THC, Hormones & Brain Development: Reward Sensitivity & Sex-Typical Behavior
The neuroendocrinology of how cannabinoids & neurohormones affect the development of reward sensitivity & sex-typical behavior
Not medical advice.
Endocrine disruptors are chemicals that interfere with the endocrine system by blocking, mimicking, or otherwise altering hormone signals. As more people are becoming aware, our modern environment is filled with endocrine disruptors—everything from microplastics to petrochemicals, pharmaceutical drugs, and dietary components are disrupting hormonal balance within the body.
Although the details of hormonal systems vary from one animal species to the next, much of the core biology exhibits a high degree of evolutionary conservation. The same hormones found in your body are also found in other species. When biological functions are conserved across diverse branches of the animal kingdom, it indicates a vital purpose common across species—something preserved by natural selection, rather than lost to the degrading effects of mutation.
A degree of evolutionary conservation in animal endocrine systems also means individual endocrine-disrupting chemicals will often have similar effects in species ranging from humans to mice and fish:
The upside to this conservation is that it enables us to dissect the mechanistic details of hormone biology in model organisms, with some hope that the findings will generalize to humans (at least partially). More troubling: the hormonal disruptions we observe in animals exposed to environmental toxins may very well apply to us, too. If pesticides in the water have gender-bending effects on frogs, they may have directionally similar effects on people—atrazine is not just an amphibian endocrine disruptor, but also of humans and other mammals.
To learn more about endocrine disruptors, try these M&M episodes:
M&M 145: Epigenetics, Hormones, Endocrine Disruptors, Microplastics, Xenoestrogens, Obesogens & Obesity, Inheritance of Acquired Characteristics | Bruce Blumberg
M&M #184: Endocrine Disruptors & Metabolism: Microplastics, BPA, Estrogen, Insulin, Pancreas Biology & Metabolic Dysfunction | Angel Nadal
When people talk about endocrine disruptors, they typically mean chemicals we’re unwittingly exposed to. Nobody is actively trying to put atrazine, BPA, or phthalates into their body. But there are plenty of chemicals with endocrine effects that we do intentionally ingest. Obvious examples are exogenous hormones themselves, taken for the express purpose of altering hormone profiles—anabolic steroids, hormonal birth control, and hormone-suppressing drugs all have powerful endocrine effects extending well beyond the specific “symptoms” they’re meant to counteract.
Many prescription pharmaceuticals have endocrine side effects. Psychiatric drugs are being taken more than ever, and many alter hormones (a common cause of metabolic side effects). And then there are numerous dietary components with endocrine effects. For example, many plant foods are abundant in xenoestrogens (compounds that mimic or modulate estrogen signaling).
Our main focus in this article will be one commonly used, non-synthetic, plant-based substance that is often knowingly consumed for psychoactive and medicinal purposes, but which isn’t widely known for its hormonal impact: THC (tetrahydrocannabinol), the principal psychoactive component of marijuana.
THC has acute neurohormonal effects in adults who choose to consume it. Chronic exposure can have long-lasting endocrine effects. That includes adults who regularly ingest THC as well as unintended (or at least overlooked) exposures during prenatal development. As we’ll see, the endogenous cannabinoid system is critical for various aspects of brain development, including sexually dimorphic circuits that control “sex-typical behavior” in animals. Similar to exposing young animals to artificial levels of sex hormones during development, exposing them to cannabinoids like THC influences the maturation of brain circuits, with lasting effects on behavior, emotion, and cognition—effects that may last a lifetime.
Endocrine and endogenous cannabinoid regulation extend to virtually every tissue system of the body, operating throughout the lifespan. We will focus mainly on the neuroendocrine effects of THC in the brain, starting with the acute effect on neurohormones in the mature brain. For prenatal exposure, we will focus on circuits that govern reward learning and sex-typical behavior. Before that, we will first do a basic overview of how hormones regulate behavior through direct action on neurons in the brain.
Readers are encouraged to look elsewhere to learn more about how THC affects hormones and fertility, beyond the areas of focus in this article.
Special note: I used Consensus to do my research for this article—an AI-powered academic research tool for finding the best science, faster. Free one-year premium subscription with code MINDMATTERSPECIAL (offer expires 12.10.2024).
Hormones, Development & Animal Behavior
Hormonal fluctuations regulate the timing and magnitude of body-wide changes across the lifespan, especially at key developmental transitions like puberty. From basic life experience, most of us have a strong intuition that hormones powerfully influence behavior. Teenagers are behaviorally and emotionally volatile (“Their hormones are raging!”), a side effect of the literal brain re-wiring taking place in response to hormone flux.
Hormones are secreted by endocrine glands, travel through the bloodstream, and orchestrate body-wide transformations that require coordinated changes in spatially separate tissues. After a female becomes pregnant, her entire body—womb, brain, and everything in between—must be systematically transformed to equip her for what’s to come. Ditto for other natural, hormone-mediated changes. Puberty does not merely transform reproductive organs and secondary sex characteristics—it’s a wholesale reorganization of the body, inside and out. This includes brain circuitry controlling cognition, emotion, and behavior generally. We effectively become a new person after these hormone-driven transformations.
To learn more about how hormones impact the brain & behavior, try these M&M episodes:
M&M #89: Neuroscience of Aggression, Sex, Behavior, Hormones, Emotion & Consciousness | David Anderson
M&M #81: Sex Differences in the Brain, Endocannabinoid Biology, Purpose of Juvenile Play Behavior, Cannabis & Pregnancy | Margaret McCarthy
Artificial hormones and endocrine disruptors exert a powerful influence on the mind-body through their ability to mimic and modulate endogenous hormone signaling. In the brain, many neurons are directly sensitive to hormones—they contain hormone receptors which, when activated, alter the expression of genes and action of proteins within the cell. These molecular changes then influence information flow through that neuron—modulating sensitivity to inputs, altering its connectivity pattern, or changing aspects of neurotransmitter release.
Dramatic behavior changes can be instigated by exogenous hormones. In animals, neuroscientists can directly stimulate hormone-sensitive neurons in real time, triggering changes in social and reproductive behavior, stress and metabolic responses, and more. These types of experiments are now routine in neuroscience, enabled by technological advancements like optogenetics. (See video example below).
Natural hormonal changes at key transition phases of life are directly tied to reconfigurations of behavior and personality. Any mother can attest to the fact that the maternal-infant bond comes with not just overwhelming feelings of love and attachment to the baby, but a new well-spring of protective and even aggressive urges. These changes are orchestrated by neurohormonal fluctuations that physically re-wire the mother’s brain, “unlocking” latent behavioral potential that she could have scarcely imagined.
Sex hormones like estrogen and testosterone affect behavior through direct influence on specific, sex hormone-sensitive neurons. The cellular signaling mechanisms activated within neurons by sex hormones influence how the neuron “talks” to others. Neuroscientists can artificially activate or inhibit hormone-sensitive neurons in specific brain circuits to immediately change behavior. For example, Dr. David Anderson (see M&M #89) has published astonishing results involving stimulation of estrogen-sensitive neurons in mice. Here’s one example, where you can see dramatic behavior change in real-time:
To summarize: hormone levels naturally change at different phases of life, such as puberty and pregnancy. In the brain, this instigates the rewiring of brain circuits, culminating in behavior change. Your personality changed during and after puberty because circuits in your brain were physically reconfigured. Sex hormones are a means by which the body orchestrates coordinated changes throughout the body in order to “reprogram” the organism.
Under naturalistic conditions, these hormone-mediated developmental changes unfold according to a particular rhythm dictated by the interaction of genetic and environmental inputs. But what if those natural rhythms are interfered with? As we saw above in laboratory animals, artificial stimulation of estrogen-sensitive neurons can rapidly and dramatically trigger behavior change.
What if an animal is exposed to exogenous hormones or endocrine disrupting drugs, especially during key phases of development? This can obviously influence how development unfolds, exaggerating or “throwing off” the maturation of brain circuits to some degree. Modern humans live in a state of hyper-novelty, inventing things at a rate much faster than the speed of evolutionary adaptation. This includes many substances which endocrine effects, including THC.
THC & the Adult Brain
An overview of how THC works in the brain, before diving into its endocrine effects.
The psychoactive effects of THC arise from activation of CB1 receptors in the brain. These receptors are located on both excitatory and inhibitory neurons throughout the brain. In many circuits, when neurons become very active there is an endogenous cannabinoid-based feedback mechanism to tone them down. A neuron that receives elevated input from another produces endocannabinoids, such as anandamide or 2-AG, from fatty acids in its membrane. This is done “on-demand,” such that the endocannabinoids act locally, at one synapse—they travel “backwards,” activating CB1 receptors on the input neuron, before being quickly degraded. CB1 activation on the input neuron has a “calming” effect, reducing neurotransmitter release. This can elevate or dampen overall activity in the circuit, depending on whether the input neuron is excitatory or inhibitory.
To learn more about endocannabinoid biology, try this content:
Podcast: Endocannabinoids, Stress, Exercise, Cortisol, Anxiety, Cannabis & Effects of Marijuana on Brain Development | Matthew Hill | #123
Article: Metabolic Effects of Cannabinoids
One area of the brain with high levels of CB1 receptor expression is the, “dopamine reward system,” critical for regulating motivation and reward learning. In general, any reward will boost dopamine release within this circuit. Natural rewards like palatable food and mate access have this effect, as do drugs with abuse potential. As a general rule, the more rewarding something is, the greater the level of dopamine release, and the more behaviorally reinforcing it will be (i.e. greater addiction liability).
THC boosts dopamine levels through a disinhibitory mechanism. CB1 receptors are especially abundant in inhibitory neurons within the reward system. Unlike endogenous cannabinoid release, which is time-limited and synapse-specific, THC ingestion more or less results in simultaneous CB1 receptor activation on all the inhibitory neurons of the reward circuit. Inhibition of inhibitory neurons promotes overall circuit excitation, elevating dopamine release within the system.
Endogenous cannabinoids are part of a negative feedback mechanism that regulates overall circuit activity, helping to prevent it from getting out of control. Unlike endogenous cannabinoids, which serve as short-lived signals at single synapses, exogenous cannabinoids like THC have lingering effects on CB1 receptors throughout the brain. This means greater overall CB1 activation, which is detected by cells and triggers another feedback mechanism meant to counteract the excessive CB1 activation—that mechanism involves a steroid hormone synthesized in the brain.
THC & Neurosteroids: Acute effects in adult brain
Steroid hormones include glucocorticoids like cortisol and sex hormones like testosterone and estrogen. The ultimate steroid hormone precursor is cholesterol, the bulk of which is synthesized in the liver. Cholesterol production is hormone-dependent and modulated by diet: the more intestinal absorption of dietary cholesterol, the less de novo cholesterol synthesis in the liver.
Starting from cholesterol, mitochondria synthesize pregnenolone using cytochrome enzymes. Pregnenolone can then undergo various enzymatic transformations to produce different steroid hormones.
Steroid hormones can also be synthesized within the brain (“neurosteroids”). In the brain, pregnenolone directly affects endocannabinoid signaling by inhibiting CB1 receptor activation, similar to the exogenous cannabinoid CBD. Pregnenolone dampens the effect of CB1 activators like THC. When THC is ingested, it activates CB1 receptors and also triggers a boost in brain pregnenolone.
As it turns out, many rewarding drugs (e.g. morphine, nicotine) boost brain pregnenolone, but THC seems to boost it most. The effect is higher in certain brain areas, including the dopamine reward pathway. Many disease states also involve changes in pregnenolone levels, and declines in neurosteroid levels have been associated with age-related impairments. (A good guess is that these changes involve altered cholesterol metabolism).
Giving pregnenolone to rodents prior to THC administration attenuates its effects. THC triggers dopamine neurons to release more dopamine, and animals tend to repeat behaviors that result in this motivating reward signal. If you give the same animals pregnenolone before THC, it dampens both the dopamine release and behavior repetition.
Why does a CB1 activator like THC boost something that counteracts its effects? This pattern is evocative of a common regulatory motif in biology called “feed-forward inhibition,” observed everywhere from neural activity to gene expression. For example, in mature neural circuits of the cerebral cortex, a volley of excitatory activity often triggers the activation of inhibitory neurons, which immediately inhibit the neurons that were just excited. This limits the spread of excitation, which might otherwise get out of control and result in a “storm” of excitation (seizure). Inhibitory neurons serve to restrain and “sculpt” the flow of information in the brain. The maturation of inhibitory circuits is a major factor shaping information flow at different phases of development—in fact, the maturation of inhibitory cells is often what determines the timing of critical periods of plasticity within the brain.
So: inhibitory circuits are pivotal for shaping and limiting patterns of information flow within neural circuits and mature at distinct phases of development. Hormones are critical regulators of development, with both short- and long-term effects on the excitability and connectivity patterns of individual neurons. Because of all this, drugs that impact neurohormones (like THC) can affect how neural circuits in the brain mature. It also means that the brain effects of THC can be dramatically different depending on the phase of development: in a less mature brain, the pattern of excitation induced by THC will be very different than it would be in a more mature brain. In turn, this affects how developing neurons “wire up” together, which is highly dependent on these excitation patterns.
When young animals are exposed to THC in the womb, it alters the development of their dopamine reward system, rendering it more sensitive to reward stimuli. Intriguingly, pregnenolone can reverse this effect. To understand the prenatal effects of THC on the reward system, it will help to first understand how the placenta regulates fetal drug exposure.
THC & the Developing Brain
The mammalian placenta is a semi-porous barrier regulating nutrient, gas, and waste exchange between maternal and fetal circulation. Its evolved purpose is to protect the growing animal, preventing “bad things” from getting in and allowing or even amplifying the concentration of “good things.”
One of the major problems we face in modernity is that we can quickly invent and be exposed to novel substances that our ancestors never encountered. When we lack an extended evolutionary history with something, our bodies are unlikely to be specifically adapted to it. Novel synthetic substances can therefore “confuse” our biological mechanisms, as they never “learned” how to deal with these things—this is not always true, but often is. For the placenta, this can mean harmful exogenous substances might cross the placenta.
Synthetic drugs that our ancestors never encountered can be harmful or beneficial, and may or may not cross the placental barrier. Drugs can be categorized into three groups based on the extent to which they cross the placenta, which is based on their physical properties:
“Complete transfer” drugs cross into the placenta and reach similar concentrations in fetal and maternal blood (e.g. opioids, many anesthetics).
“Exceeding transfer” drugs are actively transported across the placenta, resulting in higher concentrations in fetal compared to maternal blood (e.g. ketamine).
“Incomplete transfer” drugs do not cross the placenta completely, resulting in lower fetal blood concentrations compared to maternal blood. (e.g. many paralytics).
Fat-soluble drugs, including cannabinoids like THC, tend to undergo complete placental transfer. They can enter the in utero environment and interact with the developing endocannabinoid system. As a rule, earlier exposures, higher doses, and more frequent exposures have a larger impact on development. The effects of THC in the brain come largely (though not exclusively) through CB1 receptors, which come online early in development.
Let’s unpack how the endocannabinoid system helps regulate early development, and how early exposure to THC affects development of the dopamine reward system in particular. Then we’ll bring it back to pregnenolone, and how that hormone can reverse some of the developmental deficits induce by prenatal THC exposure.
Early Development of the Endocannabinoid System (ECS)
The endocannabinoid system begins functioning early in development. As development proceeds, cannabinoid and receptor levels fluctuate, determining how much influence cannabinoids will have within brain regions. The ECS plays an important role in the natural unfolding of brain development. Altering ECS activity during early stages will impact nervous system development. In severe cases, this can impact embryo viability—more commonly, brain development will be affected in more subtle ways, making specific circuits more or less active, or changing their sensitivity to inputs.
One thing that’s tricky about brain development is that perturbations that lead to measurable changes under laboratory conditions may not manifest in overt problems detectable in single individuals in the real world. For example, let’s say that you were exposed to some THC in the womb, causing your brain to develop such that you were somewhat more sensitive to rewards than you otherwise would have been. How would you know? You wouldn’t.
Now scale this thinking up to the population level: if 10% of the population is exposed to some level of THC at some point in development, such that some of those people develop personalities that deviate somewhat from what they would have been otherwise… how would we know? We wouldn’t. The effects would be all mixed together within the full spectrum of human variation—they may even fail to show up in epidemiology studies with large sample sizes, due to inability to account for person-to-person variation in timing, dosage, and a host of other variables.
This complexity makes it virtually impossible to detect all but the most glaring developmental effects at the population level in humans—one reason why we shouldn’t be too quick to dismiss non-human animal studies, especially when it comes to aspects of biology that exhibit evolutionary conservation.
Before digging into what we know about the developmental effects of prenatal THC exposure in animals, let’s get a sense for how common prenatal exposure is in humans today.
To learn more about endocrine disruptors, try these M&M episodes:
M&M 42: THC, CBD, Omega-3 Fatty Acids, L-Theanine, Opioids, Pregnancy, Brain Development, Addiction, Anxiety & Schizophrenia | Steve Laviolette
M&M #123: Endocannabinoids, Stress, Exercise, Cortisol, Anxiety, Cannabis & Effects of Marijuana on Brain Development | Matthew Hill
Prevalence of Cannabis Use During Pregnancy
In the modern West, cannabis use among pregnant women has an estimated prevalence of 3-16%. Relieving symptoms of anxiety and morning sickness are the most common reasons cited. THC may indeed provide acute relief from these symptoms (THC is an antiemetic, a drug that reduces nausea and vomiting), but as a “complete transfer” drug, it crosses the placenta.
In pregnant rodents, inhalation of THC vapor exposes developing pups to THC levels roughly one-third of those measured in the maternal blood. Based on human survey data, this could mean roughly 10% of pregnancies involve some level of fetal THC exposure. Assuming rodent studies generalize to humans, this implies that approximately one in ten pregnancies expose the fetus to THC levels that could have a meaningful impact on brain development. Again, higher and more frequent dosing will have greater impact, especially at earlier developmental time points.
What are the known effects of prenatal THC exposure on human and animal brain development? We’ll focus on the the reward system, in part because the effects THC has on its development can be reverse (at least partially) by the neurosteroid pregnenolone we discussed earlier.
Effects of early life THC exposure on the brain & behavior
On M&M #42, I talked to developmental neuroscientist Dr. Steven Laviolette about the effects of psychoactive drugs on mammalian brain development. Prenatal THC exposure affects the expression of components of the endocannabinoid system in multiple brain regions.
In humans, there are a number of developmental abnormalities that correlate with THC exposure during development. In general, prenatal exposure in humans is associated with bad outcomes like lower birth weight, pre-term birth, and neurodevelopmental issues. You can find specific studies in this area here.
These associations are mirrored by similar findings in rodents, which have established cause-and-effect between early life THC exposure and various developmental abnormalities.
Let’s take a closer look at two areas where THC exposure can lead to changes in brain development with lasting effects on adult brain function:
Drug sensitivity & reward processing
Sex-typical behavior in males vs. females
Dopamine reward system: Basic overview
The “dopamine reward system” is one of the more well-studied brain systems. It’s an ancient system, present in all vertebrates and comprised of interconnected circuits that process information about things animals like and want. This system is involved in motivation and cognition generally, not just reward processing. A reward can be anything from a euphoria-inducing drug to palatable food or social media notifications. (The architects of our digital apps are well-studied in this area of neuroscience). THC and other stimuli can trigger elevated dopamine release within this brain network, which is essentially what classifies something as a reward.
Many drugs have some abuse potential, but it’s a mistake to think of them in binary terms: addictive or non-addictive, period. Instead, all drugs carry some addiction liability—the propensity of repeated drug exposures to lead to addiction, in a given context. Some drugs have very high addition liability (e.g. nicotine, opioids). Others have a negligible liability (e.g. serotonergic psychedelics). A drug’s addiction liability depends on exactly how it works in the brain.
To learn more about the dopamine reward system, try these M&M episodes:
M&M 94: Neuroscience of Pleasure, Reward, Liking vs. Wanting, Motivation, Food vs. Drug Addiction & Emotion | Kent Berridge
M&M #162: Drugs, Addiction & Neuroplasticity | Robert Malenka
Some individuals are more sensitive to rewards than others, which makes them more prone to addiction. This is arises from variation in how the brain’s reward circuitry gets wired up during early development and refined by experience after birth. The whole process is influenced by what our brains are exposed to, both in the womb and after birth, based on what’s ingested. Prenatal exposure to THC, for example, can render the brain’s reward circuitry hyper-sensitive and more responsive to reward stimuli later in life.
THC & Brain Development: Effects of the reward system
THC and other substances can impact how the reward pathway gets put together—the baseline sensitivity of the system, and therefore how readily rewards will trigger reward-seeking behavior. Although expressed throughout the brain, endocannabinoid receptors are especially abundant in the dopamine reward system. THC exposure during early development can therefore have a substantial impact on reward processing later in life.
In general, exposure to rewarding drugs during development sensitizes the reward system. The effect is general, not drug-specific. Example: rodents exposed to THC during adolescence are more sensitive to opioids. There are also sex differences between males and females. Pregnant females given daily, low doses of THC give birth to offspring with “reward neurons” that release more dopamine in response to THC exposure during adolescence—an effect seen in sons, but not daughters. As we’ll see, sex-biased effects of cannabinoids are common because the endocannabinoid system itself regulates the development of sexually dimorphic bran circuits.
Dopamine does a lot in the brain. It’s too simplistic to simply think of it as simply a “reward signal.” When dopamine circuits are dysregulated, there can be consequences beyond “reward behavior,” including general motivation and susceptibility to stress. Exposure to exogenous cannabinoids during early development impacts how dopamine neurons mature, with consequences for emotional regulation and anxiety levels later in life. This is not surprising given the extensive overlap of the endocannabinoid system with other major neuromodulatory systems of the brain, beyond dopamine.
In addition to being intertwined with neuromodulatory systems like dopamine, the cannabinoid system is intimately tied up with hormonal systems that influence behavior, including sexually dimorphic circuits that underlie sex-typical behaviors in animals. Intruigingly, the sex hormone precursor pregnenolone can reverse some of the developmental brain abnormalities induced by prenatal THC exposure.
Pregnenolone: Reversal of THC’s Developmental Effects
Pregnenolone diminishes the effects of THC in adult animals when its administered ahead of THC, due to its ability to suppress activation of CB1 receptors. It can also reverse some of the developmental abnormalities of the dopamine reward system that arise from prenatal THC exposure.
One well known developmental effect of prenatal THC exposure is heightened sensitivity of the dopamine reward system. If exposed to THC in the womb, an animals’ dopamine reward system will often be extra responsive to rewarding stimuli. Drug rewards, including THC itself, then elicit a larger dopamine response in the reward circuitry of those animals. This arises from abnormalities in excitatory-inhibitory balance and synaptic plasticity, ultimately influencing addiction propensity. Curiously, the sensitizing effect of THC on the developing reward circuit is seen in male mice, but not females.
Remarkably, giving supplemental pregnenolone to male mice exposed to THC in the womb is able to reverse many of the THC-induced abnormalities seen in the dopamine system. This occurs even though pregnenolone is given after birth, even though THC exposure was in the womb. The exact mechanism by which pregnenolone does this is unknown, but it’s interesting that a sex hormone precursor has an effect like this, and that the developmental impact of THC on the reward system is sex-specific.
Another area of neurobiology where sex differences are often observed is in the susceptibility to psychiatric illnesses. For example, females tend to be more prone to anxiety and depression, whereas males can be more prone to certain forms of psychosis. There are many sex differences in the brain, which likely arise (at least in part) from hormonal influences on neural circuit development.
In addition to sensitization of reward circuitry, prenatal THC exposure also predisposes rodents to psychotic-like symptoms later in life. Here again the effect is seen in only in males, and can be normalized by pregnenolone.
Why would the effects of a drug like THC influence brain development in a sex-specific manner and be subject to modification by a sex hormone precursor? This might seem a little strange at first—shouldn’t a drug like THC, which impacts CB1 receptors all over the brain in both males and females, have comparable effects in both sexes?
As it turns out, the endocannabinoid system is directly involved in the development of sexually dimorphic neural circuits. Many circuits in the brain naturally develop different properties in males vs. females, due in part from the fact that the equivalent circuits in each sex are exposed to a different cocktail of hormones and other chemicals, including endogenous cannabinoids.
THC & Hormones: Developmental effects on sex-typical behavior
When scientists compare the effects of drugs on the brain in males vs. females, sex-biased effects are often observed. Differences in the male vs. female brain begin to emerge early in nervous system development. The differences are often subtle, sometimes substantial. But they are common. As Dr. Margaret McCarthy explained on M&M #81, when scientists carefully compare the brains of males or females, they more often than not find differences, even if they’re small.
THC’s effects on brain development exhibit fairly large sex differences. As it turns out, the endogenous cannabinoid system is intimately involved in the development of sexually dimorphic circuits in the mammalian brain (those that differ between males and females). This includes circuits involved in reward processing, social and reproductive behavior, and emotional regulation—things that often differ between males and females which, under normal conditions, manifest as “sex-typical” behaviors and predispositions.
At least in certain regards, young male and female mice display biases in social behavior, not unlike those of human children. For example, males engage in rough-and-tumble play more frequently. Young females do this less often—that is, unless they’re exposed to THC in the womb.
I’m going to explain some of the findings Dr. McCarthy in highly simplified terms—for for more detail, listen to her words directly. In short, with respect to juvenile play behavior, early exposure to THC has a masculinizing effect on female rodents. Similar to prenatal testosterone exposure, prenatal THC exposure transforms juvenile play behavior in females, making it look like typical juvenile male behavior.
These effects come from THC’s impact on specific circuits within the medial amygdala, which is part of an extended “social behavior network” in the rodent brain. When scientists administer either extra testosterone or CB1-activating drugs (including THC) to female mice shortly after birth, their future juvenile play behavior resembles that of normal males. The effect is seen both from systemic administration or injection into the medial amygdala specifically. In other words, exogenous cannabinoids like THC have a masculinizing effect on the juvenile play behavior of female rodents, similar to the effects of exogenous testosterone.
Timing always matters in development. When THC is given to pregnant rodents, resulting in prenatal THC exposure rather than exposure just after birth, the opposite effect is seen: juvenile play behavior is suppressed, rather than elevated. This is a common pattern in developmental biology—the effects of exogenous substances, whether hormones like testosterone or drugs like THC, depend heavily on developmental timing and sex.
The development effects of cannabinoids should probably be expected to have sex-specific effects on brain development, by default, as endocannabinoid signaling is involved in the maturation of sexually dimorphic brain circuits. To greatly simplify things, CB1 receptor expression and endocannabinoid levels vary between brain regions and across development. The density of CB1 receptors and extent to which they’re activated shapes how neurons “wire up” to others in each region. One way this happens is by determining which connections get pruned away during key phases of developmental refinement.
Certain facets of endocannabinoid biology differ naturally between males and females, just as hormone levels do. For example, males tend to have higher levels of the endocannabinoid 2-AG. These sex differences effect the overall cell density and connectivity pattern in places like the medial amygdala, which ultimately gives rise to different patterns of juvenile play behavior in males vs. females.
I’m glossing over a lot of cool biology here. The bottom line is that cannabinoids like THC can mimic the effects of hormones like testosterone in terms of their effects on the developmental of brain circuits that control sexually dimorphic behaviors in rodents. Because THC boosts levels of pregnenolone in the adult brain, and pregnenolone serves as a sex hormone precursor, it’s entirely possible that exogenous THC impacts sex hormone levels in the brain during development. (I’m not sure that’s known directly).
As hormones are responsible for coordinating long-lasting transformations throughout the brain and body, it’s plausible that the effects of exogenous cannabinoid exposure during early development extend beyond sexually dimorphic circuits governing juvenile play behavior. A quick literature search reveals that many such sex differences seem to be known.
Developmental Effects of THC: Implications for humans
As we’ve seen, the developmental effects of a substance depend on many factors, including the precise timing and level of exposure, sex of the organism, and more. Exposure to a chemical can have the opposite effect on behavior if it occurs at one developmental time point vs. another—specific, sweeping predictions for exactly how perinatal THC exposure will affect human behavior are therefore difficult to make.
As always, the devil is in the biological details. Given the fundamental role that hormones and the endocannabinoid system play in animal biology, including brain development, we can be sure that pre- and postnatal THC exposure is very likely to have developmental consequences for humans in proportion to the duration and level of exposure. There are already many clear associations between early life THC exposure and brain abnormalities in humans, some with clear sex differences.
What you consume influences not only who you become. For parents, and especially new and pregnant mothers, what you consume also has a direct influence on who someone else becomes.
Think carefully.
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To learn more about the topics covered in this essay, try these episodes of the Mind & Matter podcast: