This week, we’re taking a break from our study of the emergence of multicellular complexity to look into something else that caught my attention - how do we make sense of the world?

I’ve been thinking a lot about the situation that we’re in, culturally speaking, and realized that we live in paranoid, anxious times. It is as if, all at once, we have decided that the old ways of interpreting our world will not stand.

In many ways, I’m happy to see the old world go. It is full of dinosaurs that prevent positive change, stifling systemic regulation, widespread brutality and oppression. But I also recognize that the problems we’re confronting today are the some ones that that humans have been facing since the dawn of civilization.

There is a paranoid note, widespread on the internet, that gives me pause, though. It is as if something has reached into our minds and planted the thought that the system has been built specifically to harm us - the hallmark thought patterns of paranoia.

As I was thinking about this, I came across some research about the endocannabinoid system that made me realize it is threaded through the very heart of our perception organs - the eyes, nose, pain perception, and all levels of the central and peripheral nervous system. It’s even in the immune system!

So I started thinking about what the effects would be of widespread manipulation of this system. It got me down the trail of marijuana use, the balance between the plant as medicine vs. the plant as a drug, and has resulted in this article. It’s an exploration of what we know about our own neurochemistry, how THC and CBD affects us, and the ways that the endocannabinoid system produces the story we tell ourselves about the world.

A few things right off the bat:

1. There is no consensus understanding of what the endocannabinoid system does, what constitutes a cannabinoid receptor, or how they affect the body.

2. The best-characterized endocannabinoid interactions are between THC, the main psychoactive component of cannabis and two relatively well-characterized receptors, CB1 and CB2.

3. The receptors in question localize to the nervous system. Specifically, pre-synaptic neurons (CB1) and the immune system (CB2).

4. THC and CBD appear to have a balancing effect. The former causes anxiety, the latter is anxiolytic

5. Over the last few decades of legalization, two trends have emerged. Lifetime use of marijuana is increasing, at the same time that total THC content, as well as THC/CBD ratios, are increasing. 

In the article below I will do my best to provide supporting evidence for all these points and will end on a discussion of how the endocannabinoid system appears to be a pattern-finding/sensemaking organ. The increased prevalence of high THC sinsemilla (feminized flower), as well as resin-based distillates of these strains, may be partially responsible for the epidemic of anxiety and loneliness that many countries are experiencing. Finally, some solutions are proposed.

To start, a little history

It’s worth noting that marijuana consumption is nothing new. The plant has been part of human society as far back as we’re capable of looking. 8,000 years ago, when mastodons wandered the North American expanse, some humans were already cultivating cannabis. It makes sense! The strong fibers of the central stalk are excellent for making rope, cloth, and paper. The seeds can be pressed to produce oil, and the flowers can be used for religious, visionary purposes. 

The mechanism by which recreational/spiritual use became widespread is unclear, lost to the mists of history, but there are some clues. In the Hindu Rigveda religious text, written ~1500BC, there is mention of a ritualistic beverage, soma, that gives the drinker immortality. Swami Dayanand Saraswati interprets the text to say:

Good fruit containing food not any intoxicating drink, we drink you (soma)

You are elixir of life, achieve physical strength or light of god,

achieve control over senses;

In this situation, what our enemy can do to me?

God, what even violent people can do to me?

Academics still argue about what the substance in question was - since there’s no physical description of it and a relatively small body of evidence, scholars have suggested everything from amanita muscaria, the fly agaric, to hallucinogenic mushrooms, to cannabis - so it’s difficult to say anything more precise than the fact that ritual intoxication roots in the deep past and that specific use of cannabis may have evolved from an older tendency. 

Our ancestors likely had a more direct relationship to the qualities of plants - both cultivated and wild - and likely were interested in testing the resinous, pungent flowers. It’s the same sort of thinking that has led to the cultivation of everything from tomatoes to peas, so it isn’t surprising in the context of visionary experiences. 

In the centuries that followed, there’s widespread evidence for cannabis consumption throughout the middle east, the Ural region, and even ancient Greece. The earliest such indications come from the 8th century BC, in the form of cannabis residues found on altars that date to the Kingdom of Judeah. Shortly thereafter, the ancient Greek historians noted that the Scythians, inhabitants of the vast swath of land that stretches from modern-day Turkey to the Northern border of India and the Western border of China, would throw the flowers on the coals of public baths, rejoicing in the vapors. 

The trajectory of its spread continued for another thousand years into the common era. Clear evidence of cannabis consumption resurfaces in Iraq in the 1200s and then continues its march across the world. First across Africa, and then into the new world with the Spaniards, who brought the plant along with them to kick-start industrial hemp production in the new world.

The point of all this history isn’t to give a complete overview of the subject - there’s way too much information available to be able to catalog all of it here, and this article on the history of cannabis is a good jumping-off point for anyone interested in reading more.

 The point is simply to point out that this plant has been evolving alongside us for millennia. Industrial uses of hemp are straightforward - but the medicinal and ritualistic aspects are a little more difficult to tease apart. What happens in the body when cannabis is consumed, and why the effect been treasured for thousands of years?

The Endocannabinoid System

I said above that there is no consensus understanding of what the endocannabinoid system does, what constitutes a cannabinoid receptor, or how they affect the body. It is perhaps a little harsh but is largely accurate. Most of the research that has been done over the last few years has discovered that the system sprawls throughout the body, touching almost all functions that you can think of - through mechanisms that no one has managed to describe yet.

 What has been established, despite the ambiguous data on the subject, is that there are at least two receptors, CB1 and CB2, that have an important role in processing both endogenous and exogenous cannabinoids, and that those receptors are distributed throughout all levels of the central nervous system. They’re found in the cerebral cortex, responsible for higher-order processing, the retina, the olfactory centers, as well as the cerebellum, spinal cord, and basal ganglia. 

 The CB2 receptor is far more present in the immune system than the central nervous system and has been found in cells that mediate cytokine release (read: inflammation), as well as throughout the gastrointestinal system. It is currently thought that CB2 mediates the immune response to resident microbes in the gut, and is also related to pain processing - though the mechanistic connection is unclear.

 The major takeaway that one can take from a field that is still so early in it’s cataloging of these receptor/ligand interactions is that they are myriad and suffuse many of the major perception systems - from eyesight to pain. The situation is complicated because the two endogenous cannabinoids are known to occur naturally in the human — anandamide, and 2-arachidonoylglycerol — are still poorly characterized, and the extent of their activity is still unknown. 

Anandamide, also known as the “bliss molecule” has a relatively short half-life, and is produced during exercise. It’s thought to contribute to the euphoric side-effects of running but is quickly degraded in the aftermath of exercise. 2-Arachidonoylglycerol, on the other hand, is a longer-lasting molecule that researchers think might affect memory formation. 

The two compounds acting together recapitulate the effects of the primary psychoactive substance in cannabis - THC. The only reason we know anything about them is because of THC. Once it was understood that the psychoactive effects of cannabis were due to a receptor-ligand interaction, scientists combed through the brain and body to find anything that would trigger the receptors. They found anandamide first, but discovered that it wasn’t as powerful as THC - and continued searching until they found 2AG.

 In the decades since (the endocannabinoids were first described in the 90s) there’s been very little progress on understanding how the whole system fits together - which is at least in part because drug regulations have made studying marijuana very difficult - and because cannabis contains 113 different cannabinoids that come together to produce the full effect of the plant.

 What is apparent, though, is that humans have been breeding marijuana for millennia, passaging it between cultures, to produce a plant that has high concentrations of two cannabinoids: THC and CBD. These two compounds, administered together, seem to have a balancing effect. THC produces psychoactive visions, while CBD has predominantly anxiolytic effects.

 In a small study run in the 1980s, a team of researchers tested the push-pull effect of CBD and THC. They took 8 volunteers who had not consumed any cannabis within the last week and tested them under five different conditions. Each test was a week apart and differed only in the chemical compounds administered. The five conditions were placebo, diazepam (anti-anxiety med), CBD alone, THC alone, and CBD + THC. What the researchers found was that the administration of THC alone resulted in a series of unpleasant side effects. Subjects reported difficulty concentrating, intolerance to noise, paranoia, resistance to communication, anxiety, and depersonalization, the feeling that you’re observing yourself from a distance. 

 Administration of CBD alone appeared to have no psychotropic effects - but the most interesting phenomenon was that administration of CBD + THC reversed almost all of the negative effects experienced from the consumption of cannabis.

THC vs CBD

Consumption of sensimilla, marijuana flower, has been done for centuries. Before the last century of morality laws that have criminalized the substance, there is no reason to think there were strong contraindications to its use. 

Even in the modern-day, the substance has been used by artists, musicians, writers, even space industrialists, to break down the walls that hem thoughts into place, and have likely led to the production of some fine works of art and engineering. Not everyone is up for a vision quest, though, and not everyone has the faculties available for riding the dragon, so to speak.

The way that many have dealt with this is by demonizing marijuana as a gateway drug, the first step in a journey that ends with your brains splattered on the walls of a crack house and your mom crying quietly over your pauper’s grave. This treatment was a side-effect of prohibitionist moral panic that was deeply misplaced. In places like Portugal, where drug use is considered a health disorder rather than a crime, only about 10% of the population has reported using cannabis in the last year.

This is in direct contrast with the US and Canada, where surveys suggest closer to 25-30% of the population has used cannabis in the last month, while nearly 60% percent have done so in the last year.

In and of itself, this isn’t a problem. It’s a plant, it’s natural, etc, etc. The problem comes down to what kind of cannabis we’re consuming, and the potential effects that it might be having on mental health.

Studies, like the one cited above, have demonstrated that THC and CBD affect the psyche in opposite direction. THC induces anxiety, dysphoria, feelings of intoxication, and paranoia. On the other hand, CBD has been demonstrated to reduce depression, act as an antipsychotic, to treat certain kinds of seizures, the list goes on. In fact, the presence of CBD in marijuana appears to provide overt medical benefits and balances the negative effects of THC. 

The plant, as it was bred for millennia, provided medical, artistic, religious, and spiritual benefits. But then came legalization, plant breeding, and the pharmaceuticalization of cannabis.

The New Age

By all accounts, the relative content of THC:CBD has skyrocketed in feminized flower - sensimilla - since the legalization of marijuana. While decriminalization has, overall, been an enormous boon to the wrongfully imprisoned, has stopped wasteful spending on a never-ending war on drugs, and has prevented government mandates over personal neurochemistry, the changing chemistry of marijuana may be a dark side. 

Gradually, the market has been taken over by distillates, resins, concentrates, and highly bred flower that is optimized for a single quantity: the amount of THC. So much so that since 1995, the average ratio of THC:CBD has risen nearly 10x.  

This increase in pure THC concentration comes at the same time that we’ve seen massive increases in marijuana use in people between the ages of 25-64, which means that a much larger number of people are consuming cannabis than ever before, and they’re consuming it in a form that is known to produce loneliness, anxiety, and paranoid feelings.

This data from Canada shows that use is going up in everyone above the age of 25, and similar surveys of the population in the US indicate that something like 1/3 of people above the age of 25 has used marijuana in the last month. 

Given the importance of the endocannabinoid system(ECS) in mood control, and the well-described ability of THC to significantly destabilize one's mood, perhaps it should come as no surprise that our current epidemic of loneliness and anxiety is heavily correlated with the availability of purified marijuana products that optimize for THC intake at the expense of all 112 other cannabinoids.

Moreover, the fact that the ECS is so deeply connected to the perception organs of the body - the brain, the eyes, and the nose, then perhaps it is worth considering that the influx of pharmaceutical-grade THC into the population is not providing medicine, but is producing a serious mental health crisis that is pushed forward by the pot of gold at the end of the dispensary rainbow.

The way psychotropic effects of manipulating the endocannabinoid system also offer another tantalizing thought - what if the ECS is the “sense-making” organ, whose role is to take in information from the environment and transmute it into a narrative that can be integrated and responded to. If that is the case, the effects of THC on neurochemistry suddenly fall into place - it warps the lens of reality, and produces a sense of agonized paranoia that suffuses the user's existence.

It’s for this reason, the way that it gently pulls on the surface of perception, that it is prized so highly for religious and artistic purposes. And also why users of THC heavy raffinates experience such overwhelming negative effects that may persist for a long time after the last use.

Regulation is not the answer

Even with all of this information, I don’t think that regulation is the answer. The idea that the government can have a say in one’s neurochemistry is an unpleasant breach of privacy, even consent, that I would never agree to. But there is a great difficulty in accessing high-quality, CBD rich sensimilla in the recreational economy. Those strains are almost universally relegated to medical use - which makes sense, given the pharmacological effects of THC vs CBD. This is the result of a market-driven by a consumer desire to be taken over by a substance, to give into it, rather than to work with it.

Certainly, the data on alcohol and cigarettes, the two substances with more of a market share than marijuana, is much more ominous, and prohibition of those is similarly unwise. But I would encourage users to look deeper into the substances that they are consuming and to consider how THC hijacks the sense-making organ to alter perceptions of reality.

If the outcome is less than beautiful, perhaps it's worth reconsidering? Next time the choice is in front of you, try the more balanced strain.