How THC rots your brain?

[Chris Jay]

I am likely to be among the first in any given crowd to support drug-positive perspectives. Over 130 different psychoactive compounds have passed through my brain over the years, and Cannabis has been of incredible use to my ability to function & participate in life (I am currently a daily user).

I am also a neuroscience major pursuing a PhD in psychopharmacology. Spreading more accurate, less biased information about psychoactive drugs is my life’s purpose. But within this purpose, it’s also necessary for me to distribute accurate information about their drawbacks as well. I feel a calling to this mission akin to that which a priest might feel to their religion.

In certain communities, Cannabis is regarded as sacred medicine. Many hesitate to call it a drug, and many hesitate to claim it has any side effects at all. This neglect poses a significant threat to many people; the Cannabis of today is far different than what humans have been using for thousands of years, and treating it as harmless is neither fully informed nor constructive for the vast majority of people.

To explain exactly what a high-THC low-CBD “Cannabis diet” does to your brain, I’ll need to get into the muck & grime of neurotransmission, so you’ll probably see some crazy chemical names and stuff in this article that look really daunting, but I promise anyone can understand this stuff if they take a deep breath and keep track of the terms. I’ll also simplify it as much as I can and make it at least somewhat entertaining? Hopefully?

Your Nervous System and its Cannabinoids

The nervous system is classified into two parts: the central nervous system (CNS) and the peripheral nervous system (PNS). The CNS is the brain and spinal cord; it’s where all your complex cognition and perception takes place. The PNS is the set of nerve tendrils your brain reaches through your body so you can actually feel stuff and control your movement. There’s a lot of communication between the CNS and PNS, and the PNS can actually do some stuff that influences your perception and cognition. But for the sake of this article, I’m going to be focusing on the CNS, particularly the brain.

Your brain is made up of brain cells; the predominant cells are called neurons, and these are responsible for the vast majority of what your brain does. Your brain has 86 billion neurons (on average), and each of those neurons shares an average of 10,000 connections, or synapses, with other neurons.

For a neuron to fire, the intracellular voltage (the electrical charge on the inside of the neuron) must reach a certain level higher than the extracellular voltage (charge outside the neuron). To change the balance of charges, the neuron opens and closes ion channels, which are proteins on the cell membrane that let specific ions through. Ions are positively or negatively charged molecules; usually singular atoms such as Ca2+ (Calcium missing 2 electrons).

The balance of charges between the inside and outside of the neuron is called the membrane potential; when this reaches the neuron’s threshold potential, it becomes an action potential, at which point an electrical signal travels down the neuron’s axon to its axon terminal. This terminal is the presynaptic terminal; it’s primarily on the giving end of the synapse, where the next neuron’s dendrites will pick up what it’s putting down.

What it’s putting down is a short burst of chemical release: various ions, things like dopamine and serotonin; basically just a dump of various chemical compounds that will influence the next neuron(s) in line. These chemical compounds will bind to receptors on the next neuron and alter its own membrane potential, which will adjust how close it is to firing.

Receptors are more-or-less chemical robots; they’re highly specialized proteins that, upon receiving a ligand (a chemical key; a neurotransmitter or a drug in most cases), will accomplish certain tasks for the cells present. In nervous systems, they’re usually divided into two groups: ionotropic and metabotropic. Ionotropic receptors include things like ion channels; they directly influence membrane potentials by allowing the exchange of ions across cell membranes. They’re typically the endpoint of any signalling cascade (basically a chain reaction of communication). But metabotropic receptors are just as important; they can significantly modulate the activity of ionotropic receptors and neurons as a whole, it’s simply an indirect way they go about doing so. This includes things like dopamine receptors (D1 through D5), serotonin receptors (except 5ht3), and some glutamate receptors (MGluR1 through MGluR8), among many others.

Receptors are also classified as excitatory or inhibitory. Excitatory means their activation leads to a higher membrane potential, and inhibitory means the opposite. This gets a little complicated when talking about metabotropic receptors, because they can often activate different signalling pathways that have excitatory AND inhibitory effects, but in most cases, a receptor is considered either primarily excitatory or primarily inhibitory. Dopamine and glutamate receptors are largely excitatory, while serotonin and GABA receptors are largely inhibitory.

The Endocannabinoid System (ECS) is a system of transmission found within mammalian nervous systems that has gained sharply increased interest in the past 40 years. It has a hand in regulating everything from blood pressure to sensory input to cognitive abilities, and modulates the activity of other major neurotransmitters like serotonin, dopamine, and acetylcholine.

The transmission of the ECS in the CNS is primarily mediated by two endocannabinoids (portmanteau of endogenous, meaning “from within,” and cannabinoid, which is a compound that acts on cannabinoid receptors). These compounds are anandamide and 2-arachydonoylglycerol (2-AG). Anandamide is pretty insignificant; it’s released in very small amounts and metabolized quickly. 2-AG is far more present in your CNS and thought to play a much bigger role in mediating sensory and emotional perception. Both of these compounds are, at best, about 1/10 the potency of THC by weight. They are both metabolized (broken down) in the brain primarily by an enzyme called FAAH (Fatty Acid Amide Hydrolase).

There are two main cannabinoid receptors: CB1 and CB2. CB2 isn’t heavily present in the CNS, at least not remotely to the extent of the role it plays in the PNS. CB1 is what’s mainly responsible for creating an altered headspace. THC is an agonist at CB1 (activates the receptor), while CBD is a negative allosteric modulator (NAM; decreases the ligand’s influence on the CB1 receptor).

Brain Debriefing

The big squiggly lump on top is called your cerebral cortex (might be shortened to just ‘cortex’). It’s where the vast majority of your memories are stored, including emotional, logical, and sensory information. Your cortex does a bit of the work on its own, but it also outsources a good bit of the work to the lower portion. It’s not really an unhealthy professional dynamic though; they get along pretty well, communicate about each other’s needs, and are generally good at reaching fair compromises. But the thing to know is that the cortex primarily functions as an information warehouse, which includes some management in organization, routing, and distribution.

The cortex includes the frontal lobe, which is what the rest of your brain uses mostly for storing logical processes and higher-order cognition, including complex emotion. The structural integrity of the frontal lobe is incredibly important for functioning on a competent level: assessing nuance, comprehending abstract concepts, being able to integrate and apply previous information in new situations. Dysfunction in this region is widely seen in depression, schizophrenia, and personality disorders.

The lower part of your brain is divided into the subcortex and brainstem. Your brainstem holds the midbrain, which is responsible for a lot of sensory processing; basically routing hastily-assembled sensory input to the hippocampus, which gets other subcortical regions involved. The other regions all do their own stuff with the information, basically putting little markers on it to tell the hippocampus where in the cortex they should send it. This information gets sent to the cortex, and the cortex basically adds bits of other memories to fill in the gaps and errors, then commits this information to its memory by systematically adding and deleting synapses in the proper order if it’s important enough.

The midbrain contains the Tegmentum, which has a bunch of different incredibly complex roles that aren’t important for me to explain in this article. But the Tegmentum houses the Ventral Tegmental Area (VTA), which serves as a starting point for the mesolimbic pathway. The mesolimbic pathway is the region most closely involved in the processing of reward, motivation, and euphoria. To put it simply, the VTA receives both complete and incomplete stimuli, assesses the positive+negative effects of them (with the help of some other regions like the Lateral Habenula), and then sends them to the mesolimbic pathway. The mesolimbic pathway allows this reward transmission to affect acute (short-term) perception, and sends this reward signal to the Nucleus Accumbens (NAc) to be committed to the cerebral cortex as a rewarding stimulus. The NAc sends the signal back to the VTA to be re-assessed, and this circuit continues until it is acted upon or fades away due to other signals that outweigh it.

The Amygdala essentially does the same thing, but instead evaluates information for whether it causes noxious stimuli. This means that it detects things you experience that cause fear, anxiety, paranoia, danger, aversion. It’s closely linked with the mesolimbic pathway and NAc, as well as the Lateral Habenula (LHb, a “limiter” on reward transmission).

All of these regions are heavily involved in influencing cognitive patterns and perception of both environmental & abstract dynamics. Hyperactivity in these regions is often linked to symptoms of psychosis, anxiety, OCD, and bipolar.

What Your Receptors Can Do for You!

Your brain has many different ways it maintains homeostasis (chemical balance). It largely does this at the receptor level.

When a ligand (molecule such as a drug or neurotransmitter) binds to a receptor, it attaches itself to a certain site on the receptor. A binding site is an area of the receptor where a ligand can attach itself, thus changing the chemical composition of the receptor which modifies its behavior. When a ligand activates a receptor, this is called agonism. For example, THC is an agonist at the CB1 receptor.

There are also molecules that can block, or antagonize, a receptor. This means it can knock a previous ligand from a receptor’s binding site, bind to it, and then prevent other ligands from further activating or deactivating it. An inverse agonist is a ligand that both antagonizes and deactivates a receptor, reducing it to its resting state. Anticholinergics like benadryl and scopolamine are good examples of this; they fully deactivate acetylcholine receptors.

In order to maintain homeostasis, receptors may deactivate long-term, or downregulate. Downregulation can happen in several ways, but the two I want to focus on are internalization and heteromerization. When a receptor has experienced a certain level of stimulation for a long enough time, it undergoes a process called internalization. This is when the receptor leaves the cell membrane and retreats into the neuron. Here, it can either be metabolized and used to build other receptors (or excreted), or it can be recycled where it’s stored in the cytoplasm until it can be of future use.

Heteromerization is a bit more complex; when a receptor heteromerizes, it forms a bond with another receptor. This usually shuts off the transmission of both receptors, and creates a new type of transmission that generally has an effect counterintuitive to the normal behavior of the receptors. It rarely has the exact opposite effect, which means that some irregular stuff can pop up when enough receptors heteromerize.

The binding affinity of a molecule is how strongly it’s attracted to the binding site of a receptor. If a molecule has a high binding affinity, it’s strongly attracted to the receptor and is much more likely to occupy the binding site. This is measured as a Ki value, with lower value generally meaning the molecule binds more strongly to the receptor. Ki value does not indicate whether it is an agonist or antagonist, and it does not indicate how strong the effect is on the receptor.

Potency is typically measured by EC50, or the concentration at which 50% of the drug’s ceiling effect is reached. A drug’s ceiling is the level at which its primary target receptors are fully occupied by the drug. EC50 is generally measured by mol/L, or moles of the drug per liter of blood. It’s worth mentioning that for many drugs, the dose-response curve (graphed line of the dose with the level of effects it induced) is not linear, so EC50 is not a 100% reliable measure of potency either.

The Evolutionary Footprint of Cannabis

A ton of people know the basics of how THC works. They know it releases dopamine and serotonin in the reward system. They know CBD makes it less potent. They might even know about cannabinoid receptors. But, as brains often do, they are reaching conclusions about it based on incomplete information.

First of all, to set the record straight: the fact that we have cannabinoid receptors does not imply that we are meant to consume Cannabis. These receptors evolved with entirely different molecules in mind: the previously-mentioned anandamide and 2-AG. We named the receptors after the plant, because we discovered the plant’s effects on them before we discovered the ECS. Same reason opioid receptors are called that, despite evolving for the purpose of endorphin transmission (fun fact: endorphin is a portmanteau between ‘endogenous’ and ‘morphine!’).

That being said, mammals have likely been consuming Cannabis for millions of years. Many species of mammals are observed eating Cannabis in nature, and Cannabis itself is at least 48 million years old. Our distant ancestors likely consumed this stuff. It’s reasonably safe to say our neurocognition has evolved alongside this plant’s cannabinoids for millions of years.

People often know about how the compound largely present in Cannabis is THCa (tetrahydrocannabinolic acid), an inactive variant of THC. To make it psychoactive, it must be decarboxylated (often via heating), which knocks a carbon and oxygen atom off the structure and turns it into THC. This THC can then be consumed orally. Smoking reproduces this process very rapidly, but absorbing into your bloodstream directly from your lungs, instead of drawing out the absorption with a time-consuming liver filtration.

The thing is, for the previous 10 million years before cooked meals and handpipes, mammals have been consuming their cannabinoids raw. Not only this, but they’ve been consuming landrace plant matter that contains about 1% THCa and 2-3% CBD. The vast majority of this THCa is metabolized and excreted before ever decarboxylating or hitting your brain. So, for the past 10 million years (minus the past 5 thousand, give or take), the mammalian brain has been adjusting and getting real comfy in this zone of maybe 0.5mg THC / 3mg CBD / 1mg CBG in a healthy hemp meal, absorbed over the course of 3-5 hours by the GI tract.

Now, imagine if we suddenly learned how to get the absorption time to under 10 minutes by putting it in our lungs. Imagine if we suppressed the plant’s production of all the cannabinoids except THC (which we elevated 2000%) in the course of 100 years; a time frame 0.00001% that within which we have been co-evolving with it. Imagine if we started extracting that THC to 90% purity and just smoking it like that. You can see how that might go a little poorly perhaps?

Why High THC Kinda Really Sucks, and How Cannabinoids Help Each Other Out

There are over 140 cannabinoids known to occur within Cannabis, all with slightly varying effects. The ones I’m primarily going to focus on are THC (Δ9-tetrahydrocannabinol), CBD (cannabidiol), and CBG (cannabigerol).

THC is an incredibly potent drug, and it has properties similar to those of a lot of different drugs as well. Most of these are exerted downstream from the CB1 agonism. But too much CB1 agonism, or CB1 overstimulation, can result in a whole bunch of really nasty neurocognitive anomalies that can make you real stupid and real crazy. For one, it’ll cause CB1 downregulation, which causes tolerance.

In addition to this, THC causes a heteromerization between CB1 and 5ht2a receptors. 5ht2a is a type of serotonin receptor involved heavily in perception, thought, and creativity. This is the receptor psychedelics like psilocybin and LSD agonize to exert their effects. Causing a heterodimer between CB1 and 5ht2a ‘changes the channel’ on the signalling pathway for 5ht2a, thereby deactivating its previous effects. Typically, 5ht2a begins its intracellular signalling pathway by coupling with a protein called Gq, modulating its alpha subunit, and then sending it on its merry way to excite the neuron and induce neuroplasticity. When it’s heteromerized with CB1, it switches to a protein called Gi instead of Gq. Gi also excites neurons, but in a different and creepier way; primarily via cAMP, which is one of the ways dopamine excites neurons. And this would be all well and dandy, except for the fact that 5ht2a and CB1 receptors are expressed really densely in the prefrontal cortex (which can induce obsessive-compulsive characteristics), as well as the basal ganglia (which, over time, can potentially cause GABA interneuron downregulation or even apoptosis in this region; one of the mechanisms by which methamphetamine induces schizophrenia).

But this isn’t the only time THC and 5ht2a tango. The CB1-5ht2a induced Gi protein signalling also triggers a signalling pathway called Akt/mTOR via the subunit βγ. This causes remaining standalone 5ht2a receptors to potentiate their own signalling of Gi proteins, but instead activating the inhibitory subunits on these Gi proteins. This causes a potentiation of the pro-hallucinogenic subunits on their usual Gq proteins, which can lead to further symptoms of psychosis.

It’s worth mentioning that by ‘symptoms of psychosis,’ I don’t necessarily mean overt delusions and hallucinations, but things like paranoia, intrusive thoughts, avolition (loss of ability to do daily tasks), and disorganized thinking as well. Individuals with cannabis-induced psychotic disorders often present with irregular symptomology, so things like delusions and hallucinations are less frequently present.

Causing this rift between different 5ht2a receptors, such a fundamental receptor for neuroplasticity, can also cause fairly scattered and erratic patterns of neuroplasticity across your brain, meaning memories and lessons learned won’t last as long as they should. This can be a fantastic thing until you have to navigate daily life, re-learning the same things again and again.

Additionally, THC causes heteromerizations between D1 and D2 dopamine receptors. This inhibits both of their activities and changes the channel to Gq. When a D1-D2 mediated Gq protein goes off to do its business in NAc neurons, it causes a downstream release of dynorphin, an endorphin that’s selective for κ-opioid receptors. This isn’t as fun as it sounds; when κ-opioid receptors are stimulated without accompaniment by μ-opioid stimulation in the NAc, they cause aversion, dysphoria, dread, and derealization causing a downstream uptick of activity in the amygdala.

The amygdala gets together with the NAc and stimulates the LHb, which in turn deactivates the mesolimbic pathway and potentiates amygdala transmission. This system of receptors is thought to be heavily involved in panic disorder, PTSD, anhedonia, and dissociative disorders. The most similar drug you might’ve heard of is Salvia divinorum, known for its traumatic, reality-breaking experiences. D1-D2 heteromers are seen at highly elevated levels in schizophrenic subjects.

Furthermore, consuming THC alongside tobacco has been shown to potentially increase the activity of FAAH in your cerebral cortex. If you recall, your two major endocannabinoids are metabolized by this enzyme, and raising its activity leads to a faster metabolism of these endogenous pleasure molecules, leading to further dependence on THC.

All of that is where CBD comes in. CBD is a negative allosteric modulator (NAM) of CB1 receptors. It has a balancing effect on individual receptors, preventing overstimulation. It has been shown to prevent downregulation of CB1 receptors, and reverse the neurocognitive deficits induced by D1-D2 heteromers. It’s also a NAM of 5ht2a receptors, which reduces the pro-psychotic effects mediated by these receptors, and eventually should (hypothetically) reverse CB1-5ht2a heterodimers. It has also been shown to prevent D1 dopamine receptor internalization. On top of all this, it’s an inhibitor of the FAAH enzyme, which allows endocannabinoids to populate your cortex at long last. This all shows up on the psychological side too; CBD significantly reduces cognitive impairment and psychogenic effects of THC in multiple studies. THC has shown its peak therapeutic potential in clinical trials at a ratio of about 1:1 with CBD.

But CBD isn’t entirely without side effects either, unfortunately. Chronic CBD use has been shown to potentially have a sensitizing effect involving norepinephrine. Sensitizing norepinephrine increases symptoms of anxiety, potentially even leading to eventual cardiotoxicity.

But that’s where CBG comes in. CBG doesn’t significantly act on cannabinoid receptors at all, as a matter of fact; it’s only called a cannabinoid due to its origins in the Cannabis plant and structural similarity to other cannabinoids. CBG acts as an agonist of α-2a adrenergic autoreceptors. These receptors occur on the presynaptic terminal, acting as a braking function on natural norepinephrine release. This isn’t a pharmacologically perfect fix, as it doesn’t fix the sensitization to norepinephrine, but it does dampen the level of norepinephrine transmission that occurs.

Where do Genes Factor In?

You’ve likely heard that only those genetically predisposed to mental illness end up developing psychological disorders from cannabis use. This is 100% true, but it’s a loaded statement: a substantial chunk of people are predisposed in some way to a psychotic disorder, even without any family history. Let’s take one gene, HTR2A. This gene encodes the 5ht2a receptor, whose altered activity by THC is thought to be largely responsible for Cannabis-induced psychotic disorders.

Hypermethylation of the HTR2A gene is widely seen in schizophrenia patients. THC programs 5ht2a to genetically potentiate itself through the Akt/mTOR pathway, which results in HTR2A methylation. Over 40% of a randomly selected population tested positive for a high-activity HTR2A gene variant called rs6311. This variant is associated with increased risk of schizophrenia, bipolar, OCD, and autism. That’s over 40% of the population that could have increased susceptibility to THC-induced psychological disorders.

And that’s 1 of over 200 gene variants & mutations associated with psychotic disorders.

It’s entirely true that different people carry different levels of susceptibility to these disorders that can be induced. But there’s a very good chance that the majority of people are susceptible to some degree, regardless of family history, even without showing any symptoms previously.

What Now?

This article covers only a sliver of what we know about cannabinoid pharmacology, and there is even more we don’t know about THC. But what we do know is that it carries both creative and destructive potential, learning how to minimize its destructive potential is a necessity when it’s being introduced to society en masse.

The great thing about pure cannabinoids is, if you’re in the US, they’re extremely cheap. I personally get a 50 gram jar of pure CBD online for about forty dollars, and it lasts me about 2 years at 150-200mg/day.

If you’re smoking cannabis flower daily, incorporate at least 100mg of CBD daily into your Weed Diet. If you start to develop some symptoms of anxiety and restlessness after a while, look into CBG. Unless you’re treating chronic illness like migraine or autoinflammatory disorders, you shouldn’t need any cannabinoids beyond the Big Three.

If you’re using extracts like dabs/carts/dispos, look into switching to flower. Seriously. Gets you higher in a far more neurologically sustainable way. If you refuse to lose the juice, get on seriously high levels of CBD; I’m talking 200mg+ a day. That shit rots your brain, and that’s an informed opinion, trust. I never even mentioned the fact that most illicit carts & dispos contain THCp, which has all the side effects of THC at about 5x the potency, and 0% CBD, which means all those precious receptors of yours are getting overstimulated as hell.

Best of luck on your cognitive odyssey, and have a beautiful night!

By Somnesque, click for original post and comments.

Sources

THC induces d1-d2 heteromerization https://pmc.ncbi.nlm.nih.gov/articles/PMC6971351/

D1-D2 heteromer releases dynorphin in the NAc https://pmc.ncbi.nlm.nih.gov/articles/PMC2978591/

Cannabis use causes elevated expression of CB1-5ht2a heteromers https://pubmed.ncbi.nlm.nih.gov/29294249/

Cannabis tobacco co-use elevates FAAH activity https://pmc.ncbi.nlm.nih.gov/articles/PMC12341708/

CBD reduces D1-D2 heteromer neuroadaptations https://pubmed.ncbi.nlm.nih.gov/31972514/

CBD prevents CB1 downregulation https://www.nature.com/articles/s41386-025-02213-0

CBD inhibits FAAH https://pmc.ncbi.nlm.nih.gov/articles/PMC119890

CBD reduces THC-induced cognitive impairment https://pmc.ncbi.nlm.nih.gov/articles/PMC6820200/

Around 40% of people have rs6311 gene variant https://pmc.ncbi.nlm.nih.gov/articles/PMC4134733/