Tag: serotonin

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Psilocybin & Psilocin: Serotonin’s funny cousins

or the Magic Mushrooms Keychain

“Magic mushrooms” are fungi that contain Psylocibin. 

When we ingest Psylocibin, it gets degraded by the acid juices of our stomachs and loses its phosphate group (P), giving rise to a compound called Psilocin.

Psilocybin de-phosphorylation to Psilocin @countlesssheep.com
Psilocybin de-phosphorylation to Psilocin

What is interesting is that Psilocin (organic name: 4-hydroxy-N,N-dimetiltryptamine) is very similar to Serotonin – a very important neurotransmitter involved in our mood, learning and a plethora of other fundamental physiological processes.

Psilocin & Serotonin: similarities and differences @countlesssheeo.com
Psilocin & Serotonin: similarities and differences

As such, when Psilocin reaches our prefrontal cortex, it can easily bind to our serotonin receptors, because they look so similar – it’s like two old keys that look almost alike and can open the same door at our grandmother’s house.

But Psilocin and Serotonin are indeed different. 

As such, Psilocin is able to do certain things in our brains when it binds to the similar Serotonin “door lock”, causing hallucinations and emotional changes that seem to alter the perception of space and time. Psilocin is like that funny cousin that can create chaos when it comes to visit during summer vacations… And, not all trips seem to be good trips, because as all things in life, a lot depends on the surrounding environment and the dosage. So, if a person comes through that door in a poor state of mind, it will just go down the “dark-hole” even further – so they say…

In fact a couple of years back, psychopharmacologists Robin Carhart-Harris and David Nutt from the Imperial College London did a fMRI study (functional magnetic resonance imaging) to evaluate the effects of Psilocybin in the brain2, and decided to give it IV (intravenously) to quicken the trip-effect because they were scared the “voyage” inside of the tight-noisy fMRI machine could be scary for the 30 individuals high on Psilocybin3. The results were quite interesting and showed that the effects of this psychedelic drug could be caused by a decreased activity and connectivity in the brain’s key connector hubs, like enabling a state of unconstrained cognition3. It seems  Psilocybin reduced the blood flow and neural activity in the posterior cingulate cortex and medial prefrontal cortex – almost like making a “software reset” of the brain. 

As such, Psilocin has been considered a serotonergic psychedelic compound; and it has been banned since the 70’s because people at the time thought it had no therapeutic value.

But Psilocin seems to have an effect in the treatment of Major Depressive Disorder (MDD), a leading cause of disability worldwide. Robin von Rotz and team at the Neurophenomenology of Conscious Lab from the University of Zürich, Switzerland, have just released the results of a randomized double-blind clinical trial 1. This clinical study showed that a single, moderate dose of Psilocybin (0.215 mg/Kg) significantly reduced depressive symptoms compared to a placebo, the “sugar-pill” that they give to the control group.

Even though the results were only evaluated for a period of two weeks after ingestion, the depression severity scores significantly improved in the treated patients in comparison with controls. So, this is one of the first clinical studies to actually demonstrate improvements directly attributed to Psilocybin/Psilocin itself. If we think that the state of deep depression is actually a neural circuitry disfunction, then Psilocin with its similar key structure to Serotonin might be able to open and clean the faulty neuronal-wires that contribute to the brain disfunction seen in MDD.

Several larger clinical studies are currently under way that could eventually pave the way to full regulatory approval, and the removal of Psilocybin from the banned WHO list of pure psychedelic drugs. The U.S. Food and Drug Administration already gave psilocybin the “breakthrough therapy” designation for MDD and Treatment-Resistant Disorder; and, in Australia some psychiatrist can have permission to use it under certain conditions for Post-Traumatic Stress Disorder. The European Medicines Agency (EMA) is following suit, and its Chief Medical Officer has just released a statement that it is actively engaged with developers of psychedelic therapies and academic researchers to help them identify what it takes to move forward and fully bring psychedelics as medical therapies to our pharmacies (and not street dealers)4.

We will be on the lookout for those results…

Fan shape mushrooms

References:

1          von Rotz, R. et al. Single-dose psilocybin-assisted therapy in major depressive disorder: a placebo-controlled, double-blind, randomised clinical trial. eClinicalMedicine 56 (2023). https://doi.org:10.1016/j.eclinm.2022.101809

2 Carhart-Harris, R. L. et al. The administration of psilocybin to healthy, hallucinogen-experienced volunteers in a mock-functional magnetic resonance imaging environment: a preliminary investigation of tolerability. J Psychopharmacol 25, 1562-1567 (2011). https://doi.org:10.1177/0269881110367445

3        Miller, G. Mapping the psychadelic brain. Science Brain & Behaviour (2012). https://doi.org:10.1126/article.27824

4   https://www.linkedin.com/pulse/second-chance-psychedelics-european-medicines-agency

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The language of serotonin

Or, “What are they saying?“

When we mention the word Serotonin (5-hydroxytryptamine, 5-HT), we immediately think of the brain and the Central Nervous System (CNS). People tend to associate serotonin to depression, or mood, or feelings of well-being1. 

Although that is correct, truth be told, the majority of the serotonin in the human body is actually produced in the gut. In fact, 95% of total serotonin is manufactured by the Enterochromaffin cells (or, Kulchitsky cells) in the gastro-intestinal tract (GI)2,3. These cells live next to the gut epithelium, that covers the cavity of the GI tract, playing a crucial role in the regulation of bowel movements and secretions. If you think that the gut is almost 9 meters (or 30 feet) long, then that’s a lot of cells producing serotonin. 

When in the 50’s, Betty M. Twarog and Irvine H. Page discovered that the brain produced its own serotonin4; then, the gut-made serotonin got reduced to its “Aschenputtel” origins, and relinquished to the favela quarters of the body. As such, brain-derived serotonin always got more attention than its gut-derived counterpart – like a rich vs. poor-cousin type of reputation.

Moving-on…

Platelets, also called thrombocytes, are small un-nucleated fragment of cells that, when activated, form blood clots (thrombus) and prevent bleeding. 

Electron microscopy images of circulating platelets, extracted from Zilla et al, 19875

Platelets do not make serotonin, butcan take it up as they circulate through the gut, and carry it along the blood stream6,7. As such, the serotonin produced in the intestine can be carried all over the body. As the chemical messenger serotonin is, it can influence any other cell, in whatever other location, as long as it has a serotonin receptor on it. As such, peripheral serotonin has now discovered its path back into the limelight, and recent research has strengthened the influence that gut-made serotonin has in other parts of the body, functioning as an intestinal-derived hormone. 

Once again, the “Aschenputtel” story comes into mind, but this time through its “Cinderella” version. Let’s take a look…

For example, gut-derived serotonin can directly regulate the liver and mediate liver regeneration8. In Non-Alcoholic Fatty Liver Disease (NAFLD), a group of conditions that are characterized by excessive fat accumulation in the liver and closely track the global public health problem of obesity, researchers showed that inhibiting gut-derived serotonin synthesis could resolve hepatic fat accumulation8,9.

Peripheral serotonin can also be a negative regulator of bone density, by specifically inhibiting osteoblast formation and leading to osteoporosis10 – a common feature in patients with inflammatory bowel disease (IBD). This happens through the action of a common receptor: the low-density Lipoprotein Receptor-related Protein 5(LRP5), which is expressed in both osteoblasts and enterochromaffin cells11. LRP5 inhibits the expression of an important ingredient for serotonin production (Tryptophan hydroxylase-1, Tph1); as such, when LRP5 is deficient or inactivated due to inflammation or disease, blood levels of serotonin are elevated decreasing osteoblast formation; and, consequently, reducing bone mass1,11.

Epidemiologic data suggests a role of serotonin, or Selective Serotonin-Reuptake Inhibitors (typically used as antidepressants, SSRIs) in the development of venous thrombosis12. In fact, patients with depression were reported to have higher incidences of venous thromboembolism in general13; and, the use of SSRIs is associated with an increased venous thromboembolism risk14. No wonder, serotonin and platelets are “brothers in arms”, ready to block any blood vessel along their way…. 

Serotonin and its receptors are also present in the immune system, where evidence suggests it contributes to both innate and adaptive responses. There is now clear evidence of a straight communication between the immune system, the gut and the brain via serotonin15,16.

On top of all and because we are not alone, our gut microbiota plays a critical role in regulating our colonic serotonin. Indigenous spore-forming bacteria (Sp) promote serotonin biosynthesis in our enterochromaffin cells, and with that they can significantly modulate GI movements and platelet function – together with many aspects of our physiology17,18. We now know that the microbiota colonizes the GI tract after birth, with a continuous maturation during the first years of life19. Researchers have now showed in animal models that this developing gut microbiota regulates the development of the adult enteric nervous system via intestinal serotonin networks20. What this actually means, is that the actions of our intestinal bugs during the beginning of our life are determinant for the development of our “gut brain”, our second brain. How about that?…

If we ruminate about it, when we “think” with our gut, we are actually listening to our bugs. By directly signalling our cells to produce serotonin and develop a network of neurons as soon as we are born, our gut-bugs are actually finding a way to communicate with us – the host – in the serotonin language. 

Now, we just need to understand what are they telling us… 

Beethoven’s hearing aids, Beethoven House Museum, Bonn.

References:

1          Gershon, M. D. 5-Hydroxytryptamine (serotonin) in the gastrointestinal tract. Curr Opin Endocrinol Diabetes Obes 20, 14-21, doi:10.1097/MED.0b013e32835bc703 (2013).

2          Bellono, N. W. et al. Enterochromaffin Cells Are Gut Chemosensors that Couple to Sensory Neural Pathways. Cell 170, 185-198.e116, doi:10.1016/j.cell.2017.05.034 (2017).

3          Yaghoubfar, R. et al. Modulation of serotonin signaling/metabolism by Akkermansia muciniphila and its extracellular vesicles through the gut-brain axis in mice. Scientific Reports 10, 22119, doi:10.1038/s41598-020-79171-8 (2020).

4          Twarog, B. M. & Page, I. H. Serotonin Content of Some Mammalian Tissues and Urine and a Method for Its Determination. American Journal of Physiology-Legacy Content 175, 157-161, doi:10.1152/ajplegacy.1953.175.1.157 (1953).

5          Zilla, P. et al. Scanning electron microscopy of circulating platelets reveals new aspects of platelet alteration during cardiopulmonary bypass operations. Tex Heart Inst J 14, 13-21 (1987).

6          Morrissey, J. J., Walker, M. N. & Lovenberg, W. The absence of tryptophan hydroxylase activity in blood platelets. Proc Soc Exp Biol Med 154, 496-499, doi:10.3181/00379727-154-39702 (1977).

7          Hughes, F. B. & Brodie, B. B. The mechanism of serotonin and catecholamine uptake by platelets. J Pharmacol Exp Ther 127, 96-102 (1959).

8          Wang, L. et al. Gut-Derived Serotonin Contributes to the Progression of Non-Alcoholic Steatohepatitis via the Liver HTR2A/PPARγ2 Pathway. Frontiers in Pharmacology 11, doi:10.3389/fphar.2020.00553 (2020).

9          Choi, W. et al. Serotonin signals through a gut-liver axis to regulate hepatic steatosis. Nature Communications 9, 4824, doi:10.1038/s41467-018-07287-7 (2018).

10        Lavoie, B. et al. Gut-derived serotonin contributes to bone deficits in colitis. Pharmacol Res 140, 75-84, doi:10.1016/j.phrs.2018.07.018 (2019).

11        Yadav, V. K. et al. Lrp5 controls bone formation by inhibiting serotonin synthesis in the duodenum. Cell 135, 825-837, doi:10.1016/j.cell.2008.09.059 (2008).

12        Rieder, M., Gauchel, N., Bode, C. & Duerschmied, D. Serotonin: a platelet hormone modulating cardiovascular disease. J Thromb Thrombolysis 52, 42-47, doi:10.1007/s11239-020-02331-0 (2021).

13        Takeshima, M. et al. Prevalence of Asymptomatic Venous Thromboembolism in Depressive Inpatients. Neuropsychiatr Dis Treat16, 579-587, doi:10.2147/NDT.S243308 (2020).

14        Parkin, L. et al. Antidepressants, Depression, and Venous Thromboembolism Risk: Large Prospective Study of UK Women. J Am Heart Assoc 6, doi:10.1161/jaha.116.005316 (2017).

15        Baganz, N. L. & Blakely, R. D. A dialogue between the immune system and brain, spoken in the language of serotonin. ACS Chem Neurosci 4, 48-63, doi:10.1021/cn300186b (2013).

16        Jacobson, A., Yang, D., Vella, M. & Chiu, I. M. The intestinal neuro-immune axis: crosstalk between neurons, immune cells, and microbes. Mucosal Immunology 14, 555-565, doi:10.1038/s41385-020-00368-1 (2021).

17        Yano, J. M. et al. Indigenous bacteria from the gut microbiota regulate host serotonin biosynthesis. Cell 161, 264-276, doi:10.1016/j.cell.2015.02.047 (2015).

18        Reigstad, C. S. et al. Gut microbes promote colonic serotonin production through an effect of short-chain fatty acids on enterochromaffin cells. Faseb j 29, 1395-1403, doi:10.1096/fj.14-259598 (2015).

19        Bäckhed, F. et al. Dynamics and Stabilization of the Human Gut Microbiome during the First Year of Life. Cell Host Microbe 17, 690-703, doi:10.1016/j.chom.2015.04.004 (2015).

20        De Vadder, F. et al. Gut microbiota regulates maturation of the adult enteric nervous system via enteric serotonin networks. Proc Natl Acad Sci U S A 115, 6458-6463, doi:10.1073/pnas.1720017115 (2018).