Potency and safety analysis of hemp-derived delta-9 products: The hemp vs. cannabis demarcation problem

Edit links

Cannabis consumption in pregnancy may or may not be associated with restrictions in growth of the fetus, miscarriage, and cognitive deficits.[1] The American College of Obstetricians and Gynecologists recommended that cannabis use be stopped before and during pregnancy. There has not been any official link between birth defects and marijuana use.[2] Cannabis is the most commonly used illicit substance among pregnant women.[3]

Cannabis has an ancient tradition of usage as a medicine in obstetrics and gynecology, and a comprehensive historical review find that cannabis extracts, may represent an efficacious and safe alternative for treatment of a wide range of conditions in women including dysmenorrhea, dysuria, hyperemesis gravidarum, and menopausal symptoms.[4]

Endocannabinoid system

The role of the endocannabinoid system (ECS) in female fertility has long been suspected and studied.[5] Most studies through 2013 linking development of the fetus and cannabis show effects of consumption during the gestational period, but abnormalities in the endocannabinoid system during the phase of placental development are also linked with problems in pregnancy.[1] According to Sun and Dey (2012), endocannabinoid signaling plays a role in "female reproductive events, including preimplantation embryo development, oviductal embryo transport, embryo implantation, placentation, and parturition".[5] Karusu et al (2011) said that a "clear correlation ... in the actual reproductive tissues of miscarrying versus healthy women has yet to be established. However, the adverse effects of marijuana smoke and THC on reproductive functions point to processes that are modulated by ECS.".[6]

Recent data indicates that endometrial expression of cannabinoid receptors in marijuana smoking mothers is higher than non-smokers.[7] Keimpema and colleagues (2011) said, "Prenatal cannabis exposure can lead to growth defects during formation of the nervous system"; "[c]annabis impacts the formation and functions of neuronal circuitries by targeting cannabinoid receptors ... By indiscriminately prolonging the "switched-on" period of cannabinoid receptors, cannabis can hijack endocannabinoid signals to evoke molecular rearrangements, leading to the erroneous wiring of neuronal networks".[8] A report prepared for the Australian National Council on Drugs concluded cannabis and other cannabinoids are contraindicated in pregnancy as they may interact with the endocannabinoid system.[1][9]


Although conclusions cannot be drawn from existing data, there is some evidence that prenatal exposure to cannabis may be associated with deficits in language, attention, cognitive performance, and delinquent behaviors.[10] Other epidemiological studies demonstrate that prenatal cannabis exposure is associated with improved cognition scores, comprehension, and motor control in children ranging from 12 months to 12 years old.[11] THC exposure in rats during the prenatal developmental phase may cause epigenetic changes in gene expression, but there is limited knowledge about the risk for psychiatric disorders because of ethical barriers to studying the developing human brain.[12] While animal studies cannot take into account factors that could influence the effects of cannabis on human maternal exposure, such as environmental and social factors,[13] a 2011 review of rodent studies by Campolongo et al. said there was "... increasing evidence from animal studies showing that cannabinoid drugs ... induce enduring neurobehavioral abnormalities in the exposed offspring ..."[13] Campolongo et al. added that "clinical studies report hyperactivity, cognitive impairments and altered emotionality in humans exposed in utero to cannabis".[13] Martin et al. investigated recent trends in substance abuse treatment admissions for cannabis use in pregnancy in the US, based on Treatment Episodes Data Set (TEDS) from 1992 to 2012, and discovered that, while the proportion of treatment admissions for pregnant women was stable (about 4%), the admissions for women who were pregnant and reported any marijuana use grew from 29% to 43%.[14] A 2015 review found that cannabis use by pregnant mothers corresponded to impaired brain maturation in their children, and that those children were more predisposed to neurodevelopmental disorders; these results do not demonstrate causality.[15]

The National Institute on Drug Abuse states that further research is required to "disentangle" effects of cannabis use from a mother's concomitant drug use and other environmental factors.[16] A 2016 meta-analysis showed that after accounting for confounding factors, cannabis alone was not responsible for adverse neonatal outcomes.[17]

Pregnancy and miscarriage by endocannabinoids

The endocannabinoid (EC), a N-acylethanolamine (NAE), Anandamide (AEA: C22H37NO2; 20:4, ω-6), that is synthesized "on demand",[18] is the key to a successful pregnancy and outcome, by a temporary low amount, coursed by high FAAH activity, at the uterine lining.[19] The lower AEA content uses the CB1 receptors, that are at high levels on the blastocyst (fertilized egg), to make the attachment to the lining of the uterus.[20] Another study have also shown, that healthy women, with higher lymphocyte FAAH, have lower blood AEA compared to aborting women.[21]

As low level of AEA, called on and synthesized "on demand" if needed to activate related receptors, and broken down by FAAH, is necessary for attachment and prevention of miscarriage, and abortion, it is found that the phytocannabinoid Δ9-tetrahydrocannabinol (THC: C21H30O2), that can mimic "the called" AEA activation at CB1 and CB2 receptors,[22] is able to lower blood AEA (and the demand for it) by a biphasic reaction. Anandamide (AEA) reach maximal values at 30 min., as it increase slightly from 0.58 ± 0.21 ng/ml at baseline to 0.64 ± 0.24 ng/ml (p < 0.05). After reaching maximal concentrations, the EC plasma levels (also 2-Arachidonoylglycerol (2-AG: C23H38O4; 20:4, ω-6) decrease markedly to a nadir of 300 min after THC administration, to 0.32 ± 0.15 ng/ml for anandamide, and the plasma concentrations returned to near baseline levels until 48 hours after the experiment in 25 healthy volunteers, who received a large intravenous dose of THC (0.10 mg/kg).[23]

The endocannabinoid-CB1-receptor system is found unique in its absolute control over the initiation of the milk suckling response in new-borns, and it is further proposed that cannabis-based medicines should be developed to benefit infant failure to thrive.[24]

Developmental observations suggest that CB1 receptors develop only gradually during the postnatal period, which block for the psychoactive effects of cannabinoid treatment in the young organism. Therefore, it is suggested that children may respond positively to medicinal applications of cannabinoids without undesirable central effects. Clinical results have been reported in pediatric oncology and in case studies of children with severe neurological disease or brain trauma, and cystic fibrosis (CF) suggesting cannabinoid treatment for children or young adults, in order to achieve an improvement of their health condition including improved food intake and reduced inflammatory exacerbations.[25] In CF mice treated with THC in infancy show normal motor activity and anxiety levels in adulthood.[26] As the etiology of CF is associated with an imbalance of fatty acids (n6 and n3), and therefore assumed, that endocannabinoid activity, which plays an important role in fertility, is disrupted and could be one of the causes of infertility, a study find CF males treated with THC fully fertile, producing offspring comparable by the number of litters and the number of pups with wild-type mice, and there counterparts, not treated, were completely infertile. Thereby, mild stimulation of the endocannabinoid system in infancy and adolescence appears to normalize many reproductive processes and prevent infertility in CF males.[27]

Morning sickness/hyperemesis gravidarum

Hyperemesis Gravidarum (HG), is a debilitating ailment characterized by severe nausea and vomiting, malnutrition, and weight loss during pregnancy, and occurs to 1-2% of pregnant women globally. It is a perplexing female mystery for the present-day medical establishment. The frustration is mostly felt by women who are survivors of HG, desperately searching for a cure and increased understanding of this disease. Several pregnant women have revealed their personal experience with cannabis, having used it to relieve symptoms of HG, who would otherwise have become severely emaciated, dehydrated, and malnourished due to persistent, uncontrollable vomiting and the inability to eat and drink in their pregnancy.[28][29]

See also


  1. ^ a b c Fonseca BM, Correia-da-Silva G, Almada M, Costa MA, Teixeira NA (2013). "The Endocannabinoid System in the Postimplantation Period: A Role during Decidualization and Placentation". Int J Endocrinol (Review). 2013: 510540. doi:10.1155/2013/510540. PMC 3818851. PMID 24228028.
  2. ^ Committee on Obstetric Practice (July 2015). "Committee Opinion No. 637: Marijuana Use During Pregnancy and Lactation". Obstetrics & Gynecology. 126 (1): 234–238. doi:10.1097/01.AOG.0000467192.89321.a6. PMID 26241291.
  3. ^ Wu, CS; Jew, CP; Lu, HC (1 July 2011). "Lasting impacts of prenatal cannabis exposure and the role of endogenous cannabinoids in the developing brain". Future Neurology. 6 (4): 459–480. doi:10.2217/fnl.11.27. PMC 3252200. PMID 22229018.
  4. ^ Russo, Ethan (2002). "Cannabis Treatments in Obstetrics and Gynecology: A Historical Review". cannabis-med.org. Archived from the original on 2021-04-11. Retrieved 2021-03-25.
  5. ^ a b Sun X, Dey SK (May 2012). "Endocannabinoid signaling in female reproduction". ACS Chem Neurosci (Review). 3 (5): 349–55. doi:10.1021/cn300014e. PMC 3382454. PMID 22860202.
  6. ^ Karasu T, Marczylo TH, Maccarrone M, Konje JC (2011). "The role of sex steroid hormones, cytokines and the endocannabinoid system in female fertility". Hum. Reprod. Update (Review). 17 (3): 347–61. doi:10.1093/humupd/dmq058. PMID 21227997.
  7. ^ Neradugomma NK, Drafton K, O'Day DR, Liao MZ, Han LW, Glass IA, Mao Q (9 May 2018). "Marijuana use differentially affects cannabinoid receptor expression in early gestational human endometrium and placenta". Placenta (Research). 66: 36–39. doi:10.1016/j.placenta.2018.05.002. PMC 5995327. PMID 29884300.
  8. ^ Keimpema E, Mackie K, Harkany T (September 2011). "Molecular model of cannabis sensitivity in developing neuronal circuits". Trends Pharmacol. Sci. (Review). 32 (9): 551–61. doi:10.1016/j.tips.2011.05.004. PMC 3159827. PMID 21757242.
  9. ^ Copeland, Jan; Gerber, Saul; Swift, Wendy (2006). Evidence-based answers to cannabis questions: a review of the literature. Canberra: Australian National Council on Drugs. ISBN 978-1-877018-12-1.[page needed]
  10. ^ Irner TB (2012). "Substance exposure in utero and developmental consequences in adolescence: a systematic review". Child Neuropsychol (Review). 18 (6): 521–49. doi:10.1080/09297049.2011.628309. PMID 22114955. S2CID 25014303.
  11. ^ Talavera-Barber, M. M., Morehead, E., Ziegler, K., Hockett, C., Elliott, A. J. (22 November 2023). "Prenatal cannabinoid exposure and early language development". Frontiers in Pediatrics. 11: 1290707. doi:10.3389/fped.2023.1290707. ISSN 2296-2360. PMC 10702953. PMID 38078314.
  12. ^ Morris CV, DiNieri JA, Szutorisz H, Hurd YL (November 2011). "Molecular mechanisms of maternal cannabis and cigarette use on human neurodevelopment". Eur. J. Neurosci. (Review). 34 (10): 1574–83. doi:10.1111/j.1460-9568.2011.07884.x. PMC 3226730. PMID 22103415.
  13. ^ a b c Campolongo P, Trezza V, Ratano P, Palmery M, Cuomo V (March 2011). "Developmental consequences of perinatal cannabis exposure: behavioral and neuroendocrine effects in adult rodents". Psychopharmacology (Review). 214 (1): 5–15. doi:10.1007/s00213-010-1892-x. PMC 3045519. PMID 20556598.
  14. ^ Martin CE, Longinaker N, Mark K, Chisolm MS, Terplan M (March 2015). "Recent trends in treatment admissions for marijuana use during pregnancy". Journal of Addiction Medicine. 9 (2): 99–104. doi:10.1097/ADM.0000000000000095. PMID 25525944. S2CID 19965850.
  15. ^ Alpár, A; Di Marzo, V; Harkany, T (25 September 2015). "At the Tip of an Iceberg: Prenatal Marijuana and Its Possible Relation to Neuropsychiatric Outcome in the Offspring". Biological Psychiatry. 79 (7): e33–e45. doi:10.1016/j.biopsych.2015.09.009. PMID 26549491. S2CID 18847084.
  16. ^ "Can marijuana use during and after pregnancy harm the baby?". National Institute on Drug Abuse. Retrieved 28 October 2018.
  17. ^ Conner, Shayna N.; Bedell, Victoria; Lipsey, Kim; Macones, George A.; Cahill, Alison G.; Tuuli, Methodius G. (October 2016). "Maternal Marijuana Use and Adverse Neonatal Outcomes". Obstetrics & Gynecology. 128 (4): 713–723. doi:10.1097/AOG.0000000000001649. PMID 27607879. S2CID 10697253.
  18. ^ Brock, Tom (2008-06-01). "Cannabinoid Signaling: The Original Retrograde Signaling Pathway". Cayman Chemical.
  19. ^ Wang, Haibin; Xie, Huirong; Dey, Sudhansu K. (2006). "Endocannabinoid signaling directs periimplantation events". The AAPS Journal. 8 (2): E425–E432. doi:10.1007/BF02854916. ISSN 1550-7416. PMC 3231559. PMID 16808046.
  20. ^ Fride, Ester (2004-10-01). "The endocannabinoid-CB1 receptor system in pre- and postnatal life". European Journal of Pharmacology. SPECIAL CELEBRATORY VOLUME 500 Dedicated to Professor David de Wied Honorary and Founding Editor. 500 (1): 289–297. doi:10.1016/j.ejphar.2004.07.033. ISSN 0014-2999. PMID 15464041.
  21. ^ Bari, M. (2002). "Endocannabinoid Degradation and Human Fertility". cannabis-med.org.
  22. ^ Pertwee, R G (2008). "The diverse CB1 and CB2 receptor pharmacology of three plant cannabinoids: Δ9-tetrahydrocannabinol, cannabidiol and Δ9-tetrahydrocannabivarin". British Journal of Pharmacology. 153 (2): 199–215. doi:10.1038/sj.bjp.0707442. ISSN 0007-1188. PMC 2219532. PMID 17828291.
  23. ^ Thieme, Ulrike; Schelling, Gustav; Hauer, Daniela; Greif, Robert; Dame, Torsten; Laubender, Ruediger Paul; Bernhard, Werner; Thieme, Detlef; Campolongo, Patrizia; Theiler, Lorenz (2014). "Quantification of anandamide and 2-arachidonoylglycerol plasma levels to examine potential influences of tetrahydrocannabinol application on the endocannabinoid system in humans". Drug Testing and Analysis. 6 (1–2): 17–23. doi:10.1002/dta.1561. ISSN 1942-7611. PMID 24424856.
  24. ^ Fride, Ester (2002). "Cannabinoids and Feeding: The Role of the Endogenous Cannabinoid System as a Trigger for Newborn Suckling". cannabis-med.org.
  25. ^ Fride, Ester (2004). "The endocannabinoid-CB receptor system: Importance for development and in pediatric disease". Neuro Endocrinology Letters. 25 (1–2): 24–30. ISSN 0172-780X. PMID 15159678.
  26. ^ Bregman, Tatiana; Fride, Ester (2011-06-17). "Behavioral alterations in cystic fibrosis mice are prevented by cannabinoid treatment in infancy". Journal of Basic and Clinical Physiology and Pharmacology. 22 (1–2): 33–36. doi:10.1515/jbcpp.2011.005. ISSN 0792-6855. PMID 22865361. S2CID 42079558.
  27. ^ Bregman, Tatiana; Fride, Ester (2011-06-17). "Treatment with tetrahydrocannabinol (THC) prevents infertility in male cystic fibrosis mice". Journal of Basic and Clinical Physiology and Pharmacology. 22 (1–2): 29–32. doi:10.1515/jbcpp.2011.004. ISSN 0792-6855. PMID 22865360. S2CID 19335113.
  28. ^ Curry, Wei-Ni Lin (2002). "Hyperemesis Gravidarum and Clinical Cannabis: To Eat or Not to Eat?". cannabis-med.org.
  29. ^ Westfall, Rachel E.; Janssen, Patricia A.; Lucas, Philippe; Capler, Rielle (2006-02-01). "Survey of medicinal cannabis use among childbearing women: Patterns of its use in pregnancy and retroactive self-assessment of its efficacy against 'morning sickness'". Complementary Therapies in Clinical Practice. 12 (1): 27–33. doi:10.1016/j.ctcp.2005.09.006. ISSN 1744-3881. PMID 16401527.