Your Brain is on Weed (even if you have never smoked before)

Imagine being a brain scientist, or a pothead (or both) in the 1990’s, and waking up to this headline¹:

That is exactly what happened in December 1992, when the field reported two ground-breaking discoveries in a single issue of Science² (the NY Times of modern scientific research). Scientists had finally identified a specific receptor–the delta opioid receptor– to which morphine and the brain’s self-produced opioids (like endorphins), bind. The discovery brought a whole new era of our understanding of the opioid system, eventually influencing everything from pain medicine, to gut health, to motivation-reward studies.

A mere 6 pages separated the announcement of another major breakthrough, the discovery of the body’s own cannabis-like molecule, an endocannabinoid. The Israeli scientists, led by Raphael Mechoulam, decided to name it “anandamide”, for the Sanskrit ananda, meaning “bliss” or “joy”, alluding to cannabis’ known psychoactive effects (or more simply, the “high”)³.

I wouldn’t know exactly what went on in Dr Mechoulam’s mind when he decided on this (in my opinion) ingenious and poetic name, but science is quickly understanding how anandamide, and other endocannabinoids, are some of the most important molecules in the human nervous system. No wonder cannabis sativa, the plant that produces cannabis, is so closely linked with Lord Shiva, the Destroyer and the Creator of the Universe⁴. To me, endocannabinoids truly exemplify this beautiful paradox of creation from destruction, balance from disruption, and transcendence from withdrawal. But before I get too ahead of myself, perhaps I should talk a little more about endogenous and exogenous cannabinoids, why they are different, and why they matter to your brain, your body and possibly your bliss.

Who thought about brain’s own weed?

There was a time when scientists paid little attention to studying cannabinoids. Mechoulam’s lab had isolated and determined the structure of ∆⁹-THC, the most potent psychoactive compound in cannabis. For one thing, he had to ask the police for 5kgs of confiscated cannabis to even start experiments¹. But more importantly, they found that THC was lipid (aka fat). This led scientists to think that perhaps these molecules did not require specific receptors to function. Maybe they could just solubilize into the cell membrane (the outer covering of cells that is also made of lipids), and have non-specific effects.

But that thinking completely changed in the mid-80’s, when another group of scientists, led by Allyn Howlett, found the first ever cannabinoid receptor– the CB1 receptor. Later, a second CB2 receptor was also found, and it was now obvious to scientists that these receptors must have some internal (“endogenous”) binders too. After all, it did not make sense for your brain to develop a whole bunch of receptors just so a random teenager would decide to smoke pot someday, right?

So scientists started looking for the body’s own cannabis-like molecules. A few years later, cue in the iconic Science issue that finally declared existence of “brain’s own weed” (although I am pretty sure nobody calls it that).

So why does the brain produce its own stash⁵?

Turns out, the endocannabinoids (ECs) are some of the most curious chemicals produced by the brain, and that is exactly why I decided to write about them. To begin with, there are two major molecules in this class– we already met the exotically named “anandamide”. But the real workhorse, silently doing most of the heavy-lifting without the fancy titles and media coverage, is 2-Acyl-glycerol, or 2-AG for short.

ECs are by far the most abundant signaling molecules in your brain, and the CB receptors are virtually found in every single neuron! Imagine this– we have stoners to thank for uncovering one of the most crucial information systems of our brains (:|).

ECs also function unlike most other neurotransmitters (or chemical messengers of the brain). Instead of the usual being released from one neuron, binding to and activating the second neuron (feed-forward signaling), ECs work backwards. They are released by the second neuron, and they travel back to the first one to inhibit its activity– kind of like shutting down their own production (retrograde signaling). What’s more, they are not fancifully packed and stored in vesicles (like other neurotransmitters), but rather are produced from the lipids in the cell membrane as and when they’re needed.

Such an arrangement might seem puzzling at first; why does the brain have such an elaborate system to essentially inhibit its own activity? But, it might help to understand that this negative feedback does far more than just suppress activity. It helps in synchronizing firing of different neurons, makes the system more precise and can help enhance contrast between signal and noise. Indeed, the brain functions on a delicate “excitation-inhibition balance”, and its breakdown can lead to scary things, like seizures and maybe even schizophrenia. No wonder the EC system is one of the oldest systems of the body, having evolved even before vertebrates, and having stayed pretty much the same across species!

Cannabis and endocannabinoids: are they the same?

Easy answer–NO. For starters, they are structurally very different, but they somehow still bind to the same receptors.

More importantly, they have very different patterns of activity. On the one hand, ECs are mellow; they are released only when and where they are needed, bind weakly and briefly with CB1 receptors, act quickly and discretely, and then disappear from the scene (immediately broken down by an enzyme, FAAH). In this way, they control almost everything the brain does– from learning and memory to mood, appetite and pain perception. They are also essential during brain development in the womb, removing unnecessary brain connections (synaptic pruning) so that new ones can form⁶.

Serious class act.

THC on the other hand is loud and stubborn. Once administered, it floods the entire brain at once, binding strongly and persistently with CB1 receptors diffusely across many brain areas. It is not degraded by FAAH, and so stays bound for much longer, altering brain signaling in unusual ways. The result is the characteristic cannabis “high”, along with possible effects like impaired memory, altered perception and in some cases, anxiety and paranoia.

In ChatGPT’s eloquent words: “THC is like a blunt instrument in a system that normally runs on precise chemical whispers like anandamide.” (One of those rare moments I genuinely like AI’s input, so credits due.)

I would be remiss not to mention CBD here, the other major cannabinoid found in cannabis plants. It is quite different from THC, in that it is a very weak binder of its receptors, and has little to no intoxicating effects. Given its relatively safe profile, CBD is being studied for its potential use as an anti-seizure and anti-anxiety drug, although more research is needed to separate its reputation from the shadow of its notorious cousin, THC.

Sooooo… to smoke or not to smoke?

I know you’re all thinking it, but as with most things science, I do not have a straight answer for you. Pot lobbyists would argue about the potential benefits of exogenous cannabinoids in reducing pain and nausea, especially from chemotherapy. It definitely can stimulate appetite, and particularly CBD can help with seizures and inflammation⁷.

Pot might also help reduce anxiety, and allow for processing deep-seated emotions, although sometimes it might actually backfire and cause people to go into dangerous emotional spirals.

So, here are my two cents:

1. Trust your body’s own mechanisms: Through years of numbing out my body’s signals, I finally understand that it truly knows best. The endocannabinoid system has evolved the way it has for a reason, so instead of hijacking it from the outside, we might actually want to focus on helping it out by taking care of it. Perhaps the two most important ways to do that are: exercise and meditation.

Heard of the “runner’s high”? That’s not really endorphins, but in fact, ECs that primarily surge during a run and make you feel blissful.

2. Be honest about your intent (no point trying to fool yourself): why do you really want to smoke up? Oftentimes, its just peer pressure. Sometimes, the urge stems from deep-seated emotional stressors that youis are unable to deal with consciously. A joint might feel like an escape from a reality you feel stuck in. That is precisely when you SHOULD NOT smoke. Please, please, ask for help. You will be heard.

3. Chronic use is a no-go: Studies abound of how long-term regular use of cannabis can actually have lasting effects, making a person more anxious and jittery, and even affecting memory. In essence, the body’s own endocannabinoid system loses its modulation when it is constantly disturbed by outside chemicals, making it confused and unable to do its job. Would you really want to do this to yourself?

4. Supervised settings might be fine: With advancements in psychotherapy, especially with conversations around psychedelics, we might come to a day where better-informed decisions about using cannabinoids might actually become a reality. Till then, maybe we just have to be vary of falling for misinformed marketing and propaganda. It is easy to sell marijuana as a magical super-drug, because that is what people want to hear. But what you want to hear is not always (or in fact usually) what you need to hear.

The greatest harm, in my opinion, is when something is normalized without complete understanding of its consequences. We’ve seen this with alcohol, nicotine, and even simple things desk-job lifestyle or bottle-feeding infants. I might be inclined to comment on how cannabis actually seems much more benign than many other substances of abuse. But that does not belittle the havoc it wreaks on the endocannabinoid system; a system, mind you, that holds the key to experiencing true balance, peace and even bliss.

But “bliss” for me is not something you can smoke or swallow; bliss comes from within.

References:

1. Barinaga M. Pot, Heroin Unlock New Areas for Neuroscience. Science. 1992;258(5090):1882-1884. doi:10.1126/science.1335165

2. Devane WA, Hanuš L, Breuer A, et al. Isolation and Structure of a Brain Constituent That Binds to the Cannabinoid Receptor. Science. 1992;258(5090):1946-1949. doi:10.1126/science.1470919

3. Raphael Mechoulam and the history of cannabis research // International League Against Epilepsy. Accessed January 18, 2025. https://www.ilae.org/journals/epigraph/epigraph-vol-21-issue-1-winter-2019/raphael-mechoulam-and-the-history-of-cannabis-research

4. Sci-Hub | Shiva, Lord of Bhang. Substance Use & Misuse, 47(10), 1067–1072 | 10.3109/10826084.2012.684308. Accessed January 5, 2025. https://sci-hub.se/https://pubmed.ncbi.nlm.nih.gov/22742944/

5. Scherma M, Masia P, Satta V, Fratta W, Fadda P, Tanda G. Brain activity of anandamide: a rewarding bliss? Acta Pharmacol Sin. 2019;40(3):309-323. doi:10.1038/s41401-018-0075-x

6. Rodrigues RJ, Marques JM, Köfalvi A. Cannabis, Endocannabinoids and Brain Development: From Embryogenesis to Adolescence. Cells. 2024;13(22):1875. doi:10.3390/cells13221875

7. Crocq MA. History of cannabis and the endocannabinoid system. Dialogues Clin Neurosci. 2020;22(3):223-228. doi:10.31887/DCNS.2020.22.3/mcrocq