As a growing number of U.S. states legalize the medicinal and recreational use of marijuana, an increasing number of American women are using cannabis before becoming pregnant and during early pregnancy often to treat morning sickness, anxiety, and lower back pain.
Although emerging evidence indicates that this may have long-term consequences for their babies’ brain development, how this occurs remains unclear.
A University of Maryland School of Medicine study using a preclinical animal model suggests that prenatal exposure to THC, the psychoactive component of cannabis, makes the brain’s dopamine neurons (an integral component of the reward system) hyperactive and increases sensitivity to the behavioral effects of THC during pre-adolescence.
This may contribute to the increased risk of psychiatric disorders like schizophrenia and other forms of psychosis later in adolescence that previous research has linked to prenatal cannabis use, according to the study published today in journal Nature Neuroscience.
The team of researchers, from UMSOM, the University of Cagliari (Italy) and the Hungarian Academy of Sciences (Hungary), found that exposure to THC in the womb increased susceptibility to THC in offspring on several behavioral tasks that mirrors the effects observed in many psychiatric diseases.
These behavioral effects were caused, at least in part, by hyperactivity of dopamine neurons in a brain region called the ventral tegmental area (VTA), which regulates motivated behaviors.
More importantly, the researchers were able to correct these behavioral problems and brain abnormalities by treating experimental animals with pregnenolone, an FDA-approved drug currently under investigation in clinical trials for cannabis use disorder, schizophrenia, autism, and bipolar disorder.
More importantly, the researchers were able to correct these behavioral problems and brain abnormalities by treating experimental animals with pregnenolone, an FDA-approved drug currently under investigation in clinical trials for cannabis use disorder, schizophrenia, autism, and bipolar disorder.
“This is an exciting finding that suggests a therapeutic approach for children born to mothers who used cannabis during pregnancy,” said Joseph Cheer, PhD, a Professor of Anatomy & Neurobiology and Psychiatry at the University of Maryland School of Medicine.
“It also raises important questions that need to be addressed such as how does pregnenolone exert its effects and how can we improve its efficacy?
Do these detrimental effects persist into adulthood, and if so, could they also be treated in a similar way?”
The researchers concluded that as physicians caution pregnant women against alcohol and cocaine intake because of their detrimental effects to the fetus, they should also, based on these new findings, advise them on the potential negative consequences of using cannabis specifically during pregnancy.
Funding: The study was funded by an international collaborative program on marijuana research issued by the U.S. National Institute on Drug Abuse, the National Research, Development and Innovation Office of Hungary and the University of Cagliari as well as private European foundations.
Cannabis is the most commonly used illicit drug worldwide. Although its use is associated with multiple adverse health effects, including the risk of developing addiction, recreational and medical cannabis use is being increasing legalized.
In addition, use of synthetic cannabinoid drugs is gaining considerable popularity and is associated with mass poisonings and occasional deaths.
Delineating factors involved in cannabis use and addiction therefore becomes increasingly important.
Similarly to other drugs of abuse, the prevalence of cannabis use and addiction differs remarkably between males and females, suggesting that sex plays a role in regulating cannabinoid sensitivity. Although it remains unclear how sex may affect the initiation and maintenance of cannabis use in humans, animal studies strongly suggest that endogenous sex hormones modulate cannabinoid sensitivity.
In addition, synthetic anabolic-androgenic steroids alter substance use and further support the importance of sex steroids in controlling drug sensitivity.
The recent discovery that pregnenolone, the precursor of all steroid hormones, controls cannabinoid receptor activation corroborates the link between steroid hormones and the endocannabinoid system. This article reviews the literature regarding the influence of endogenous and synthetic steroid hormones on the endocannabinoid system and cannabinoid action.
Introduction
Drug use causes considerable harm because of premature death and disability as well as other adverse health effects. The United Nations Office on Drugs and Crime estimated that around 0.6% of the world population suffers from substance use disorders (United Nations Office on Drugs and Crime [UNODC], 2017). Although opioids are considered the most harmful drugs for their addiction potential and negative consequences, cannabis use is a much larger problem when it comes to the number of users. Around 183 million “past-year” cannabis users were reported worldwide in 2015, which is 2.6 times higher than the cumulative number of “past-year” worldwide users of opioids, amphetamines and cocaine, making cannabis the most widely used illicit drug at a global level (United Nations Office on Drugs and Crime [UNODC], 2017). Although worldwide cannabis use has remained stable (3.4% in 1998 versus 3.8% in 2015), the absolute number of cannabis users has increased because of the growing world population, especially in Africa and Asia (United Nations Office on Drugs and Crime [UNODC], 2017). Legalization of marijuana for medical and recreational purposes might increase cannabis use even further (Hopfer, 2014). In addition to traditional marijuana use, the use of synthetic cannabinoids (i.e., designer drugs that mimic the physical and psychological effects of delta-9-tetrahydrocannabinol (THC), the primary active constituent in cannabis) is gaining considerable popularity. Since 2008, when the first synthetic cannabinoid (JWH-018) was detected in the market, at least 169 different synthetic cannabinoids have been discovered (Fattore and Fratta, 2011; European Monitoring Centre for Drugs and Drug Addiction [EMCDDA], 2017). The emergence of synthetic cannabinoids is becoming an increasing concern because of their undetermined addiction potential and adverse health effects (Fattore, 2016; Weinstein et al., 2017; De Luca and Fattore, 2018; Zanda and Fattore, 2018).
Acute toxicity of traditional cannabis use is considered low (Nahas, 1972); yet, long-term cannabis use is associated with serious adverse health effects which include lower birth weight of offspring (maternal cannabis smoking), diminished lifetime achievement, development of psychosis, depression or anxiety, symptoms of chronic bronchitis, motor vehicle accidents, and risk of cannabis addiction (Hall and Degenhardt, 2009; Volkow et al., 2014; United Nations Office on Drugs and Crime [UNODC], 2017). Although the existence of cannabis addiction was disputed in the 1990s, current evidence predicts that around 1 in 10 cannabis users will develop cannabis addiction or dependence (Lopez-Quintero et al., 2011), which is currently defined as cannabis use disorder (CUD) in the fifth edition of the Diagnostic and Statistical Manual for Mental Disorders (5th ed.; DSM-5; American Psychiatric and Association, 2013). CUD is characterized by high cannabis intake over longer periods of time, problems with controlling cannabis use, tolerance, withdrawal signs, craving and negative effects on personal, social and occupational activities (DSM-5).
The demand for CUD treatment is increasing dramatically. The European Monitoring Centre for Drugs and Drug Addiction reported a 50% increase in the number of first-time entrants for CUD treatment in 2011 (European Monitoring Centre for Drugs and Drug Addiction [EMCDDA], 2013). The increasing need for CUD treatment is thought to be driven by the increased availability of cannabis products containing higher concentrations of THC or synthetic cannabinoids (Freeman and Winstock, 2015). Regrettably, current CUD treatment protocols show modest effects only (Budney et al., 2007; Weinstein and Gorelick, 2011). Delineating risk factors involved in the initiation and maintenance of cannabis use therefore becomes increasingly important and critical for optimizing evidence-based prevention and treatment protocols.
Similarly to other drugs of abuse, cannabis use differs remarkably between males and females (European Monitoring Centre for Drugs and Drug Addiction [EMCDDA], 2005), indicating a different sensitivity to cannabinoid-induced effects in the two sexes (Davis and Fattore, 2015; Figure Figure1).1). Although it remains uncertain which specific biological (i.e., sex) and socio-cultural (i.e., gender) factors affect cannabis use in humans, animal studies strongly suggest the involvement of sex (Fattore and Fratta, 2010) and anabolic-androgenic steroids (AAS) hormones (Struik et al., 2017) as important modulators of cannabinoid sensitivity. This review aims to describe the role of sex differences in cannabis use with reference to the modulating role of sex and AAS hormones (Figure (Figure2)2) in cannabinoid sensitivity.
Risk Factors for Cannabis Use
As for other drugs of abuse, both genetic and environmental factors play a role in cannabis use and addiction (Agrawal and Lynskey, 2006; Verweij et al., 2010). Twin studies estimate that the genetic contribution to cannabis use is between 17 and 67%, while the genetic contribution to cannabis addiction is much higher and ranges from 45 to 78% (Verweij et al., 2010; Vink et al., 2010; Distel et al., 2011; Lynskey et al., 2012). Interestingly, the genetic contribution to the initiation of cannabis use increases with age (Distel et al., 2011) and is higher in males than in females (van den Bree et al., 1998). Although it is clear that genetics is an important risk factor in cannabis use and abuse, it has so far proved difficult to identify specific gene variants that alter cannabis sensitivity. At present, most genome-wide association studies (GWAS) failed to detect significant associations between cannabis use and genetic variants (Agrawal et al., 2011; Verweij et al., 2013; Stringer et al., 2016). However, using gene-based testing, four genes that are significantly associated with lifetime cannabis use have been recently identified, which include the neural cell adhesion molecule 1 (NCAM1), the cell adhesion molecule 2 (CADM2), the Short Coiled-Coil Protein (SCOC) and the potassium sodium-activated channel subfamily T member 2 (KCNT2) (Stringer et al., 2016). Interestingly, NCAM1 has been associated with substance abuse (Gelernter et al., 2006) and is part of the NTAD gene cluster (NCAM1-TTC12-ANKK1-DRD2) which is linked to neurogenesis and dopaminergic signaling (Yang et al., 2008). In the most recent GWAS, single-nucleotide polymorphisms (SNPs) in novel antisense transcript RP11-206M11.7, solute carrier family 35 member G1, and the CUB and Sushi multiple domains 1 gene were significantly associated with cannabis dependence (Sherva et al., 2016). However, whether or not these genes contribute to altered cannabinoid action remains unclear. Next to genetic variation, epigenetic-dependent changes in gene expression might contribute to altered cannabinoid sensitivity. Interestingly, a recent study reported increased DNA methylation of the NCAM1 gene in cannabis users compared to control subjects (Gerra et al., 2018).
The vulnerability to initiation of cannabis use and CUD development appears heritable. Yet, numerous social and environmental factors (e.g., age of cannabis use initiation, peer drug use, availability of drugs, low socio-economic status, experience of childhood sexual abuse, cigarette smoking or alcohol drinking during early adolescence) and the presence of pre/comorbid psychopathology (e.g., mood disorders, ADHD, psychosis) are thought to enhance the risk of transitioning from initiation of cannabis use to CUD (reviewed in Courtney et al., 2017). Personality/biological traits, such as impulsivity, schizotypy and sensation-seeking, are also positively correlated with the initiation of cannabis use in adolescents and young adults (Haug et al., 2014; Muro and Rodríguez, 2015).
As for other drugs of abuse, the prevalence of cannabis use differs remarkably between males and females (Figure (Figure1;1; European Monitoring Centre for Drugs and Drug Addiction [EMCDDA], 2005) and sex is considered an important risk factor for cannabis use (Cooper and Craft, 2017). Among 15–16-years-old students, lifetime cannabis use is higher in males than in females and the male to female ratio (M/F) of lifetime cannabis use increases even further among all adults (M/F: 1.25–4.0) (European Monitoring Centre for Drugs and Drug Addiction [EMCDDA], 2005). Although males have a higher risk of developing CUD (Zhu and Wu, 2017), progression toward CUD is slightly faster in females than in males (Khan et al., 2013; European Monitoring Centre for Drugs and Drug Addiction [EMCDDA], 2017). Males also show different cannabis use patterns as compared to females and appear to use cannabis more frequently and at higher amounts (Cuttler et al., 2016). However, a faster progression to problematic cannabis use (Cooper and Haney, 2014) and more severe withdrawal symptoms (Levin et al., 2010) could explain why women typically show greater propensity to relapse to drug use than men (Becker and Hu, 2008; Fattore et al., 2008).
The fact that differences in cannabis use between males and females vary across countries suggests an influence of environmental (i.e., socio-cultural) factors. However, animal studies clearly indicate that biological factors, such as sex hormones and chromosomes, are significant modulators of drug sensitivity (Quinn et al., 2007; Marusich et al., 2015). In keeping with this, gender-tailored detoxification treatments and relapse prevention strategies for patients with CUD are increasingly requested (Fattore, 2013).
Sex Steroid Hormones
Sex differences arise because of differences in sex chromosomes. The presence of the sex-determining region of Y (Sry) gene on the Y chromosome induces testicular development and consequently the production of testosterone (Polanco and Koopman, 2007). Testosterone and its derivative dihydrotestosterone (DHT) are responsible for the development of the male phenotype. Absence of the Sry gene leads to the development of ovaries that produce estradiol and progesterone. Estrogens, progesterone and testosterone have a strong impact on sexual differentiation, maturation and adult sexual behavior (Arnold and Breedlove, 1985; McEwen et al., 1987; Wallen, 1990; Meisel and Sachs, 1994; Hull et al., 1999; Morris et al., 2004; Becker, 2009; Argiolas and Melis, 2013; Motta-Mena and Puts, 2017). The presence of sex hormones during development gives rise to various organizational differences in the male and female brain, which ultimately affect reproductive and non-reproductive behavior (Beatty, 1979).
Sex hormones are synthesized by conversion of cholesterol into pregnenolone, which is the precursor of all steroid hormones (Hanukoglu, 1992). Interestingly, pregnenolone protects the brain from cannabinoid type-1 receptor (CB1R) overactivation, by acting as a potent endogenous allosteric inhibitor of CB1Rs (Vallée et al., 2014), and prevents cannabinoid-induced psychosis in mice (Busquets-Garcia et al., 2017). Sex hormones can be divided into three main subtypes with distinct molecular functions and sexually dimorphic expression and distribution: androgens (e.g., testosterone, dehydroepiandrosterone, androstenedione), estrogens (e.g., 17-alpha and 17-beta estradiol, estrone, estriol) and progestogens (e.g., progesterone, allopregnanolone, pregnenolone) (Figure (Figure2).2). Sex hormones are produced by the gonads in response to the stimulating activity of the pituitary gonadotropins whose release is, in turn, under the control of the hypothalamic gonadotropin releasing hormone (GnRH). At the central level, several neurotransmitters are able to modify the release of GnRH, including norepinephrine, dopamine, serotonin, gamma-aminobutyric acid (GABA) and glutamate (Sagrillo et al., 1996). Cannabinoids were found to significantly modulate the activity of the hypothalamic-pituitary-gonadal (HPG) and -adrenal (HPA) axes (Brown and Dobs, 2002) and their interactions (Karamikheirabad et al., 2013). Interestingly, sex hormones influence the action of cannabinoids on these axes (López, 2010) suggesting bidirectional interactions between sex hormones and the endocannabinoid system (Table (Table11).
The main molecular targets of sex hormones are members of the nuclear hormone receptor family, which areligand-activated transcription factors involved in the regulation of gene expression (Mangelsdorf et al., 1995). Testosterone, estrogen and progesterone target the androgen receptors (ARα and ARβ), the estrogen receptors (ERα and ERβ) and the progesterone receptor, respectively, although considerable receptor “promiscuity” might exist in each case. Nuclear receptors are ubiquitously expressed in the central nervous system (CNS), including areas associated with reward and addiction (Bookout et al., 2006). Besides transcriptional effects, sex hormones are also reported to have fast non-genomic actions by modulating the activity of G protein-coupled receptors (GPRCs), ion channels and signaling proteins (Simoncini and Genazzani, 2003).
Sex hormones cause permanent organizational sex differences that are fixed during early development but they also maintain certain sex differences during the adult phase as long as these hormones are present, i.e., induce activational effects (McCarthy et al., 2012). For example, gonadectomy in adulthood completely suppresses sexual behavior in males and receptive and proceptive behaviors in females, all effects being reverted by exogenous hormonal replacement (Micheal and Wilson, 1974; Mitchell and Stewart, 1989; Jones et al., 2017). When released, sex hormones are also able to deeply influence the organization and activity of one of the most important target organs of hormonal action, which is the brain (Arnold and Breedlove, 1985; McEwen and Milner, 2017). Gonadal hormones thus provide a biological basis for sex differences in endocannabinoid-related behaviors and are expected to contribute to the sexual dimorphic actions of cannabinoids (Craft and Leitl, 2008; Craft et al., 2013)
Source:
University of Maryland School of Medicine
Media Contacts:
Deborah Kotz – University of Maryland School of Medicine
Image Source:
The image is credited to Louisa Kulke.
Original Research: Closed access
“Prenatal THC exposure produces a hyperdopaminergic phenotype rescued by pregnenolone”. Roberto Frau, Vivien Miczán, Francesco Traccis, Sonia Aroni, Csaba I. Pongor, Pierluigi Saba, Valeria Serra, Claudia Sagheddu, Silvia Fanni, Mauro Congiu, Paola Devoto, Joseph F. Cheer, István Katona & Miriam Melis.
Nature Neuroscience doi:10.1038/s41593-019-0512-2.
