Sometimes depression can literally hurt. Interestingly, this has a lot to do with our endocannabinoid systems (ECS) – a network made up of a few receptors and two neurotransmitters. Pain and emotions are linked through these messengers. And through the ECS, magic mushrooms and cannabis can often, if not intuitively, have therapeutic effects. (1)
This infographic describes various serotonin receptors and their effects. The ECS and serotonin (5-HT) bind to many receptors, but the main focus of magic mushrooms is on 5-HT2a. (2, 3) However, other receptors can be the cause of side effects such as nausea. Photo courtesy of Maroteaux et al 2016.
How does psilocybin change the ECS?
Luck can strengthen your endocannabinoid system according to some scientific studies over the past two decades. (1, 4-6) This is because a receptor that uses the Happy Messenger to express serotonin can also help release natural cannabinoids in your body.
A special form of serotonin also acts as a non-intoxicating but still full agonist to the cannabinoid 1 (CB1) receptor. (1) This means that a better mood can prevent cancer and other diseases – through the body’s own cannabinoids. And there is a blissful feedback loop that occurs between serotonin and the ECS. After all, our endocannabinoids increase serotonin and vice versa – the crosstalk between the two systems. (5)
Anandamide and serotonin go hand in hand in mental health therapy.
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 create a deeper synergy
The intoxicant in medicinal mushrooms, psilocin, and its prodrug, psilocybin, are similar to serotonin. (1, 2) Therefore, psilocin binds to a similar receptor as serotonin, namely 5-HT2a. In fact, this is one of the main magic mushroom effects that has caught the attention of researchers.
5-HT2a binds magic mushrooms and cannabis in a complicated synergy, as the receptor also helps release ECS messengers and their derivatives. In conclusion, serotonin will torment an endocannabinoid that is vital to daily survival. Psilocin, however, overturns this function and instead promotes unassociated and less important ECS derivatives that benefit therapy. (3, 7)
Psilocin counteracts serotonin at 5-HT2a receptors and creates its only signaling pathway, which is marked with purple arrows. (5, 7, 8) The regular signaling pathway of serotonin (5-HT), which is marked with red arrows, is interrupted when consuming 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 describe the unknown meaning of IP (inositol phosphate).
Serotonin releases the enzyme PLC as soon as it docks with the 5-HT2a receptor, which in turn helps release the workhorse endocannabinoid 2-AG (red path). After psilocin (purple path) takes the space of the 5-HT2a, the receptor releases PLA2 instead of PLC.
Psilocin’s purple path suggests potentially profound but unexplored effects on ECS signaling. Magic mushrooms drop the regular function of 2-AG in feedback and instead concentrate serotonin signal transmission on PEA and OEA, a main component of chocolate. Mushrooms chocolates, anyone?
Magic mushrooms and the ECS – combined with a happy endorphin
A doubling of the feedback loop and the fact that endocannabinoids increase serotonin – the role of the ECS is not exactly an easy one. (1, 4) Endocannabinoid activity can decrease the functionality of serotonin receptors while increasing their signaling activity. The endocannabinoid system regulates the effects of psilocybin. However, magic mushrooms alter the endocannabinoid system and form a synergistic connection. (4-7)
The endocannabinoid system acts as a safety net during a mushroom journey. But not everyone will experience positive benefits from adding cannabis to psilocybin when the functionality and crosstalk between the ECS and the serotonin system changes completely.
The 5-HT2a receptor that psilocin binds to is biphasic, which means it has two different effects. For example, LSD and 5-MEO-DMT activate the left side and express together with dopamine. Psilocin does not express with dopamine and instead goes the right way by expressing along with the CB1 receptor. (4) Photo courtesy of Maroteaux et al. 2019.
Psilocin’s key and translocation of ECS serotonin signaling
Fungi will essentially reverse the role of serotonin in the endocannabinoid system and control the CB1 receptor through anandamide-like derivatives. While serotonin normally enables a unique relationship with dopamine through CB2 receptors via 2-AG.
The terpene, caryophyllene. can therefore compensate for side effects caused by magic mushrooms.
In summary, the effects of magic mushrooms are partially facilitated by your ECS and can either be supplemented or complicated with cannabis. Unfortunately, the science on this subject is not yet well founded. Parrish et al. 2006 found a massive difference in the ability of psilocin to produce 2-AG via the serotonin (5-HT2a) receptor in mice compared to other 5-HT2a agonists including 5-MEO-DMT, LSD and theirs Control – serotonin.
Unfortunately, no conclusions were drawn for the psilocin anomaly in the study. The conclusion was drawn by Maroteaux et al. 2019. Now Health Canada has given a licensed cannabis research laboratory permission to study magic mushrooms. We may soon get a more detailed answer to these questions.
Show your work
- When serotonin and LSD stimulate the DAG to metabolize to 2-Ag via 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 neglecting the PLC pathway, psilocin 2-AG can activate with a serotonin-like affinity by a mechanism that this author has not yet found in the literature.
- Magic mushrooms should alter postsynaptic CB1R signaling, not neglect it. And psilocybin will lead to a deluge of IP after metabolism to psilocin.
- Arnold, WR, Carnevale, LN, Xie, Z. et al. Anti-inflammatory endocannabinoid epoxides based on dopamine and serotonin mutually regulate the cannabinoid receptors and the TRPV1 channel. Nat Commun 12 926 (2021). https://doi.org/10.1038/s41467-021-20946-6
- 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.
- Maroteaux, Luc and Ayme-Dietrich, Estelle and Aubertin, Gaelle and Banas, Sophie and Quentin, Emily and Roland, Lawson and Monassier, Laurent. (2016). New therapeutic options for 5-HT2 receptor ligands. Pharmacology & Therapeutics. 170.10.1016 / j.pharmthera.2016.10.008
- Maroteaux, Luc & Béchade, Catherine & Roumier, Anne. (2019). Dimers of serotonin receptors: influence on ligand affinity and signal transmission. Biochemistry. 161.10.1016 / j.biochi.2019.01.009.
- Parrish, JC & Nichols, DE (2006). Activation of the serotonin 5-HT (2A) receptor induces the release of 2-arachidonoylglycerol via a phospholipase-c-dependent mechanism. Journal of Neurochemistry, 99 (4), 1164-1175. https://doi.org/10.1111/j.1471-4159.2006.04173.x
- Best, AR & Regehr, WG (2008). Serotonin induces the release of endocannabinoids and retrograde suppresses the excitatory synapses. The Journal of Neuroscience: the official journal of the Society for Neuroscience, 28 (25), 6508-6515. https://doi.org/10.1523/JNEUROSCI.0678-08.2008
- Berg, KA, Maayani, S., Goldfarb, J., Scaramellini, C., Leff, P. & Clarke, WP (1998). Effector pathway-dependent relative potency at serotonin type 2A and 2C receptors: evidence of agonist-directed trafficking in receptor stimuli. Molecular Pharmacology, 54 (1), 94-104.
- Davies, MA & Setola, Vincent & Strachan, Ryan & Sheffler, Douglas & Salay, E & Horseshoe, S & Roth, Bryan. (2006). The pharmacological analysis of non-synonymously coding h5-HT2A-SNPs shows changes in the atypical efficacy of antipsychotics and agonists. The Pharmacogenomics Journal. 6. 42-51. 10.1038 / sj.tpj.6500342.
- Sun, YX, 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 Journal, 380 (Pt 3), 749-756. https://doi.org/10.1042/BJ20040031.
- Uyama, T., Okamoto, Y. & Ueda, N. (2018). Endocannabinoids and Related N-Acylethanolamines: Biological Activities and Metabolism. Inflammation and Regeneration, 38, 28. https://doi.org/10.1186/s41232-018-0086-5