5-HT₃ Receptor ( IC50 = 308 nM ); D₂ Receptor ( IC50 = 483 nM )

Metoclopramide hydrochloride hydrate (0.01-10 μM) stimulates the release of aldosterone in rat zona glomerulosa cells that have been perfused and isolated[3].
Metoclopramide hydrochloride hydrate causes prokinesis through four different mechanisms: it inhibits D2 postsynaptic receptors, stimulates presynaptic excitatory 5-HT4 receptors, and antagonizes the presynaptic inhibition of muscarinic receptors, which increases the release of acetylcholine (ACh) from intrinsic cholinergic motor neurons[2].

Metoclopramide (6.7 µg/g; s.c. daily for 50 days) hydrochloride hydrate dramatically raises the pituitary gland's lactotroph cell count and volume aall stages of the estrous cycle[4].
Metoclopramide (5–40 mg/kg; intraperitoneal) hydrochloride hydrate causes catalepsy and counteracts the behavior of cage climbing induced by apomorphine in mice[5].
Metoclopramide (1.25–2.5 mg/kg; i.p.) causes a stereotyped cage-climbing behavior in mice[5].

Adult, virgin female mice of the Swiss EPM-1 strain
6.7 µg/g
S.c. daily for 50 days

Effects During Pregnancy and Lactation
◉ Overview of Lactation Use
Metoclopramide is excreted into breast milk to varying degrees. After oral and intranasal administration, most infants ingest doses less than 10% of the mother's weight-adjusted dose, but some infants ingest doses reaching pharmacologically active serum concentrations, leading to elevated serum prolactin levels and potentially gastrointestinal side effects. Although most studies have found no adverse effects in breastfed infants while their mothers are taking Metoclopramide, many studies have not adequately observed side effects.
Metoclopramide can increase serum prolactin levels and has been used as a galactagogue. A meta-analysis of five placebo-controlled studies concluded that two weeks of Metoclopramide use did not lead to an increase in serum prolactin levels, but three weeks did. A more recent meta-analysis concluded that Metoclopramide, as a galactagogue, offers no benefit to mothers of preterm infants. The third meta-analysis included eight trials involving 342 lactating women (whose infants were either preterm or full-term). The results showed that Metoclopramide increased serum prolactin levels but did not increase milk production. The clinical value of Metoclopramide in increasing milk production is debatable. Lactation stimulants should never replace assessment and counseling of controllable factors affecting milk production. In well-designed studies, researchers evaluated the effectiveness of Metoclopramide as a lactation stimulant in women who had difficulty producing milk despite optimized breastfeeding techniques, showing no additional benefit. Prophylactic use of Metoclopramide also offered little benefit to mothers of preterm infants. There is currently no officially established dose of Metoclopramide for increasing milk production. Most studies used a dose of 10 mg two to three times daily for 7 to 14 days. Some studies used a tapering method in the last few days of treatment to avoid a sudden drop in milk production after discontinuation. There is currently no published literature supporting the efficacy or safety of higher doses, longer treatment durations, or repeated treatments. Postpartum mothers have a relatively high risk of postpartum depression, and one of the side effects of Metoclopramide is depression. Therefore, women with a history of major depressive disorder should avoid using Metoclopramide, and any mother in a high-risk period should not use it long-term. Long-term use of Metoclopramide also increases the risk of tardive dyskinesia. Other reported side effects in breastfeeding mothers include fatigue, nausea, headache, diarrhea, dry mouth, breast discomfort, dizziness, restless legs syndrome, flatulence, hair loss, irritability, and anxiety. In a US survey of breastfeeding mothers, all 32 respondents who used Metoclopramide as a lactation stimulant reported adverse drug reactions. A large survey of women taking Metoclopramide to promote lactation found that 4.8% experienced palpitations or rapid heartbeat, 12% reported depression, and 1% to 7% reported other central nervous system side effects, including dizziness, headache, involuntary facial contortions, and tremors. Diarrhea, irritability, and fatigue are also common.
◉ Effects on Breastfed Infants
In an earlier report, five infants were breastfed while their mothers were taking Metoclopramide (10 mg three times daily) for 7 to 10 days. No adverse reactions were observed.
In a placebo-controlled study of 37 women investigating the effects of Metoclopramide on milk production, one infant whose mother took 15 mg of Metoclopramide three times daily was reported to have gastrointestinal upset. Infants whose mothers took 5 mg or 10 mg of Metoclopramide three times daily or a placebo did not experience any adverse reactions. Metoclopramide may be the cause of the adverse reaction.
Seventeen mothers with poor lactation received oral Metoclopramide treatment for 3 weeks at a dose of 10 mg three times daily. One of the mothers reported increased intestinal gas in both herself and her infant during treatment. Metoclopramide may be the cause of the adverse reaction.
32 mothers with complete or partial milk failure received 10 days of oral Metoclopramide at a dose of 10 mg three times daily, and were advised to breastfeed every 3 hours. No adverse reactions were reported in their infants by any of the mothers.
23 mothers of preterm infants who had difficulty maintaining milk production experienced stable weight gain in their infants during Metoclopramide treatment, and no adverse reactions related to feeding tolerance or bowel movement frequency occurred. Mothers began oral Metoclopramide 10 mg three times daily for 7 days, starting at a mean of 32 days postpartum, followed by a gradual reduction of the dose over 2 days.
13 women with insufficient milk production 4 to 20 weeks postpartum were randomly assigned to receive either Metoclopramide or a placebo, 10 mg orally three times daily. There was no difference in mean plasma prolactin levels between infants born to women receiving Metoclopramide and those receiving placebo before and 3 weeks after treatment. Eleven mothers who were breastfeeding infants were given oral Metoclopramide 10 mg three times daily for five days starting on day 1 postpartum and compared with eleven infants born to matched mothers who did not receive Metoclopramide treatment. There was no difference in mean serum prolactin levels between the groups, indicating that very little of the drug was passed to the infants through breast milk. Five breastfed infants were included in the study whose mothers were given oral Metoclopramide 10 mg three times daily starting on days 3 to 9 postpartum. Before treatment, the infants' plasma prolactin levels were similar to their mothers'. On day 4 of maternal administration, three infants had plasma prolactin levels higher than the highest level in the age-matched control group; on day 14, one infant had a plasma prolactin level higher than the highest level in the age-matched control group. The remaining three infants had plasma prolactin levels within the normal range during treatment. A 21-week-old breastfed male infant developed unexplained acute extrapyramidal syndrome 48 hours after his mother administered Metoclopramide 10 mg suppositories. Metoclopramide was detected in both blood and hair samples from infants. Adverse reactions are likely caused by Metoclopramide in breast milk.
◉ Effects on Lactation and Breast Milk
Metoclopramide increases serum prolactin levels in both lactating and non-lactating women. This effect is believed to be due to the drug's anti-dopaminergic properties. There have been reports of galactorrhea following long-term use of Metoclopramide to treat migraine-related nausea. The patient took 10 to 40 mg 1 to 4 times per week for approximately 4 months. Another case of galactorrhea has been reported in a woman with slightly low serum prolactin levels who experienced galactorrhea 5 days after treatment.
Many papers have reported studies on the use of Metoclopramide to increase milk production. All studies were small, with no more than 40 patients. Most studies did not meet current standards of evidence-based medicine. Many studies lacked placebo controls; only 7 studies used randomization; and only 2 studies used clear and adequate blinding. Studies that meet or nearly meet current standards of evidence-based medicine will be described in detail below. In an early double-blind study, 20 women undergoing emergency or elective cesarean sections were randomly assigned to two groups. One group received oral Metoclopramide 10 mg three times daily starting from day one post-cesarean (n=10), while the other group received a placebo for 7 days (n=10). All mothers indicated a desire to breastfeed their infants for at least 3 months. Researchers conducted daily home visits to discuss breastfeeding and provide advice and encouragement. The two groups of mothers were largely matched, with the only difference being that three preterm infants in the Metoclopramide group were separated from their mothers in the intensive care unit and initially breastfed there, continuing to be fed expressed breast milk until discharge. At 10 days postpartum, there was no difference in the number of breastfed infants between the two groups; at 6 weeks postpartum, 9 women in the Metoclopramide group were breastfeeding, compared to 8 women in the placebo group; at 3 months postpartum, 4 women in each group were breastfeeding. Although this study was small, it was rigorously designed and conducted. This study preliminarily confirms that counseling and encouragement to patients can help improve breastfeeding success rates. In a randomized, double-blind study, 13 primiparous women (without breastfeeding difficulties and healthy infants) were randomly assigned to two groups: one group received oral Metoclopramide 10 mg three times daily (n=7), and the other group received a placebo (n=6), for 8 days, starting from the first day postpartum. The study did not attempt to improve breastfeeding techniques, but the mothers breastfed every 3 hours, starting at 6:30 am on the second day postpartum. The study did not mention feeding methods, the number of feedings from birth to the start of breastfeeding, or any differences between the two groups in these aspects. All women completed the trial. During the 28-day observation period, there were no differences in serum prolactin levels between the treatment and control groups. Milk intake was measured by changes in infant weight before and after the second feeding between days 3 and 8 postpartum. The treatment group had an average milk intake 24.3 ml higher than the control group (51.1 ml vs. 75.4 ml); however, a statistically significant difference in milk production did not appear until day 5 postpartum. This study has several serious flaws. First, it does not specify the number of feedings per day, thus failing to determine the proportion of each feeding to the total daily feedings. Second, it does not report continuous weight gain during the study period. These serious problems invalidate the results.
Fifty mothers who experienced complete or partial lactation failure received comprehensive guidance on how to increase breast milk production. Their infants, aged 29 to 100 days, were hospitalized for various illnesses. The lactation histories of the two groups of mothers were comparable. Mothers were randomly assigned to one group, receiving Metoclopramide 10 mg three times daily for 10 days. Although the control group mothers did not receive a specific Metoclopramide placebo, all mothers took multivitamins, iron, and folic acid daily, which the authors did to prevent them from discerning whether they were taking the active drug. During the 96-day study period, no statistically significant differences were found between the two groups in terms of initiation of lactation, partial resumption of breastfeeding, exclusive breastfeeding, and infant weight gain. The authors concluded that successful resumption of lactation can be achieved without the use of galactagogues such as Metoclopramide. This study lacked a true placebo control; however, it employed excellent breastfeeding guidance and infant assessment techniques and was the best overall designed among all studies involving older infants and mothers with insufficient breast milk at the start of the study. In a well-controlled and well-analyzed randomized, double-blind study of mothers of preterm infants (23 to 34 weeks), mothers received either Metoclopramide 10 mg three times daily (n=31) or a placebo (n=29) for 10 days starting within 96 hours of delivery. Both groups were well-matched, and all mothers received standardized guidance from lactation counselors and access to breastfeeding support. The study did not screen mothers with difficulty producing milk. Six participants withdrew from both the drug and placebo groups, a relatively high dropout rate of 17.4%. Although this study is the most well-designed and executed lactation stimulant study to date, it included all mothers of preterm infants without assessing their lactation capacity. While this population may generally require breastfeeding support, the study may have also included women with adequate lactation capacity, thus narrowing the difference between the two groups. A study of 20 primiparous women with underweight infants compared the effects of Metoclopramide (n=10) and placebo (n=10) on increasing breast milk production. All mothers received brief training on improving breastfeeding techniques and the benefits of breastfeeding before enrollment. All infants gained weight over the following two weeks. There was no significant difference in weight gain between the Metoclopramide and placebo groups. Two women who delivered via surrogacy were also included. One woman stopped taking Metoclopramide one week before her due date, while the other continued taking it postpartum. They also received postpartum nipple stimulation using an electric breast pump. Successful lactation meant each mother was able to partially breastfeed her infant for 3 months. A double-blind, randomized study compared the effects of Metoclopramide 10 mg versus placebo three times daily for 10 days on milk production in mothers of preterm infants born between 28 and 34 weeks of gestation. At the start of the study, all participating women received training in standard breastfeeding methods. Mothers used a breast pump for 10 to 15 minutes every 2 hours, and the amount of milk pumped each time was measured and recorded for 10 days. There was no difference in daily milk production between the two groups until day 7 postpartum. On day 7, the treated mothers pumped an average of 373 ml of milk, while the placebo mothers pumped an average of 352 ml. This difference of approximately 20 ml per day persisted until day 10 at the end of the study, with the treatment group pumping 446 ml of milk and the placebo group pumping 422 ml. The clinical significance of this additional 20 ml of milk per day remains questionable. A randomized, double-blind study enrolled 26 mothers who delivered at 34 weeks of gestation or earlier, comparing the effects of Metoclopramide 10 mg three times daily with a placebo. Participants began taking either the medication or placebo within 36 hours of delivery for 8 days. All women received support with breast pumps and lactation counselors. Participants recorded their daily pumped milk volume, and 19 completed the entire study protocol. Although milk production increased over the 8-day period, Metoclopramide was not superior to placebo or standard care. No differences were reported in side effects. Mothers (mean gestational age 28 weeks) who were expressing milk for their infants in the neonatal intensive care unit (NICU) received instructions on methods to increase breast milk production. If their daily milk production fell below 160 ml per kilogram of infant body weight after a few days, mothers were randomly assigned to either domperidone or Metoclopramide, 10 mg orally three times daily for 10 days, in a double-blind manner. Thirty-one mothers who took domperidone and 34 mothers who took Metoclopramide provided data on daily milk production over 10 days. Over 10 days, milk production increased by 96% in the domperidone group and by 94% in the Metoclopramide group; there was no statistically significant difference between the two groups. Some mothers continued to measure milk production after the medication period ended. Results were similar in both groups. Side effects in the domperidone group (3 women) included headache, diarrhea, mood swings, and dizziness. Side effects in the Metoclopramide group (7 women) included headache (3 women), diarrhea, mood swings, changes in appetite, dry mouth, and breast discomfort. After the trial, 29 women continued taking Metoclopramide; 8 of them reported side effects, including diarrhea, mood swings, depression (2 women), itchy skin, fatigue, leg discomfort, and decreased lactation. Due to the lack of a placebo group and missing data for some mothers, researchers filled data gaps by predicting milk production, which weakened the reliability of the study results. A triple-blind, randomized, controlled study conducted in Iran compared mothers who received a placebo (n = 51) or Metoclopramide 10 mg (n = 50) starting 2 to 10 hours postpartum with mothers who received Metoclopramide 10 mg three times daily for 5 days. The results showed differences in maternal serum prolactin levels, milk volume, and infant bilirubin levels. In the protocol-compliant analysis, serum prolactin levels in the domperidone group increased from 271.5 mcg/L to 287.5 mcg/L on day 6 postpartum, while those in the placebo group decreased from 273.3 mcg/L to 250.7 mcg/L; the difference was statistically significant. On day 6 postpartum, there were no statistically significant differences in manually expressed milk volume 2 hours after morning breastfeeding between the groups. In a randomized preprint study published in Singapore, 105 mothers of preterm and full-term infants were randomly assigned to either a placebo group (n = 49) or a Metoclopramide group (n = 56), receiving 30 mg of Metoclopramide daily (specific regimen not specified), starting within 12 hours postpartum. Metoclopramide increased the rate of lactation stage II initiation by 25%, but the difference was not statistically significant; mothers of preterm infants expressed higher amounts of milk. Compared to the placebo group of full-term mothers (control group), mothers of preterm infants receiving Metoclopramide expressed higher daily amounts of milk. This difference was statistically significant on day 2 (19.9 ml vs 2.4 ml) and day 3 (32.6 ml vs 8.8 ml). By the end of the first week, total breast milk production had increased 8.2-fold. Most mothers reported initiating lactation stage II on day 6, with 95-100% of full-term mothers confirming initiation by day 5, with no significant difference between groups. In an Australian survey of breastfeeding mothers, 21 mothers used Metoclopramide as a lactation stimulant. On average, mothers rated the efficacy of Metoclopramide as "slightly effective" to "moderately effective" according to the Likert scale. 29% of mothers taking Metoclopramide reported adverse reactions, the most common being weight gain, nausea, headache, dry mouth, fatigue, irritability, depression, and involuntary movements. A 50-year-old transgender woman wishing to breastfeed her grandchild was receiving basic treatment including a 0.3 mg estradiol transdermal patch every 72 hours and a once-daily oral dose of 200 mg micronized progesterone. To induce lactation, her estradiol dose was increased to 0.4 mg transdermal patch every 72 hours, and nipple stimulation was initiated. The patient's progesterone dose was then increased to 300 mg daily, and she began taking oral Metoclopramide, 10 mg three times daily. She lactated for a total of two weeks and breastfed the four-month-old baby multiple times. During her peak lactation period, her larger right breast produced 30 ml of milk, while her smaller left breast produced 8 ml.

[1]. Synthesis and structure-activity relationships of 4-amino-5-chloro-N-(1,4-dialkylhexahydro-1,4-diazepin-6-yl)-2-methoxybenzamide derivatives, novel and potent serotonin 5-HT3 and dopamine D2 receptors dual antagonist. Chem Pharm Bull (Tokyo) . 2002 Jul;50(7):941-59.

[2]. Review article: metoclopramide and tardive dyskinesia. Aliment Pharmacol Ther. 2010 Jan;31(1):11-9.

[3]. In vivo and in vitro studies on the effect of metoclopramide on aldosterone secretion. Clin Endocrinol (Oxf). 1980 Jul;13(1):45-50.

[4]. Dose-dependent response of central dopaminergic systems to metoclopramide in mice. Indian J Exp Biol. 1997 Jun;35(6):618-22.

[5]. Effects of metoclopramide on the mouse anterior pituitary during the estrous cycle. Clinics (Sao Paulo). 2011;66(6):1101-4.

Metoclopramide hydrochloride is a monohydrate of Metoclopramide hydrochloride. It is a gastrointestinal drug with dopamine antagonist and antiemetic effects. It is a hydrate and hydrochloride salt. It contains Metoclopramide (1+). Metoclopramide hydrochloride is the hydrochloride salt of benzamide-substituted Metoclopramide, a para-aminobenzoic acid (PABA) derivative whose structure is related to procainamide, possessing gastric motility and antiemetic activity. Metoclopramide binds to dopamine 2 (D2) receptors in the peripheral nervous system (PNS), antagonizing dopamine-mediated relaxation of gastrointestinal smooth muscle, thereby promoting gastric motility; relaxation of the pyloric sphincter and duodenal bulb, enhanced duodenal and jejunal peristalsis, and accelerated gastric emptying and intestinal transit. This drug may also increase the resting tone of the lower esophageal sphincter (LES), thereby preventing acid reflux. In the central nervous system (CNS), Metoclopramide antagonizes D2 dopamine receptors in the chemoreceptor trigger zone (CTZ) of the medulla oblongata, thereby preventing nausea and vomiting. It is a dopamine D2 receptor antagonist used as an antiemetic.

C14H25CL2N3O3

354.2726

353.13

54143-57-6

Metoclopramide; 364-62-5; Metoclopramide hydrochloride; 7232-21-5

441347

White to off-white solid powder

418.7ºC at 760mmHg

207ºC

3.776

4

5

7

22

300

0

KJBLQGHJOCAOJP-UHFFFAOYSA-N

InChI=1S/C14H22ClN3O2.ClH.H2O/c1-4-18(5-2)7-6-17-14(19)10-8-11(15)12(16)9-13(10)20-3;;/h8-9H,4-7,16H2,1-3H3,(H,17,19);1H;1H2

4-amino-5-chloro-N-[2-(diethylamino)ethyl]-2-methoxybenzamide;hydrate;hydrochloride

Metoclopramide hydrochloride hydrate

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Note: This product requires protection from light (avoid light exposure) during transportation and storage.

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

DMSO: 50~71 mg/mL (141.1~200.4 mM)
Water: ~71 mg/mL
Ethanol: ~71 mg/mL

Solubility in Formulation 1: ≥ 2.5 mg/mL (7.06 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL.
Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution.

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Solubility in Formulation 2: ≥ 2.5 mg/mL (7.06 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly.

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 (Please use freshly prepared in vivo formulations for optimal results.)