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  • Writer's pictureLaura Smith

So what does Serotonin have to do with psychedelics

Updated: Feb 2, 2021

Key Takeaways

· Serotonin is thought to play a key role in regulating mood, patience and coping

· Low levels of serotonin have been linked to depression and served as the initial thesis surrounding how anti-depressants work in the brain

· There are a number of psychedelics, classed classical psychedelics, that have a similar structure to serotonin and thought to interact with serotonin receptors in the brain

· Serotonergic activity in the brain is believed to be one mechanism which relates to the mood related effects related to psychedelics.


Understanding signalling in the brain

Have you ever wondered how our brain sends messages from one nerve to the next, in order to propagate a signal and deliver an output? Communication between two nerve cells occurs by the release of neurotransmitters. Neurotransmitters are sometimes referred to as ‘chemical messengers’. These are small molecules used by the nervous system to transmit messages from one nerve to the next nerve, or to muscle.

For a signal to work its way through the nervous system, electrical signals called action potentials, travel down the nerve via the axon. Once the electrical signal reaches the synaptic cleft, which is the small gap between two nerves, it is converted to a chemical signal and neurotransmitters are released to carry the signal to the receiving nerve cell.

Neurotransmitters can be classed as excitatory or inhibitory, depending on the effect they have on the receiving nerve cell. If excitatory, the neurotransmitter will generate an electrical signal in the receiving nerve cell, so the signal will continue to move down the nervous system pathway to give an output. An inhibitory neurotransmitter has the opposite effect, and prevents the electrical signal reaching the next nerve. When a neurotransmitter is released it floats across the synaptic cleft where it can bind to a receptor to cause an excitatory or inhibitory effect.


So what is serotonin?

Serotonin is a neurotransmitter. It is often known as the ‘happiness chemical’ as it contributes to happiness and wellbeing. Serotonin is known scientifically as 5-hydroxytryptamine, or 5-HT. It is an excitatory neurotransmitter, and communicates between nerve cells. It is produced in the intestines and the brain and can influence a variety of body and physiological functions.

It is believed that serotonin can help regulate mood and social behaviour, digestion and appetite, memory and sexual desire and function. It is also involved in regulating the body’s sleep-wake cycles as it is the precursor for melatonin.

The serotonin system is complex, with over 14 different receptors [1]. These receptors are highly expressed throughout the brain. One of the key functions of this system in the brain is to modulate anxiety and stress, and promote patience and coping.

The serotonin system is split into two branches: 5HT1A receptors and 5HT2A receptors. The 5HT1A branch is thought to play a role in mediating something called ‘passive coping’ which is tolerating but not necessarily dealing with a source of psychological pain. The 5HT2A branch is thought to have a role in mediating ‘active coping’ which actively deals with psychological pain (Puglisi-Allegra). Combining signals from both pathways is thought to have a positive influence on a person's mood [1].


And, how do psychedelics influence the serotonin system?

Psychedelics can enhance the signals in the serotonin system. This can happen because many psychedelics are similar in structure to serotonin and can bind to the serotonin receptors. It is widely believed that the 5HT2A receptors are the main target of many psychedelic drugs [2]. These drugs are known as serotonergic psychedelics and they have profound effects on the brain and behaviour.

Classic serotonergic psychedelics include LSD, DMT and psilocybin. These all activate the 5HT2A branch of serotonin receptors. It is this receptor that is said to be the trigger for the mind-bending psychedelic experience [1]. The environment in which the psychedelic was taken can also influence the trip.


So what is the link between serotonin and mental health?

Serotonin has been implicated in several psychiatric disorders. A key theory is that depression may involve an imbalance of neurotransmitters, including serotonin. Scientists have used compounds to deplete serotonin in the brain and shown that this causes depression in individuals [3, 4]. Drugs that increase serotonin levels in the brain also have antidepressant properties.

The most commonly prescribed anti-depressants are selective serotonin reuptake inhibitors (SSRIs). Normally, when serotonin is released from a synapse it is reabsorbed so it can be reused. For this to happen, serotonin needs to be taken back up into a nerve via a receptor. SSRIs, such as Prozac, block this receptor and prevent serotonin being taken back up into the nerve. This increases the concentration of serotonin and causes the receiving nerve to continue firing.

These drugs target mainly the 5HT1A receptors. Sadly, not all people respond to this treatment, and are classed as ‘treatment-resistant’.

Unlike SSRIs, psychedelics act mainly on 5HT2A receptors. This has been shown to be a good target when treating depression, with several studies reporting positive effects on mental health and wellbeing [5]. Treatment with the psychedelic psilocybin in clinical trials for example has shown improvement in mood in treatment-resistant depression [6].

Want to find out more? Check out the references

1. Carhart-Harris, R.L. and D.J. Nutt, Serotonin and brain function: a tale of two receptors. J Psychopharmacol, 2017. 31(9): p. 1091-1120.

2. Gonzalez-Maeso, J., et al., Hallucinogens recruit specific cortical 5-HT2A receptor-mediated signaling pathways to affect behavior. Neuron, 2007. 53(3): p. 439-452.

3. Achor, R.W., N.O. Hanson, and R.W. Gifford, Jr., Hypertension treated with Rauwolfia serpentina (whole root) and with reserpine; controlled study disclosing occasional severe depression. J Am Med Assoc, 1955. 159(9): p. 841-5.

4. Antkiewicz-Michaluk, L., et al., Antidepressant-like effect of tetrahydroisoquinoline amines in the animal model of depressive disorder induced by repeated administration of a low dose of reserpine: behavioral and neurochemical studies in the rat. Neurotox Res, 2014. 26(1): p. 85-98.

5. Carhart-Harris, R.L. and G.M. Goodwin, The Therapeutic Potential of Psychedelic Drugs: Past, Present, and Future. Neuropsychopharmacology, 2017. 42(11): p. 2105-2113.

6. Carhart-Harris, R.L., et al., Psilocybin with psychological support for treatment-resistant depression: an open-label feasibility study. Lancet Psychiatry, 2016. 3(7): p. 619-27.

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