Sometimes depression can hurt, literally. Interestingly, this has a lot to do with our Endocannabinoid Systems (ECS)—a network that consists of a few receptors and two neurotransmitters. Pain and emotions are tied together through these messengers. And, it is through the ECS that magic mushrooms and cannabis can often bind into a therapeutic (yet counterintuitive) mistake. (1)

This infographic details different serotonin receptors and their effects. The ECS and serotonin (5-HT) bind at many receptors, but the focal point of magic mushrooms is 5-HT2a. (2, 3) Other receptors might be the cause of side effects like nausea, though. Photo courtesy of Maroteaux et al 2016.

How does psilocybin alter the ECS?

Happiness can boost your endocannabinoid system, according to a few scientific studies throughout the past two decades. (1, 4-6) This is because a receptor that expresses with the happy-messenger, serotonin, can also help release natural cannabinoids in your body.

Also, a special form of serotonin acts as a nonintoxicating but still full agonist towards the cannabinoid 1 (CB1) receptor. (1) This means that a better mood can prevent cancer and other ailments – through our bodies’ own cannabinoids. And, there is a blissful feedback loop that occurs between serotonin and the ECS. After all, our endocannabinoids will boost serotonin and vice versa – the two systems crosstalk. (5)

Anandamide and serotonin go hand in hand in mental health therapeutics.

Top left: a serotonin molecule courtesy of PubChem. Top right: a serotonin receptor courtesy of Davies et al. 2006 . Bottom right: psilocybe cubensis courtesy of Alan Rockefeller, Wikipedia. Bottom left: A psilocin molecule, courtesy of Pubchem.

Serotonin and mushrooms a deeper synergy

The intoxicant in therapeutic mushrooms, psilocin, and its prodrug, psilocybin, is similar to serotonin. (1, 2) Therefore, psilocin will bind to a similar receptor as serotonin, namely 5-HT2a. In fact, this is one of the primary effects of magic mushrooms that has seen the attention of researchers.

5-HT2a is what binds magic mushrooms and cannabis into an intricate synergy given the receptor also helps release ECS messengers and their derivatives. In summary, serotonin will agonize an endocannabinoid that is crucial for everyday survival. But, psilocin flips this function and instead promotes non-associated and less important ECS derivatives that benefit therapy. (3, 7)

Psilocin counters serotonin at 5-HT2a receptors and creates its only signalling pathway, labelled in purple arrows. (5, 7, 8) The regular signalling path of serotonin (5-HT), labelled in red arrows, will be shut down upon consumption of magic mushrooms. Like anandamide (AEA), OEA and PEA are derived from N-acyl-PE after being metabolized by enzymes, PLD and PLA2. (5, 9, 10) The liner notes detail the unknown importance of IP (inositol phosphate).

Serotonin releases the enzyme, PLC, once it docks to the 5-HT2a receptor, which will in turn help release the workhorse endocannabinoid, 2-AG (red path). After psilocin (purple path) occupies the 5-HT2a’s space, the receptor releases PLA2 instead of PLC.

Psilocin’s purple path possibly purports profound but unexplored impacts on ECS signalling. Magic mushrooms will drop the regular function of 2-AG in the feedback and instead focuses serotonin signalling on PEA as well as OEA, a major constituent in chocolate. Mushrooms chocolates, anyone?

Magic Mushrooms and the ECS—tied by a happy endorphin

Doubling back on the feedback loop and the fact that endocannabinoids boost serotonin—the ECS’s role isn’t exactly straightforward. (1, 4) Endocannabinoid activity can decrease the functionality of the serotonin receptors while still elevating their signalling activity. So, the endocannabinoid system regulates the effects of psilocybin. But, magic mushrooms will alter the endocannabinoid system, forming a synergistic connection. (4-7)

The endocannabinoid system acts as a safety net during a mushroom trip. But, not everyone will experience positive benefits from adding cannabis to psilocybin given a complete shift in the functionality and cross-talk between the ECS and serotonin system.

ECS receptors that respond to cannabis will cross-talk with receptors that respond to magic mushrooms

The 5-HT2a receptor that psilocin binds to is biphasic, meaning it has two different effects. LSD and 5-MEO-DMT, for example, will activate the left side and coexpress with dopamine. Psilocin does not express with dopamine and instead takes the right path, coexpressing with the CB1 receptor. (4) Photo courtesy of Maroteaux et al 2019.

Psilocin’s key and translocation of ECS-serotonin signalling

Mushrooms will essentially flip serotonin’s role in the endocannabinoid system and drive the CB1 receptor through anandamide-like derivatives. Whereas, serotonin normally facilitates a unique relationship with dopamine through CB2 receptors via 2-AG.

The terpene, caryophyllene. can therefore balance side effects caused by magic mushrooms.

Conclusively, the effects of magic mushrooms are, in part, facilitated through your ECS and can either be complimented or complicated with cannabis. Unfortunately, though, science is not yet sound on the subject. Parrish et al 2006 did note a massive difference in psilocin’s ability to produce 2-AG through the serotonin (5-HT2a) receptor in mice compared to other 5-HT2a agonists, including 5-MEO-DMT, LSD, and their control – serotonin.

Unfortunately, the study did not adopt any conclusions for psilocin’s anomaly. The conclusion was still left incomplete by Maroteaux et al. 2019. But now, Health Canada has granted a licensed cannabis research lab permission to study magic mushrooms. So, we might finally get a more detailed answer to these questions soon.

Show your work

  • When serotonin and LSD encourage DAG to metabolize into 2-Ag through a 5-HT2a mechanism, an equal amount of inositol phosphate (IP) is produced. Conversely, ten times as much IP is produced when the 5-HT2a mechanism is activated by psilocin. (4)
  • Despite its neglect of the PLC path, psilocin can still activate 2-AG with an affinity similar to serotonin through a mechanism this author has yet to find in the literature.
  • Magic mushrooms should alter, not neglect, post-synaptic CB1R signalling. And psilocybin will lead to a flood of IP after metabolism to psilocin.

Sources

  1. Arnold, W.R., Carnevale, L.N., Xie, Z. et al. Anti-inflammatory dopamine- and serotonin-based endocannabinoid epoxides reciprocally regulate cannabinoid receptors and the TRPV1 channel. Nat Commun 12, 926 (2021). https://doi.org/10.1038/s41467-021-20946-6
  2. Klein, Adam & Chatha, Muhammad & Laskowski, Lauren & Anderson, Emilie & Brandt, Simon & Chapman, Stephen & McCorvy, John & Halberstadt, Adam. (2020). Investigation of the Structure−Activity Relationships of Psilocybin Analogues. ACS Pharmacology & Translational Science. XXXX. 10.1021/acsptsci.0c00176.
  3. Maroteaux, Luc & Ayme-Dietrich, Estelle & Aubertin, Gaelle & Banas, Sophie & Quentin, Emily & Roland, Lawson & Monassier, Laurent. (2016). New therapeutic opportunities for 5-HT2 receptor ligands. Pharmacology & Therapeutics. 170. 10.1016/j.pharmthera.2016.10.008
  4. Maroteaux, Luc & Béchade, Catherine & Roumier, Anne. (2019). Dimers of serotonin receptors: Impact on ligand affinity and signaling. Biochimie. 161. 10.1016/j.biochi.2019.01.009.
  5. Parrish, J. C., & Nichols, D. E. (2006). Serotonin 5-HT(2A) receptor activation induces 2-arachidonoylglycerol release through a phospholipase c-dependent mechanism. Journal of neurochemistry99(4), 1164–1175. https://doi.org/10.1111/j.1471-4159.2006.04173.x
  6. Best, A. R., & Regehr, W. G. (2008). Serotonin evokes endocannabinoid release and retrogradely suppresses excitatory synapses. The Journal of neuroscience : the official journal of the Society for Neuroscience28(25), 6508–6515. https://doi.org/10.1523/JNEUROSCI.0678-08.2008
  7. Berg, K. A., Maayani, S., Goldfarb, J., Scaramellini, C., Leff, P., & Clarke, W. P. (1998). Effector pathway-dependent relative efficacy at serotonin type 2A and 2C receptors: evidence for agonist-directed trafficking of receptor stimulus. Molecular pharmacology54(1), 94–104.
  8. Davies, MA & Setola, Vincent & Strachan, Ryan & Sheffler, Douglas & Salay, E & Hufeisen, S & Roth, Bryan. (2006). Pharmacologic analysis of non-synonymous coding h5-HT2A SNPs reveals alterations in atypical antipsychotic and agonist efficacies. The pharmacogenomics journal. 6. 42-51. 10.1038/sj.tpj.6500342.
  9. Sun, Y. X., Tsuboi, K., Okamoto, Y., Tonai, T., Murakami, M., Kudo, I., & Ueda, N. (2004). Biosynthesis of anandamide and N-palmitoylethanolamine by sequential actions of phospholipase A2 and lysophospholipase D. The Biochemical journal380(Pt 3), 749–756. https://doi.org/10.1042/BJ20040031.
  10. Uyama, T., Okamoto, Y., & Ueda, N. (2018). Endocannabinoids and related N-acylethanolamines: biological activities and metabolism. Inflammation and regeneration38, 28. https://doi.org/10.1186/s41232-018-0086-5
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