How Does THC Get You High?
THC stimulates the brain's reward system to initiate that euphoric feeling we describe as a high

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THC stimulates the brain's reward system to initiate that euphoric feeling we describe as a high, which includes regions that control the response to healthy pleasurable activities like sex and eating.

It is believed that THC found in marijuana stimulates the brain's reward system to initiate that euphoric feeling we describe as a high, which includes regions that control the response to healthy pleasurable activities like sex and eating, by acting on cannabinoid receptors. THC, like most other abused drugs, triggers reward system neurons to release the signaling chemical dopamine at higher levels than are normally seen in response to natural stimuli. This influx of dopamine leads to the pleasurable "high" sought by recreational cannabis users.

THC activates the brain's reward system via cannabinoid receptors, although it's unlikely that it does so by "flooding the brain with dopamine." In comparison to early animal research that endorsed this position — a position that is still shared by a (shrinking) majority of addiction scientists — human studies have largely been unsupportive of this theory.

In reality, multiple human studies show that cannabis consumption produces only a small amount of dopamine, much less than the five to ten times amount commonly claimed. (Note that the media's depiction of dopamine as the brain's greatest "pleasure chemical" is often inaccurate.) Although there is strong evidence that stimulants like cocaine and amphetamines do indeed trigger a surge of dopamine, the same cannot be said about cannabis.

In 2015, King's College London researchers conducted a systematic analysis of every published study — 25 in all — and discovered that there is "no direct evidence to indicate that cannabis use affects acute striatal dopamine release or chronic dopamine receptor status in healthy human volunteers."

What, if not dopamine, is responsible for cannabis's effect on the pleasure circuitry of the brain?

Dr. Raphael Mechoulam, the man who first recognized (and synthesized) THC, discovered a neurotransmitter named anandamide in the early 1990s. Anandamide has been dubbed the "bliss molecule" because it appears to increase feelings of joy and satisfaction.

"Anandamide is a lipid mediator that acts as an endogenous ligand of CB1 receptors. These receptors are also the primary molecular target responsible for the pharmacological effects of Δ9-tetrahydrocannabinol, the psychoactive ingredient in Cannabis sativa." - APS, Brain activity of anandamide: a rewarding bliss 

Anandamide, it turns out, is responsible for a lot more than happiness. Anandamide is involved in memory, motivation, movement, pain, appetite, and fertility, as well as possibly inhibiting cancer cell proliferation. Anandamide is an anti-anxiety and antidepressant drug because of its role in neurogenesis, or the development of new nerve cells. Unfortunately, anandamide, like other neurotransmitters, breaks down easily in the body, so it doesn't produce a constant state of bliss.

Since anandamide is an endocannabinoid (meaning "inside" in the sense of "within the body"), it has a phytocannabinoid twin (phyto" meaning "of the plant"). Anandamide is produced naturally in the body, while THC is contained in cannabis. Both of these cannabinoids have a good affinity for binding to the CB1 and CB2 receptors of the endocannabinoid system. It is the attachment to CB1 is that is suspected to cause the euphoric effects desired by recreational users.

Since THC and anandamide have similar properties, cannabis consumption may have similar effects. THC enters your brain and goes to work on your brain's neurons within seconds of smoking or vaping cannabis. When a neurotransmitter attaches to — or fits in — the right receptor, it sends a signal to your body, just like a key in a door. It induces a feeling of "bliss" in this situation. Notably, anandamide production is affected by chocolate, yoga, and running, so you can get a similar — but weaker — high from these practices as well (think "runner's high").

Although marijuana appears to have a relaxing, friendly effect on the majority of users, it is estimated that one out of every five (20%) people has the opposite reaction. Anandamide is deactivated by a naturally occurring enzyme called FAAH (fatty acid amide hydrolase, a promising target for  analgesic, anti-inflammatory, anxiolytic, and antidepressant drug targets), and certain people are genetically predisposed to produce less FAAH. As a result, anandamide does not break down in the same way in these people, and they are naturally more comfortable. They have a paradox effect when they ingest cannabis, and they can actually become anxious or nervous. They're much less likely to enjoy (or consume) cannabis, as one would expect.

Furthermore, we know that people respond differently to low and high doses of THC. So, while a small amount of THC can make you feel fine, too much of it can make you feel bad, causing anxiety and discomfort.

Nonetheless, cannabis gives a sense of harmony and peace for most people, helping to calm the mind and body.

How Does THC Get You High?
JD 28 December, 2021
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