Would Mammals Exist Without Internal Cannabinoids?

Evolution of brain cannabinoid chemistry, hunger, and suckling.

Posted May 29, 2020

The brain’s THC-like endogenous cannabinoid system (ECS) outlined in the previous blog post—consisting of CB1 receptors, endocannabinoid neurotransmitters such as anandamide and 2-AG—is ancient. The ECS is found in almost all animals, invertebrates, and vertebrates, including worms, fish, amphibians, birds, and mammals. Only insects lack an internal cannabinoid system for reasons not yet discovered.

The ECS exists in the primitive hydra, the first organism to develop a neural network. It may be only an odd coincidence, but anandamide and CB1 receptors are involved in the hydra’s contraction of tentacles to gather in food, perhaps the original munchies.

The hydra has no central cluster of neurons to organize its behavior. Brains had not yet evolved. Nerve cells apparently needed to develop endocannabinoid chemistry before they could link together into networks, and eventually into an organized central nervous system. This fact demonstrates how important the negative feedback function of the ECS is for modulating neural activity and maintaining balance among multiple linked neurotransmitter systems.

Although the ECS was discovered relatively recently, this is not because it is small or unimportant. There are more CB1 receptors inside the human brain than receptors for any other neurotransmitter, and this is particularly true early in life, especially at birth. The discovery of the ECS was completely incidental to research efforts to understand why cannabis does what it does to humans. Without our trying to understand the interaction between bud and brain, we would not have had the tools to detect the existence of our natural internal cannabinoid chemistry.

Discovering the ECS helps us understand the pure sensory pleasure of eating and the drive to satisfy this desire, technically known as the munchies, which is experienced by nearly everyone who has consumed cannabis. CB1 receptors densely packed in a collection of neurons the size of an almond called the hypothalamus regulate hunger and satiety. Fasting releases anandamide in the hypothalamus, and anandamide increases appetite. The THC in cannabis is an even more powerful and longer-lasting appetite stimulant

The drug rimonabant blockades CB1 receptors. Rimonabant is an anandamide and THC antagonist. When given to morbidly obese people, rimonabant reduces appetite and causes weight loss. Unfortunately for the pharmaceutical company that briefly sold rimonabant in France, blocking CB1 receptors too often has the serious side effect of causing dangerous depressive reactions. Apparently a well-balanced ECS is necessary for good mental health.

On the other hand, medical marijuana gained early advocates among AIDS patients suffering from wasting syndrome. The THC in cannabis effectively stimulated appetite and counteracted the wasting. Terminally ill cancer patients with wasting syndrome have experienced the same benefit.

In utero, mammalian fetuses are continuously fed by the mother’s blood flowing through the placenta. Immediately at birth, this passively absorbed free lunch stops abruptly. All mammals need to begin suckling soon after birth. While it is easy to say that suckling is instinctual, or reflex behavior, these terms only hide our ignorance. What is the precise mechanism that stimulates suckling behavior?

A fascinating experiment with newborn rat pups throws an interesting light on infant suckling, and perhaps on the evolution of all mammalian species. An Israeli scientist, Ester Fride, wondered what role the ECS plays in early suckling behavior. She administered the cannabinoid antagonist rimonabant to rat pups in the first 24 hours of life to shut down their endocannabinoid system. The pups failed to suckle despite their mothers’ increased licking near their mouths, and they died. Fride concluded that a well-functioning ECS is necessary for infants to engage in early breastfeeding. The concept of a well-balanced ECS being necessary for good health keeps reappearing. 

While there may be other interpretations for the results of this experiment, and the causes of the pups’ failure to suckle are undoubtedly more complex, several facts remain. The pups died once the endocannabinoid system was blocked. The human ECS is most active at birth, and human breast milk contains the endocannabinoids anandamide and ten times as much 2-AG.

A few interesting questions and speculations occur to me when I draw my attention to the phenomenon of the munchies. Does cannabis stimulate appetite equally for all foods? Most people who have used cannabis describe an urge for comfort foods. There also seems to be an emotional component to the munchies. Is this related to the emotional comfort of being held, warm, connected, and bonded when snuggled to the breast?  Are there echoes of an oceanic comfort lost at birth, but not wholly forgotten and evoked upon return to an elevated cannabinoid state? Pure speculation. 

Hippies called marijuana the “love drug” back in the 1960s. Does the infant’s endocannabinoid system play a role in relaxing into a bond with parents? Maybe, but just another hypothesis needing someone clever enough to test.

As for the emergence of mammals from reptiles roughly 200 million years ago, we can be sure the immediate need for newborns to suckle benefited from an endocannabinoid system in the hypothalamus. 

My next blog post will explore the difficulty of maintaining a well-balanced ECS in the hypothalamus and throughout the brain when THC is consumed too frequently.