Hedges JC, Lo JO (2021) Effects of marijuana on reproductive health: Preconception and gestational effects. Curr Opin Endocrinol Diabetes Obes 28(6):558–565. https://doi.org/10.1097/MED.0000000000000686 Ryan KS, Mahalingaiah S, Roberts VHJ, Boniface ER, Hedges JC, Hanna CB, Hennebold JD, Lo JO (2021) DOSE-DEPENDENT EFFECT OF CONTEMPORARY MARIJUANA EXPOSURE ON FEMALE REPRODUCTIVE HEALTH IN A NON-HUMAN PRIMATE MODEL. Fertil Steril 116(3):e75–e76. https://doi.org/10.1016/j.fertnstert.2021.07.213 Steger RW, DePaolo L, Asch RH, Silverman AY (2008) Interactions of ∆9-Tetrahydrocannabinol (THC) with Hypothalamic Neurotransmitters Controlling Luteinizing Hormone and Prolactin Release. Neuroendocrinology 37(5):361–370. https://doi.org/10.1159/000123576 Steger RW, Silverman AY, Siler-Khodr TM, Asch RH (1980) The effect of Λ9-tetrahydrocannabinol on the positive and negative feedback control of luteinizing hormone release. Life Sci 27(20):1911–1916. https://doi.org/10.1016/0024-3205(80)90438-5 Tyrey L (2008) Reversal of the Delta-9-Tetrahydrocannabinol Inhibitory Effect on Prolactin Secretion by Rostral Deafferentation of the Medial Basal Hypothalamus. Neuroendocrinology 44(2):204–210. https://doi.org/10.1159/000124646 Vorherr H (1979) Hormonal and biochemical changes of pituitary and breast during pregnancy. PubMed 3(3):193–198 Wang S, Jia X, Zhang D, Chen S, Xu M, Jin X, Zhu Z, Li H (2022) Association of prenatal depression and plasma prolactin concentrations with neonatal birthweight. Res Square. https://doi.org/10.21203/rs.3.rs-1460839/v1 Wenger T, Fragkakis G, Giannikou P, Probonas K, Yiannikakis N (1997) Effects of anandamide on gestation in pregnant rats. Life Sci 60(26):2361–2371. https://doi.org/10.1016/S0024-3205(97)00296-8 Wenger T, Fragkakis G, Giannikou P, Yiannikakis N (1997) The Effects of Prenatally Administered Endogenous Cannabinoid on Rat Offspring. Pharmacol Biochem Behav 58(2):537–544. https://doi.org/10.1016/S0091-3057(97)00250-5 Wenger T, Tóth BE, Juanéda C, Leonardelli J, Tramu G (1999) The effects of cannabinoids on the regulation of reproduction. Life Sci 65(6):695–701. https://doi.org/10.1016/S0024-3205(99)00292-1 Wenger T, Tóth BE, Martin BR (1995) Effects of anandamide (endogen cannabinoid) on anterior pituitary hormone secretion in adult ovariectomized rats. Life Sci 56(23):2057–2063. https://doi.org/10.1016/0024-3205(95)00189-D World Health Organization (2025) Cannabis. World Health Organization. https://www.who.int/teams/mental-health-and-substance-use/alcohol-drugs-and-addictive-behaviours/drugs-psychoactive/cannabis Additional Declarations The authors declare no competing interests. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-7403198","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Systematic Review","associatedPublications":[],"authors":[{"id":502221739,"identity":"337c0c8b-a22b-4685-bb78-73f128b13b09","order_by":0,"name":"Nataly Ayoub","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA10lEQVRIiWNgGAWjYJACZgYGCTmStVgYQ5gJxGupSGwgWgv/jORj0oU7JNLXtp9O/Pjzh00+A/vhB3i1SNxIS5OeeUYid9uZ3M3SPAlplg08aQb4rbmRYybN2wbUcoN3gzRDwmEDBgkG/FrkoVrSzW7wbv75I+E/UAv7B7xaDKBaEoBatknwJBwAauHBb4vhmWfJ1jPbJAyBftlmzZOWbMDGk1OAV4vc8eSDtwvb6uTNjp/dfPOHjZ0BP/vxDXi1MAgkoAmw4VcPBPwHCCoZBaNgFIyCkQ4A795B0fnMN0gAAAAASUVORK5CYII=","orcid":"https://orcid.org/0009-0003-0155-5358","institution":"McMaster University","correspondingAuthor":true,"prefix":"","firstName":"Nataly","middleName":"","lastName":"Ayoub","suffix":""},{"id":502221740,"identity":"5191b8d2-c4a3-415e-a5f7-88b4875ca85d","order_by":1,"name":"Abjot Basra","email":"","orcid":"","institution":"McMaster University","correspondingAuthor":false,"prefix":"","firstName":"Abjot","middleName":"","lastName":"Basra","suffix":""},{"id":502221741,"identity":"642551ef-ae7b-48d1-b1d4-c3edb6f021e4","order_by":2,"name":"Leticia Galan","email":"","orcid":"","institution":"St. Joseph Healthcare Hamilton","correspondingAuthor":false,"prefix":"","firstName":"Leticia","middleName":"","lastName":"Galan","suffix":""},{"id":502221742,"identity":"12076ec9-7e60-41e1-a02e-1a7ec25fc3c9","order_by":3,"name":"Alison Shea","email":"","orcid":"","institution":"McMaster University","correspondingAuthor":false,"prefix":"","firstName":"Alison","middleName":"","lastName":"Shea","suffix":""}],"badges":[],"createdAt":"2025-08-19 00:19:45","currentVersionCode":1,"declarations":{"humanSubjects":false,"vertebrateSubjects":true,"conflictsOfInterestStatement":false,"humanSubjectEthicalGuidelines":false,"humanSubjectConsent":false,"humanSubjectClinicalTrial":false,"humanSubjectCaseReport":false,"vertebrateSubjectEthicalGuidelines":true},"doi":"10.21203/rs.3.rs-7403198/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-7403198/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":89471203,"identity":"85610031-db9c-4df6-8179-247dc63a2e38","added_by":"auto","created_at":"2025-08-20 09:27:46","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":124813,"visible":true,"origin":"","legend":"\u003cp\u003ePRISMA flow chart showing a screening of studies, selection, final, \u0026nbsp;\u0026nbsp;and exclusion of the studies\u003c/p\u003e","description":"","filename":"floatimage1.png","url":"https://assets-eu.researchsquare.com/files/rs-7403198/v1/9832204d27d41bc9d04a64c8.png"},{"id":89472735,"identity":"8edf0154-9849-45b4-a155-d4c0c61be6ad","added_by":"auto","created_at":"2025-08-20 09:51:47","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":768653,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-7403198/v1/54538086-10a9-4ffa-a1f0-2e2ce8c90734.pdf"},{"id":89471204,"identity":"8025f1b3-1655-436e-9d04-3ebe407013f3","added_by":"auto","created_at":"2025-08-20 09:27:46","extension":"docx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":64153,"visible":true,"origin":"","legend":"","description":"","filename":"AppendixAD.docx","url":"https://assets-eu.researchsquare.com/files/rs-7403198/v1/e07063dcf89833c77adaa763.docx"}],"financialInterests":"The authors declare no competing interests.","formattedTitle":"\u003cp\u003eThe Effect of Cannabis on Prolactin: A Scoping Review of Endocrine Implications for Maternal and Fetal Health\u003c/p\u003e","fulltext":[{"header":"INTRODUCTION","content":"\u003ch2\u003eBackground\u003c/h2\u003e\n\u003cp\u003eCannabis is the most cultivated, traded, and used illicit drug worldwide (\u003cu\u003eWorld Health Organization\u003c/u\u003e, 2025). Around 147 million people, or 2.5% of the global population, used cannabis in 2024 (\u003cu\u003eWorld Health Organization\u003c/u\u003e, 2025). Canada has seen a significant increase in cannabis use since its legalization through the Cannabis Act in October 2018. In 2024, more than 26% of Canadians had used cannabis in the past year, among whom 6% consumed cannabis nearly daily (\u003cu\u003eHealth Canada, \u003c/u\u003e2023). The information presented above represents the increasing acceptance of cannabis as well as global trends in cannabis opinions. Although cannabis use has its effects on various groups, normalization can be especially alarming among vulnerable populations, such as women of childbearing age, pregnant and lactating women. Until 2018, it was estimated that 47.6% of women of childbearing age (15-44 years) had used cannabis (\u003cu\u003eStatistics Canada, 2019\u003c/u\u003e). In 2020, among the age group 20-24, the prevalence of cannabis use in the previous 12 months was 20% (\u003cu\u003eHealth Canada, 2021\u003c/u\u003e). \u0026nbsp;\u003c/p\u003e\n\u003cp\u003ePrevalence rates reported among pregnant women in Canada have ranged from 2.6-11%. An anonymous questionnaire-based study in a large urban center in Ontario found 11.3% of respondents used cannabis at any point of pregnancy, 4.2% were continuing cannabis use, and 4.8% had plans to use cannabis while breastfeeding (\u003cu\u003eKaarid et al.\u003c/u\u003e, 2020). A Canadian maternal health survey of 7111 women also recently reported cannabis use during pregnancy at 3.1% and during breastfeeding at 2.6% \u003cu\u003eGrywacheski \u003cem\u003eet al.\u003c/em\u003e, 2021\u003c/u\u003e). Comparable rates were also reported in regional studies such as the BORN Ontario database, which demonstrated a 61% rise in cannabis use during pregnancy, from 1.2% in 2012 to 1.8% in 2017 (\u003cu\u003eCorsi \u003cem\u003eet al.\u003c/em\u003e, 2019\u003c/u\u003e). \u0026nbsp;Cannabis use during pregnancy has been associated with poor birth outcomes but there is a paucity of information on how cannabis may affect lactation, and the hormones involved (Luke et al., 2019; \u003cu\u003eKim, 2020\u003c/u\u003e).\u003c/p\u003e\n\u003cp\u003eProlactin (PRL) plays a critical role in lactation during pregnancy and milk synthesis in the postpartum period as it participates in lactogenesis, enabling the production of essential ingredients in human milk for infant growth and immune maturation (\u003cu\u003eKim, 2020\u003c/u\u003e). In stage II lactogenesis, which commences after parturition, lactogenesis is coupled with a rise in the secretion of PRL and metabolic adaptation necessary for milk secretion, while stage I lactogenesis takes place several weeks prior to parturition when PRL accumulation of milk substrate (Hartmann, 1973). Peak PRL levels during stage III lactogenesis further regulate milk composition, promoting the synthesis of proteins like \u0026beta;-casein (Kobayashi et al., 2016; Vorherr H, 1979). In addition to its lactation function, PRL is synthesized in various sites other than the pituitary, such as the brain and placenta, where it plays an important role in neuroendocrine and immune system development during fetal growth (Lawrence \u0026amp; Lawrence, 2011, p. 69). Low PRL levels in mothers are related to negative infant birth and developmental outcomes. Compared to newborns exposed to normal range PRL levels, the birth weight Z-scores decreased by 0.169 units for newborns of mothers with low PRL levels (\u003cu\u003eWang \u003cem\u003eet al.\u003c/em\u003e, 2022\u003c/u\u003e). Apart from birth weight, maternal PRL levels also seem to have an impact on postnatal growth and neurodevelopment. Higher PRL levels were positively correlated with elevated insulin-like growth factor 1 (IGF-1), a growth promoting hormone, of the offspring, but with no statistically significant relationship with placental growth hormone (\u003cu\u003eWang \u003cem\u003eet al.\u003c/em\u003e, 2022\u003c/u\u003e). Alongside prolactin\u0026rsquo;s role in lactation, downstream effects on cognitive development through breastfeeding are also evident. Breastfeeding has been previously demonstrated to promote brain structure, white matter growth and cognitive abilities (Chade et al., 2024). However, little is known about how cannabis may affect PRL in pregnancy and lactating individuals.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eObjective\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe objective of this scoping review is to systematically map what is known regarding the association between cannabis exposure and PRL levels in females, particularly when considering pregnant and lactating individuals. This article aims to summarize existing literature on the acute and chronic effects of cannabis use on PRL, to explore methodological patterns and constraints, and to discuss the relevance for maternal and infant health.\u003c/p\u003e\n\u003cp\u003eInformed by the Population\u0026ndash;Concept\u0026ndash;Context framework, the following research question is addressed: \u003cem\u003eWhat is the effect of cannabis use on PRL levels in female participants, particularly in the context of maternal and fetal health? \u003c/em\u003e\u003c/p\u003e\n\u003cul\u003e\n\u003cli\u003e\u003cstrong\u003ePopulation:\u003c/strong\u003e Female subjects, with an emphasis on pregnant and lactating individuals (including human and animal studies)\u003c/li\u003e\n\u003cli\u003e\u003cstrong\u003eConcept:\u003c/strong\u003e Exposure to cannabis or cannabinoids and their effects on PRL levels\u003c/li\u003e\n\u003cli\u003e\u003cstrong\u003eContext:\u003c/strong\u003e Clinical, preclinical, and epidemiological settings involving reproductive and endocrine health\u003c/li\u003e\n\u003c/ul\u003e"},{"header":"METHODS","content":"\u003ch2\u003eScoping Review Protocol:\u003c/h2\u003e\n\u003cp\u003eThere was no registered protocol for this scoping review. The approach was designed based on Arksey and O\u0026rsquo;Malley\u0026rsquo;s model and the PRISMA-ScR extension criteria.\u003c/p\u003e\n\u003ch2\u003eSearch Strategy\u003c/h2\u003e\n\u003cp\u003eTo obtain a comprehensive review of existing literature, a search was performed on OVID Medline, Scope and Embase between September and December 24th, 2024. A comprehensive and structured search strategy was used to search for the concept of the review using various search terms (Appendix A).\u003c/p\u003e\n\u003cp\u003eThe\u0026ensp;PICOS framework was used to select the studies with the population of interest being females who were pregnant or non-pregnant. The exposure was cannabis, and the outcome of interest was PRL. Eligible studies could or could not have been with control; and included study designs could be experimental (e.g. randomized controlled trials,\u0026ensp;preclinical animal studies) or observational studies (e.g. cohort, case-control, cross-sectional). Papers were excluded if they focused on topics unrelated to PRL regulation or lactation (i.e., schizophrenia, Parkinson\u0026rsquo;s Disease), analyzing the effect of other substances (e.g., alcohol, amphetamines) with cannabis interaction in PRL regulation.\u003c/p\u003e\n\u003ch2\u003eData Extraction\u003c/h2\u003e\n\u003cp\u003eTo present the key findings of studies included in this scoping review, a data extraction form was developed. Major headings, such as authors, publication year, study design, population descriptions, intervention, control, outcome, period and duration of exposure are captured. It also included methods of cannabis administration and dosage. The main results of each study were also reported, with particular emphasis on the impact of cannabis in women, either in the general population or during pregnancy, regarding PRL levels. The screening was independently conducted by two reviewers, which contributed to the accuracy and consistency of the information collected.\u003c/p\u003e\n\u003ch2\u003eData Analysis\u003c/h2\u003e\n\u003cp\u003eTo enable an efficient synthesis of the evidence, the extracted data were charted based on several study characteristics including study design, type of cannabis, and outcome measures. A narrative synthesis methodology was then used to describe the literature.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCritical Appraisal of Individual Sources of Evidence\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAs per the objectives of a scoping review, no formal critical appraisal or risk of bias assessment was conducted. The focus was on the mapping of the current literature and not on the quality or strength of the evidence.\u003c/p\u003e"},{"header":"RESULTS","content":"\u003ch2\u003eFlow Diagram\u003c/h2\u003e\n\u003cp\u003eThe study selection is shown in a flowchart that presents the progress of the articles from the search to the exclusion steps (Figure 1). First, a total of 596 studies were found, and 203 duplicates were removed, resulting in 393 unique studies for screening. 269 studies were excluded after the screening phase due to failure to meet the exclusion criteria. Of these, 94 articles were excluded following the full text review as they were not consistent with the prespecified eligibility criteria (Appendix B). A total of 30 studies were finally included in the review.\u003c/p\u003e\n\u003ch2\u003eSource of Evidence Characteristics\u003c/h2\u003e\n\u003cp\u003eOf the 30 studies included in our review, most had been published before 2000, that is: 24 (80.0%)\u0026ensp;in the pre-2000 period, 4 (13.3%) in the 2000‒2010 period, 1 (3.3%) in the 2010‒2020 period, and 1 (3.3%) in the 2020‒2025 period (Appendix C\u003cu\u003e)\u003c/u\u003e. Most of the studies were experimental studies in animals (n=23/76.7%) followed by observational human studies (n=7/23.3%). All studies incorporated female populations as the primary aim, where 22 (73.3%) included non-pregnant populations, 7 (23.3%) pregnant populations and 1 study (3.3%) both non-pregnant and pregnant populations.\u003c/p\u003e\n\u003cp\u003eAmong the 23 experimental animal studies included, 9 studies (39.1%) were carried out in ovariectomized (OVX) animals, to mimic the absence of hormones. Rats were the animal model in 17 (73.9%) studies where 3 (13.0%) utilized monkeys and 3 (13.0%) contained unspecified mice or rodent strains. Pregnancy-related models were used in 7 studies (30.4%), employing naturally pregnant, pseudopregnant, or postpartum rats and mice. Few studies (n=1, 4.3%) among these 7 animal studies combined pregnant and non-pregnant groups. Sample sizes among studies were quite variable, with as few as 3 animals per group to 20 animals per group, with the majority of studies making use of 8-10 animals per group as a standard for hormones.\u003c/p\u003e\n\u003cp\u003eOf\u0026ensp;the seven studies examined in humans, age was only indicated in 6, and 5 studies reported both mean and SD. Age was reported inconsistently even among these five studies: some studies averaged ages across the entire sample (e.g., users and controls grouped together); others reported separate user subgroup means. The age of all females was between 18 to 55 years; and the mean ages of participants in each of the reviewed studies were between 23 and 29 years. A summary of reported mean ages results in an average age of 25.3 years, describing young to early middle-aged adult females as the main population studied for cannabis and PRL modulation.\u003c/p\u003e\n\u003cp\u003eStudy designs differed in classification of cannabis exposure: frequent users were often defined as using cannabis \u0026ge;10 times monthly or \u0026ge;100 times ever, and this was confirmed by a positive urine drug screen. Several studies classified users into types based on frequency (e.g., frequent, moderate, infrequent); one study requested only a minimum of one year of history of use with abstinence before testing. Three of these studies applied acute administration paradigms (e.g., vaporized or IV \u0026Delta;⁹- tetrahydrocannabinol (THC)), the remaining ones medicated chronic or combined chronic-acute exposure profiles, three of them testing PRL response to THC in regular consumers. Duration of exposure was also different, with most studies reporting findings based on chronic use (repeated or habitual use over weeks to years), and three studies of acute administration of THC, whether IV or inhalation, respectively.\u003c/p\u003e\n\u003cp\u003eIn terms of the impact of cannabis on PRL levels in all 30 studies, 14 (46.7%) reported a decrease in PRL, 10 (33.3%) had mixed effects, and 6 (20.0%) reported no effect. Within the 23 animal in vivo studies, 11 (47.8%) saw a reduction, 9 (39.1%) showed inconsistent effects, and 3 (13.0%) found no effect. Of the 7 human in vivo studies, similar heterogeneity existed: 3 (42.9%) reported a reduction in PRL,\u0026ensp;1 (14.3%) reported mixed results, and 3 (42.9%) reported no effect. Regarding the classes of cannabis compounds tested in vivo animal studies, \u0026Delta; 9-THC was the most common compound that was researched (n = 19, 82.6%), and was followed by anandamide (ANA, n = 2, 8.7%), a combination of \u0026Delta; 9-THC and ANA (n = 1, 4.3%) and HU-210 (n = 1, 4.3%).\u003c/p\u003e\n\u003cp\u003eIn general, much of the evidence consists of older animal studies reports. The small number of recent human studies, particularly amongst pregnant populations, highlights an important gap of knowledge.\u003c/p\u003e\n\u003ch2\u003eFindings\u003c/h2\u003e\n\u003cp\u003eSee Appendix D for an overview of the included studies.\u003c/p\u003e\n\u003ch3\u003eAnimal Studies (Pregnancy):\u003c/h3\u003e\n\u003cp\u003eSeveral significant findings are considered based on experimental animal studies. Wenger et al. (\u003cu\u003e1997\u003c/u\u003e) examined the effects of ANA, an endogenous cannabinoid, on pregnant rats, compared to the exogenous cannabinoid THC, the principal psychoactive agent in marijuana. Daily intraperitoneal injections of ANA and THC (0.02 mg/kg) were given between the third week of pregnancy (a developmental time point similar to the final stage of pregnancy in humans). Hormonally, ANA and THC decreased luteinizing hormone (LH) and serum PRL, whereas ANA also inhibited pituitary PRL and serum growth hormone. Furthermore, Wenger and his colleagues (\u003cu\u003e1999\u003c/u\u003e) also studied the effect of cannabinoids on reproduction where a single injection of ANA was given. Two additional groups of female rats were treated with ANA by intraperitoneal administration at a dose of 0.02 mg/kg daily in acute-sub chronic exposure lasting days during the third week of pregnancy. They demonstrated that ANA exposure at this sensitive time led to maternal hyperprolactinemia, a lower LH and PRL level, prolonged pregnancy, and a higher rate of stillbirth.\u003c/p\u003e\n\u003cp\u003eBromley et al. (\u003cu\u003e1978\u003c/u\u003e) studied the immediate effects of THC on PRL release in lactating rats and found that suckling-induced PRL levels were significantly inhibited, accompanied by impaired maternal behaviors specifically involving pup retrieval and crouching. Lactating rats were trained to nurse their pups and then were administered either intravenous THC (1.25 or 4.0 mg/kg) or a vehicle on the training day. This brief time interval (30 min-2 h post-treatment) corresponds to an acute exposure study. However, the single THC injection was enough to disturb the hormonal responses, suppressing suckling-induced PRL rise within 30 min and lasting 2 hrs. It indicates THC's ability to disrupt maternal behaviors during lactation, possibly mediated through centralized hormone action.\u003c/p\u003e\n\u003cp\u003eHughes Jr. et al. (\u003cu\u003e1982\u003c/u\u003e) also investigated THC\u0026rsquo;s influence on releasing PRL in pseudopregnant rats, a condition similar to normal pregnancy observed in female rats, where the animals basal blood levels of hormones resemble those found in pregnant animals even in absence of embryo implantation achieved through stimulation of the cervix. The use of this model isolated maternal hormone regulation. THC was given briefly as dosing occurred acutely, but repeatedly (hourly \u0026times; 1.0 mg/kg body weight) for roughly 17h of exposure. This acute, time-restricted exposure was designed to interfere with the nocturnal surge of PRL which drives early pseudopregnancy. This study demonstrated that THC effectively inhibits the secretion of PRL until 6:00 a.m. on Day 2, after which levels returned to control levels. Despite this short-term disruption, the length of pseudopregnancy was unaffected, indicating that short-term THC exposure can cause temporary disruption to hormonal control without the potential for broader reproductive impacts.\u003c/p\u003e\n\u003cp\u003eAll previous studies showed how PRL levels can be suppressed to some extent by using pregnant animals in experiments, but the research below shows nuanced results. Garc\u0026iacute;a-Gil et al. (\u003cu\u003e1997\u003c/u\u003e) evaluated the consequences of chronic perinatal exposure to \u0026Delta;9-THC in Wistar rats, with the administration of daily oral doses of 5 mg/kg from gestational day 5 to postnatal day 24, which cuts across a significant period of development including those of the late gestation and lactation. The extended exposure potentially evoked greater adaptive neuroendocrine responses that would have maintained regulation of basal PRL levels, while avoiding the decreases in acute models observed. Moreover, Raine et al. (\u003cu\u003e1978\u003c/u\u003e) studied the impact of \u0026Delta;1-THC on plasma PRL concentrations, and on the development of the mammary gland of the mouse in late pregnancy and of the lactating gland. The study included chronic exposure in which animals were monitored from late pregnancy (approximately day 17) to early (day 2) and maximum lactation (day 12) with their pup. They found that high lipoprotein lipase activity, which occurs normally in the mammary gland at parturition, was greatly reduced by THC. Furthermore, the elevation of plasma PRL to peak levels was advanced in the control group compared with THC treated mice suggesting that THC delayed the PRL surge during lactation. This late PRL peak may hold responsibility for impaired mammary gland development and the delayed onset of a peak lipoprotein lipase activity necessary for lactation. Wenger et al. (\u003cu\u003e1997\u003c/u\u003e) administered daily THC injections from gestational day 14 until delivery (equivalent to the third week of pregnancy), and found that the effects on PRL were time-dependent: pituitary PRL initially decreased on days 0 and 5 but rebounded by day 10, while serum PRL declined in both sexes on day 0 and remained suppressed in females through day 10.\u003c/p\u003e\n\u003cp\u003eCollectively, this series of studies underscore the complex effects of cannabinoids on pregnancy and lactation, with a focus on effects at the level of\u0026ensp;hormone control, maternal behavior and offspring development.\u003c/p\u003e\n\u003ch3\u003eAnimal Studies\u003c/h3\u003e\n\u003cp\u003eVariability of the cannabinoid-regulated PRL secretion in female experimental animals depends on various parameters, such as the phase of the estrous or the reproductive cycle, cannabinoid dose, treatment duration and hormonal status. The results of the acute and chronic cannabinoid treatment on PRL vary from inhibition to no changes and on occasions also biphasic effects in the 16 studies, indicating dynamic neuroendocrine interactions.\u003c/p\u003e\n\u003cp\u003eEarly studies of acute effects of cannabinoids displayed mixed results. Asch et al. (\u003cu\u003e1981\u003c/u\u003e) gave one-time doses of THC (2.5 mg/kg) to sexually mature female rhesus monkeys in the follicular phase and found no significant changes in PRL levels. It remains unclear whether the results were due to confounding factors, such as sampling that did not align with natural estrogen fluctuations, or if it reflects a true null result, suggesting that the endogenous PRL response may not be particularly sensitive to THC exposure. In contrast, Field et al. (\u003cu\u003e1986\u003c/u\u003e) have shown in prepubertal female rats that acute THC 10 mg-1 kg decreased PRL significantly, noting that it blocked the late afternoon surge of PRL in proestrus rats, an effect which diminished with repeated exposures to the drug.\u003c/p\u003e\n\u003cp\u003eMore subtle inferences could be drawn from observed effects of reproductive cycle stages. In a more elaborate approach, Bonnin et al. (\u003cu\u003e1993\u003c/u\u003e) examined THC-induced changes in PRL and dopaminergic mechanisms in female rhesus monkeys in relation to the phases of the cycle. They observed that THC also enhanced PRL during the afternoon on the day of estrus, and this change was associated with a decrease in anterior pituitary D2 dopamine receptor density, a receptor through which inhibitory dopaminergic control of PRL is mediated. Acute high-dose THC also reduced PRL on the day of estrus in adult females rats (Chakravarty et al., \u003cu\u003e1975\u003c/u\u003e). Consistent with these findings, Martin-Calderon et al. (\u003cu\u003e1998\u003c/u\u003e) studied the effects of HU-210, a cannabinoid synthetic analogue, on PRL in female rats, showing a biphasic response. Low doses of HU-210 (4 \u0026mu;g/kg) induced PRL secretion, whereas higher doses (20 and 100 \u0026mu;g/kg) were associated with a marked inhibition of PRL release. Wenger et al. (\u003cu\u003e1995\u003c/u\u003e) demonstrated that THC and ANA (both at 0.02 mg /kg) produced a decrease in serum PRL and LH\u0026ensp;(but not FSH) in OVX. These findings raise the possibility that cannabinoids, in the absence of ovarian hormones, modulate pituitary hormone secretion directly via a neuroendocrine mechanism rather through the integrated hormonal pathways that are functioning during pregnancy. Consistent with this, Steger et al. (\u003cu\u003e1983\u003c/u\u003e) observed that\u0026ensp;in estrogen-primed OVX rats THC inhibited PRL surges provoked by progesterone, a result confirmed later by Hughes et al. (\u003cu\u003e1981\u003c/u\u003e) which showed that the reduction of PRL by THC occurred centrally and not directly in the pituitary, since the effect was absent in hypophysectomized rats or isolated pituitary tissue. Similarly, Asch et al. (\u003cu\u003e1979\u003c/u\u003e) reported that acute THC treatment decreased PRL levels in oophorectomized female rhesus monkeys. However, the suppressive effect of THC on\u0026ensp;PRL secretion was reversed by TRH (thyrotropin-releasing hormone) administration. This indicates that the suppression of response to TRH by THC is at the hypothalamic level involving estrogen release, rather than at the level of the pituitary. Although these acute effects are important to consider, we must also explore more chronic exposure as may be the case for pregnant and lactating individuals.\u003c/p\u003e\n\u003cp\u003eOur investigation has suggested that chronic cannabinoid exposure is complicated, but the effects appear to be similar. Chakravarty et al. (\u003cu\u003e1979) \u003c/u\u003edescribed long-term decreases in serum PRL levels, and disruption of the estrous cycle of rats treated for 10 days with THC. Murphy et al. (\u003cu\u003e1991) \u003c/u\u003edemonstrated that THC reduced levels of estradiol-induced PRL surges in immature female rats only at certain times of day, without affecting dopaminergic function (indicating estrogen-cannabinoid interactions that are not mediated via the classical dopaminergic pathways). Hormonal influences over the cannabinoid effects were experimented by Scorticati et al. (\u003cu\u003e2003)\u003c/u\u003e, which reported that ANA by itself did not have a significant effect on PRL, however, these effects were modulated by estrogen presence, indicating that cannabinoid responsiveness is hormone dependent. Tyrey (\u003cu\u003e1986) \u003c/u\u003ealso evaluated THC in ovariectomized female rats and reported that it reduced plasma levels of PRL; yet the medial basal hypothalamus of the brain was removed, THC no longer produced decreases in PRL levels, suggesting that this region of the brain is crucial to THC\u0026rsquo;s effect on PRL. More recently, Ryan et al. (\u003cu\u003e2021)\u003c/u\u003e treated female rhesus monkeys with THC 1 mg/kg s.c. for 4 months and reported no alterations to PRL. Even with chronic use in a primate model, PRL levels remained steady. Nonetheless, tolerance may be evident after chronic exposure, and cannabinoid effects may depend on the administration time as well\u0026ensp;as the hormonal status of the animal. Only one study was located that examined perinatal THC administration and this produced long-term PRL suppression in adult female offspring (Murphy et al., \u003cu\u003e1995)\u003c/u\u003e.\u003c/p\u003e\n\u003ch3\u003eHuman Studies (Pregnancy \u0026amp; General Women):\u003c/h3\u003e\n\u003cp\u003eThe effect of cannabis on PRL in humans studies are inconsistent, with some indicating no effect and others observing reductions. A comprehensive investigation was carried out by Block et al. (\u003cu\u003e1991\u003c/u\u003e), long-term use of cannabis, defined as using marijuana on more than a weekly basis in the last two years, was not linked to a change in serum PRL levels in comparison with non-users. There were 149 participants, aged 18\u0026ndash;42 (mean age was 23.5), with frequent users categorized as consuming cannabis at least seven days per week. The research did not, however, detail what type of cannabis had been used, and the results could be different with higher-potency products or another length of exposure.\u003c/p\u003e\n\u003cp\u003eRanganathan et al. (\u003cu\u003e2009\u003c/u\u003e) reported significantly reduced baseline PRL in frequent cannabis users (defined as having used cannabis 10+ times the month prior to recruitment: all with positive (\u0026Delta;9-THC concentration \u0026gt;50 ng/mL) urine toxicology compared to non-cannabis users. Schander et al. (\u003cu\u003e2008\u003c/u\u003e) had the same methodology but reported decreased change in PRL post-administration. D\u0026rsquo;Souza et al. (\u003cu\u003e2008\u003c/u\u003e) also observed decreased baseline PRL secretion in frequent female cannabis users. The study involved 28 participants (17 healthy controls and 11 frequent cannabis users) who received a placebo and an active challenge with haloperidol (0.057 mg/kg) on two separate test days, each preceded by placebo/active \u0026Delta;-9-THC (0.0286 mg/kg) intravenously. Heavier users were determined by 100+ lifetime uses, use in the last week, or diagnosis of cannabis abuse disorder. They were exposed not chronically, but with THC, 90- and 215-minutes following haloperidol. The lower baseline PRL levels of frequent users indicated chronic cannabis use could alter long-term, but not short-term, dopaminergic activity,\u0026ensp;particularly in the tuberoinfundibular pathway, responsible for the regulation of PRL release.\u003c/p\u003e\n\u003cp\u003eBy contrast, other studies have described initial suppression of PRL after THC. In a study by Klumpers et al. (\u003cu\u003e2012\u003c/u\u003e), THC inhalation resulted in a 21% reduction in PRL levels compared to placebo, among women of reproductive age (18-45 years) particularly after repeated doses (2-, 6-, and 6 mg) or placebo via inhalation with 1.5 h intervals. Similarly, Mendelson et al. (\u003cu\u003e1985\u003c/u\u003e) reported that PRL decreased significantly over time after smoking a marijuana cigarette containing 1.8% \u0026Delta;-9-THC on the day of ovulation in the woman's menstrual cycle. Eight healthy adult females aged 21\u0026ndash;33 years (mean age 26 years), who regularly used cannabis (14 occasions per month) were enrolled. This was an acute exposure trial in which each participant smoked one marijuana cigarette weighing 1 gram over approximately 12 minutes. Estradiol and progesterone remained unchanged, whereas LH and PRL revealed modest but significant pulses of \u0026sim;45-minute duration indicating that there are acute yet tangible endocrine shifts due to THC.\u003c/p\u003e\n\u003cp\u003eWith respect to pregnancy, only one study could be located with this population of female humans. Braunstein et al. (\u003cu\u003e1983\u003c/u\u003e) compared 13 pregnant participants who were cannabis users, all at different trimesters to a matched group of 13 non-users. Cannabis use was verified via tests for THC in blood serum, varying from 3.2 to 70.6 ng/ml (suggesting recent use during 2\u0026ndash;4 h before testing). Hormone levels were measured, and they found no difference in the secretion of PRL and other hormones among users and non-users.\u003c/p\u003e"},{"header":"DISCUSSION","content":"\u003ch2\u003eInterpretation of Findings\u003c/h2\u003e\n\u003cp\u003eThrough this scoping review, we found that the relationship between cannabis and PRL concentrations among females is complex, and the literature are heterogeneous.\u003c/p\u003e\n\u003cp\u003eIn animal studies, particularly in rats, cannabinoids have a general inhibitory impact on PRL secretion. These effects are most pronounced in acute exposure. THC has been shown to reduce pituitary and serum PRL levels in pregnant rats, to inhibit suckling-induced PRL release in lactating rats, and to interfere with maternal behavior, possibly impairing reproductive and maternal functioning. Furthermore, THC delayed nocturnal PRL surge in pseudopregnant rats, and inhibited PRL release depending on the time of administration during the estrous cycle, with suppression observed in the morning of estrus but stimulation noted in the afternoon. Such data emphasizes the circadian control of PRL. Because PRL peaks nocturnally, during the hours breastfeeding infants typically nurse, cannabis use by a lactating mother, especially early in the morning, could affect this circadian surge, alongside declining milk production. The consumption of cannabis among women, could interfere with the natural hormonal surge with potential negative ramifications on their milk quantity. This is particularly important in neonates who require regular night feeds for growth, development, and immune function. The failure to control for circadian variations, particularly for its nocturnal and early morning peaks may explain the heterogeneity in the effects of cannabis observed in human studies. ANA-induced inhibition of PRL was also demonstrated in ovariectomized rats, and estrogen was found to modulate the response of PRL. In terms of mechanisms, these inhibitory effects may be located centrally, presumably involving THC-induced stimulation of hypothalamic dopamine activity and subsequent PRL suppression via dopaminergic blockade of the pituitary. Species-dependent effects, differences in doses, hormonal status, and experimental design (e.g., timing of the sampling and using single time-point measurement of PRL) contribute to the difficulty of comparing results across studies.\u003c/p\u003e\n\u003cp\u003eThe currently available human studies display mixed findings. Some have observed a decrease in serum PRL, particularly in the luteal phases of nonpregnant women, while others have no effect or rather an elevation in PRL levels. Considering the length and nature of exposure, acute exposure may lead to temporary PRL suppression, but with chronic exposure, there may be compensatory action through a new homeostasis. In pregnant human users, a single study that was located indicated that cannabis intake did not affect placental hormones or PRL levels, yet functional lactation success is less frequently evaluated. Clearly, we need more studies investigating this possible association (or lack thereof).\u003c/p\u003e\n\u003cp\u003eFrom a clinical perspective, these results highlight the importance of early detection and counseling in reproductive care. Providers should not only inquire about cannabis use, but the timing, frequency, and route of administration. Providing evidence-based information on the hormonal effects of cannabis to patients is critical, especially when cannabis is a common choice for anxiety or nausea management, to facilitate empowered decision-making. From a healthcare practice management perspective, childcare providers need to consider cannabis use as a possible factor when assessing concerns about breastfeeding, such as low milk production or abrupt end to lactation. Long-term management may involve breastfeeding support, monitoring of PRL as indicated, and individualized support to address patients\u0026rsquo; inability to cease treatment. Pediatric Nurse Practitioners and pediatric oriented Family Nurse Practitioners are ideally placed to recognize early signs of cannabis-induced hormonal disruptions, particularly in the postpartum period. Nurse practitioners should incorporate these findings in anticipatory guidance, lactation consultations, and care plans, to advance maternal-child outcomes with routine screening and patient-centered education.\u003c/p\u003e\n\u003ch2\u003eStrengths \u0026amp; Limitations\u003c/h2\u003e\n\u003cp\u003eThis review has a particular strength in its incorporation of animal and human studies, examining the interactions of cannabinoids, including THC, anandamide, and synthetic analogs, on PRL control over distinct reproductive states. This cross-species, cross-context process makes it possible to elaborate mechanisms by which cannabinoid exposure in specific \u0026ldquo;critical periods\u0026rdquo;, including pregnancy, lactation, estrous or menstrual cycle phases, may lead to various endocrine changes. The review provides a holistic, yet in-depth view of cannabinoid-PRL interactions through interpretation of experimental models and real-life human data.\u003c/p\u003e\n\u003cp\u003eHowever, some limitations hinder interpretability and generalizability of the results. A large percentage of this information comes from rodent models, which provide useful mechanistic insights but are too simplistic to model the complexities of human hormonal control. In addition, a minority of studies included non-human primates or a pregnancy intervention, limiting their relevance to specific populations, including pregnant and lactating persons. The sizes of samples in both animal and human studies were often small, underpowering the detection of subtle or long-lasting effects. Human studies exhibited heterogeneity in the definitions of cannabis exposure such as frequency, dose, route of administration, and cannabinoid composition. Critically, limitations are also inherent in the nature of the scoping review method. As opposed to systematic reviews or meta-analyses, the goal of scoping reviews is to map the unindexed literature and determine knowledge gaps rather than critique the quality of studies or combine effect sizes. The inclusion criteria were thus deliberately broad, and there is heterogeneity in the quality of studies and method used. In addition, the lack of formal risk-of-bias does not allow presented findings to be weighted to their confidence in their rigor of study.\u003c/p\u003e"},{"header":"CONCLUSION","content":"\u003ch2\u003eSummary\u003c/h2\u003e\n\u003cp\u003eThis scoping review aimed to explore the effects of cannabis on PRL secretion in relation to the reproductive stages among both animals and humans. In animal models, exposure to cannabis (acute or chronic) predominantly inhibits PRL. This action was evident across various reproductive contexts (pregnant, lactating, pseudopregnant, and estrous cycling), and seems to be a centrally mediated event, likely through the hypothalamic dopaminergic pathways. Some studies demonstrated biphasic responses depending on dosage, timing, and hormonal context. During pregnancy, PRL suppression did not always equate with obvious reproductive dysfunction, but aberrations in rhythms and lactational signaling were observed. Findings from human studies were less consistent. Some studies reported reduced PRL after acute THC exposure, especially in nonpregnant women, whereas other studies found no change or even increases according to hormonal phase and tolerance. Pregnancy-specific data in human studies is extremely limited.\u003c/p\u003e\n\u003ch2\u003eFuture Directions\u003c/h2\u003e\n\u003cp\u003eWell-designed human studies are needed to explain the effects of cannabis on PRL in distinct populations and levels of use with longitudinal studies, as well as definite studies during pregnancy and lactation. More detailed studies of biphasic reactions and the underlying mechanisms, with standardized protocols considering different cannabinoid profiles, are also urgently necessary.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cdiv class=\"DefinitionList\"\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eTHC\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eTetrahydrocannabinol\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003ePRL\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eProlactin\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003c/div\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate\u003c/strong\u003e\u003cbr\u003e\u0026nbsp;Not applicable.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication\u003c/strong\u003e\u003cbr\u003e\u0026nbsp;Not applicable.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of data and materials\u003c/strong\u003e\u003cbr\u003e\u0026nbsp;All data generated or analyzed during this study are included in this manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests\u003c/strong\u003e\u003cbr\u003e\u0026nbsp;The authors declare that they have no competing interests.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003cbr\u003e\u0026nbsp;This research received no external funding.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthors' contributions\u003c/strong\u003e\u003cbr\u003e\u0026nbsp;A.S. supervised the project and, together with L.G., contributed to the interpretation of the data and revision of the manuscript. A.B. served as a second reviewer during data screening and contributed to editing the scoping review. N.A. participated in data screening, conducted analysis and interpretation of results, drafted the manuscript, prepared the figures and appendix, edited content, and implemented feedback during revision. All authors approved the submitted version of the manuscript and agree to be personally accountable for their own contributions as well as to ensure the integrity and accuracy of the work as a whole.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgements\u003c/strong\u003e\u003cbr\u003e\u0026nbsp;The authors would like to thank the Faculty of Health Sciences at McMaster University for providing institutional support for this research.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eAsch RH, Smith CG, Siler-Khodr TM, Pauerstein CJ (1979) Acute Decreases in Serum Prolactin Concentrations Caused by ∆9-Tetrahydrocannabinol in Nonhuman Primates*\u0026dagger;. 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World Health Organization. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://www.who.int/teams/mental-health-and-substance-use/alcohol-drugs-and-addictive-behaviours/drugs-psychoactive/cannabis\u003c/span\u003e\u003cspan address=\"https://www.who.int/teams/mental-health-and-substance-use/alcohol-drugs-and-addictive-behaviours/drugs-psychoactive/cannabis\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":true,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":true,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"Pregnancy, Lactation, Reproduction, Cannabinoids, Perinatal Care","lastPublishedDoi":"10.21203/rs.3.rs-7403198/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-7403198/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eBackground: \u003c/strong\u003eCannabis use is increasing among women of reproductive age, yet its effects on prolactin (PRL), a hormone critical to lactation and maternal health, are poorly understood, especially in pregnancy and lactation contexts.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eObjectives: \u003c/strong\u003eA scoping review exploring cannabis and prolactin levels in reproductive states was conducted to map the evidence and identify gaps for future research.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMethod: \u003c/strong\u003eEnglish peer-reviewed studies investigating the effect of cannabis or cannabinoids on prolactin in female or maternal models, either animal or human, were included. Medline, Scopus, and Embase were searched. Two reviewers screened data on study design, population, cannabis exposure, prolactin measures, and outcomes.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eResults:\u003c/strong\u003e Thirty studies were included. In animals, tetrahydrocannabinol exposure often suppressed prolactin, especially during key reproductive stages. Human studies were inconsistent, with limited data on pregnancy or lactation.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusions: \u003c/strong\u003eCannabis impacts prolactin in a species- and context-specific manner. More rigorous human studies are urgently needed to guide perinatal care.\u003c/p\u003e","manuscriptTitle":"The Effect of Cannabis on Prolactin: A Scoping Review of Endocrine Implications for Maternal and Fetal Health","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-08-20 09:27:42","doi":"10.21203/rs.3.rs-7403198/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"2779e937-b2af-4e58-ab7c-47521a3121e3","owner":[],"postedDate":"August 20th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[{"id":53342732,"name":"Drug Discovery, Design, \u0026 Development"}],"tags":[],"updatedAt":"2025-08-20T09:27:42+00:00","versionOfRecord":[],"versionCreatedAt":"2025-08-20 09:27:42","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-7403198","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-7403198","identity":"rs-7403198","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}