Eat, store, heal, let go
A theory of the whole system
▶ Play this chapter The script
Every line as it is spoken in the film, in order.
Here's what I think all of this adds up to. I want to propose a theory.
Start with how old this lock is. A sea squirt has a version of it, so it's more than 500 million years old. Early in the vertebrates, the gene doubled. CB1 went mostly to the nerves. CB2 went mostly to the immune cells.
In 1977, Ilya Prigogine won a Nobel Prize for explaining how a flow of energy keeps matter organized. A whirlpool. Spirals in a dish of chemicals. A cell. Stop the flow, and the pattern falls apart.
For an animal, the flow starts with food, and this system runs the hunger. It's in your first meal. It turns up the smell of food. In mice, switching on CB1 even turns the brain's 'I'm full' cells into 'keep eating' cells.
It also decides what to keep. CB1 tells fat cells to store. Mice born without it stay lean, even on a rich, fatty diet. For most of history, food was scarce, and storing it kept animals alive.
Now food is everywhere, and the same switch works against us humans. People with obesity carry more of these keys in their blood. And when the geniuses at a drug company made a pill that blocked the lock, people lost weight. But it also brought anxiety and depression, bad enough that the drug was pulled from shelves two years later.
Burning all that energy leaves damage, and damage brings inflammation. That's the second lock's job. CB2 turns the immune fire down when the work is done.
And the brain lets go of what no longer fits: the old platform, the old fear. Mice born without CB1 age early. In old mice, a tiny daily dose of THC brought their learning back to the level of young ones. In young mice, it made it worse.
Bob saw the same split in people. Backward-looking people hold on to the old shape. Forward-looking people keep the flow going.
So here's my theory. You're a whirlpool. Food comes in, energy flows through, and the pattern has to keep changing to stay itself. Your endocannabinoid system runs that flow. It makes you hungry, stores what you need, cools the fire, and lets go of what's old. Eat, store, heal, let go. The lock is ancient. My guess is that the more an animal has to learn and unlearn, the more it leans on this system, and that's part of what makes humans so unique. Of course, this is just my theory, not textbook science. But it ties everything together.
Sources
Every claim in this chapter with its grade: E established · M emerging (one or two studies, or animals only) · F framework.
- EElphick MR, Satou Y, Satoh N. The invertebrate ancestry of endocannabinoid signalling: an orthologue of vertebrate cannabinoid receptors in the urochordate Ciona intestinalis. Gene 2003;302:95–101. (one receptor in the sea squirt, from before the duplication that made CB1 and CB2; none in flies or worms) link
- EPrigogine I. Time, structure, and fluctuations. Science 1978;201:777–85. (his 1977 Nobel lecture: far from equilibrium, energy flow can create and keep order, the dissipative structures) link
- MFride E et al. Critical role of the endogenous cannabinoid system in mouse pup suckling and growth. Eur J Pharmacol 2001;419:207–14. link
- MSoria-Gómez E et al. The endocannabinoid system controls food intake via olfactory processes. Nat Neurosci 2014;17:407–15. (fasted mice) link
- MKoch M et al. Hypothalamic POMC neurons promote cannabinoid-induced feeding. Nature 2015;519:45–50. (mice: switching on CB1 made the fullness neurons release β-endorphin and drive eating) link
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- EVan Gaal LF et al. Effects of the cannabinoid-1 receptor blocker rimonabant on weight reduction and cardiovascular risk factors in overweight patients: 1-year experience from the RIO-Europe study. Lancet 2005;365:1389–97. (20 mg: 6.6 kg lost in a year, against 1.8 kg on placebo) link
- EChristensen R et al. Efficacy and safety of the weight-loss drug rimonabant: a meta-analysis of randomised trials. Lancet 2007;370:1706–13. (4 trials, 4,105 people: 4.7 kg more weight lost; 2.5 times as likely to stop for depressed mood, 3 times for anxiety) link
- MTurcotte C et al. The CB2 receptor and its role as a regulator of inflammation. Cell Mol Life Sci 2016;73:4449–70. (review: mice lacking CB2 repeatedly show worse inflammation) link
- MVarvel SA, Lichtman AH. Evaluation of CB1 receptor knockout mice in the Morris water maze. J Pharmacol Exp Ther 2002;301:915–24. link
- EMarsicano G et al. The endogenous cannabinoid system controls extinction of aversive memories. Nature 2002;418:530–4. link
- MBilkei-Gorzo A et al. Early age-related cognitive impairment in mice lacking cannabinoid CB1 receptors. Proc Natl Acad Sci USA 2005;102:15670–5. (without CB1, mice of 3–5 months learned like old mice and lost hippocampal neurons) link
- MBilkei-Gorzo A et al. A chronic low dose of Δ9-tetrahydrocannabinol (THC) restores cognitive function in old mice. Nat Med 2017;23:782–7. (3 mg/kg a day for 28 days: mice of 12 and 18 months learned like young ones; in young mice it worsened performance) link
- FRobert (Bob) Melamede, PhD. Backward-looking and forward-looking: a far-from-equilibrium reading of the endocannabinoid system. His framework, not scientific consensus.