Inside the Endocannabinoid System: UC-Irvine Professor Speaks on “The Brain’s Own Cannabis”

Learn more on how anandamide interacts with the body's endocannabinoid system.


In a conversation on cannabis, Cannabis Pharmacy author Michael Backes mentioned that in archery, one should not focus on the arrow, but the target. Similarly, for most cannabinoid researchers, the plant has its uses, but what matters most is the system within the human body that it triggers, known as the endocannabinoid system.

This was, by and large, the focus of the UCLA Cannabis Research Initiative’s “The Brain’s Own Cannabis,” where Dr. Daniele Piomelli of UC-Irvine spoke with Dr. Christopher Evans about the endocannabinoid system. Portions of the hour-long conversation touched on the as-yet-undetermined connection between the endocannabinoid system and the body’s opioid receptors — the prime focus of Dr. Evans’s research. However, most of the discussion focused on anandamide, a fatty acid neurotransmitter created by the body’s cells which alongside the molecule 2-AG serves as one of the two prime activators of the endocannabinoid system.

Named after the Sanskrit term Ananda, or “bliss,” anandamide is often referred to as “the bliss molecule” for its association with calm and pleasurable moods (for instance, it’s rumored to be responsible for the “runner’s high” experienced by long-distance athletes). The THC molecule in cannabis closely resembles anandamide, which allows it to bind to the same cellular receptors and create the “high” we’re familiar with. Eventually, a molecule in the body called fatty acid amide hydrolase (FAAH) dissolves anandamide. Future pharmaceuticals which suppress the creation of FAAH, Piomelli asserts, could treat anxiety without the intoxicating effects that, believe it or not, some patients would rather do without.

As opioid expert Evans stated, cannabis was critical to our discovery of the endocannabinoid system just as poppy was to the opioid receptors — were it not for the plants that trigger them, we probably would never know they existed. In fact, Piomelli’s earliest work focused on a molecule called arachidonic acid, a precursor to anandamide, before anandamide was discovered “serendipitously” in 1992. Because of the anandamide discovery, Piomelli pivoted to exploring how this descendent of his original focus worked in this brand-new system.

Anandamide and its partner 2-AG behave differently than most other neurotransmitters. Within our minds, sense perception is conveyed as chemical exchanges through slender brain tissues called neurons – and there’s about 80 billion neurons in our brains. One neuron delivers a signal to another neuron, which is the initial transmission. However, the neuron that receives the initial transmission can “talk back” to the first neuron. Anandamide and 2-AG serve this talk-back function to modulate future messaging from the first neuron or stop certain flows of information altogether. (That’s not all they do in the brain – Piomelli suggested they can travel to other areas of the brain as well and perform other tasks, but this talk-back function, which is called “retrograde signaling,” is a primary function of the endocannabinoid system).

FAAH assists in ending endocannabinoid signaling by dismantling anandamide in the brain. Researchers like Piomelli have begun to question what FAAH inhibitors and the resulting surplus of anandamide could accomplish in the mind. Piomelli shared an intriguing anecdote regarding a Scottish woman who needed next to no pain medication after a grueling hand surgery. Upon further exploration, doctors also discovered she had never really felt severe pain in her entire life, and that her wounds healed quickly. In addition, she also possessed an easygoing, carefree personality. Examining her genome, the doctors tied this to a mutation in the genes that encoded for FAAH. Simply put, she had no FAAH, and more anandamide, than the average human.

While Piomelli did not want to overgeneralize from this case, it does suggest the possibility of significant pain reduction properties offered by FAAH inhibitors. Piomelli reminded his audience however, that messing with the endocannabinoid system is no joke. A 2016 FAAH inhibitor trial conducted by the French company Biotrial ended in disaster when one person died and two suffered permanent neurological damage. Piomelli condemned the study’s drug as “dirty” (i.e. a drug that has multiple uncontrollable and potentially toxic effects). In the meantime, researchers have continued to explore FAAH inhibitors and potential usage In anxiety, cannabis withdrawal and osteoarthritis.

Aside from the promise of FAAH inhibitors, both Piomelli and Evans have long been intrigued by the certain, but little-understood, connection between endocannabinoid and opioid receptors. Important work is being done on cannabis’s potential to curb problematic opioid usage by enhancing its analgesic effects, associated with both its cannabinoids and terpenes. For those concerned about the 30% uptick in opioid-related deaths last year, gaining greater insight into this connection could prove vital. Evans’s own exploration of opioid overdoses in Colorado found a reduction after adult-use legalization of cannabis, however, there did not seem to be an equivalent reduction for fentanyl overdoses. So more research is needed to find out how these systems interact.

In closing, Piomelli gave the usual instructions regarding cannabis use — wait until you’re at least 21, avoid it if you’re pregnant or if you have a family history of schizophrenia. But certainly, choose it over tobacco. He mentioned his own cigarette-smoking daughter in this regard. “I said to her, ‘Why don’t you just smoke pot?,’” he related as the webcast drew to a close.

Sidebar: Some may wonder why synthetic anandamide hasn’t popped up in the market. Apparently, anandamide is pretty volatile — it degrades quickly when digested, so the only way to circumvent that is to inject it directly into the brain. So probably not a good idea.