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→Proposed method of action: Changed Patent names of SSRI's to the generic equivalents as most people would recognise the generic names, as they are more commonly prescribed in many countries (especially in the United Kingdom). In relation to potential harm reduction for the reader of the article, this edit allows for more easier and faster recognition of SSRI's that possibly affect the dosage of Serotonergic Psychedelics.
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'''Serotonergic psychedelics''' (also known as '''serotonergic hallucinogens''') are a class of [[hallucinogenic]] drugs with a method of action strongly tied to the [[neurotransmitter]] [[serotonin]]. Serotonin (often referred to as '''5-HT''', short for its full chemical name ''5-'''h'''ydroxy'''t'''ryptamine'') is a naturally occurring neurotransmitter which is tied to positive mood, certain involuntary muscle control, and countless other functions, many of which are not yet fully understood.
'''Serotonergic psychedelics''' (also known as '''serotonergic [[hallucinogens]]''') are a class of [[hallucinogenic]] substances with a method of action strongly tied to modifying the normal [[neurotransmitter|neurotransmission]] of [[serotonin]] in the central nervous system (CNS).
While the method of action of serotonergic psychedelics is not fully understood, serotonergic psychedelics are known to show affinities for various 5-HT receptors in different ways and levels, and may be classified by their activity at different 5-HT sub-sites, such as 5-HT<sub>1A</sub>, 5-HT<sub>1B</sub>, 5-HT<sub>2A</sub>, etc. Many serotonergic psychedelics, such as the family of [[tryptamines]], have very strong structural similarities to serotonin itself, which partially explains the affinity for certain 5-HT sites. It is almost unanimously agreed that serotonergic psychedelics produce their effect by acting as strong partial [[agonists]] at the 5-HT<sub>2A</sub> receptors. How this produces the psychedelic experience is unclear, but it is likely that it acts by increasing excitation in the cortex, possibly by specifically facilitating input from the [[thalamus]], the major relay for sensory information input to the [[Cerebral cortex|cortex]].<ref>Hallucinogens | http://www.sciencedirect.com/science/article/pii/S0163725803001657</ref> Worth noting is that [[selective serotonin reuptake inhibitor]]s (a class of [[antidepressants]] including [[Paxil]], [[Prozac]], and [[Zoloft]]) can increase the dosage required for hallucinogenic effects of serotonergic psychedelics, in some people, based on anecdotal reports. Some users, however, have found this to be entirely untrue for them.{{Citation needed|date=March 2007}}
Serotonin, which is also referred to as '''5-HT''' (from its chemical name '''5'''-'''h'''ydroxy-'''t'''ryptamine), is a naturally-occurring [[monoamine neurotransmitter]] that is tied to functions including developmental, cardiovascular, gastrointestinal, and endocrine function, sensory perception, behaviors such as aggression, appetite, sex, sleep, mood, cognition, and memory, many of which have yet to be fully understood.<ref>David E. Nichols and Charles D. Nichols, Serotonin Receptors. Chemical Reviews. 2008. 108 (5), 1614-1641. https://doi.org/10.1021/cr078224o</ref>
==Proposed method of action==
[[File:Psilocybin neural connections.jpg|315px|thumbnail|right|The diagram above demonstrates the neural connections associated with sobriety in comparison to being under the influence of psilocybin as demonstrated through the use of MRI scans. <p>The width of the links is proportional to their weight and the size of the nodes is proportional to their strength. Note that the proportion of heavy links between communities is much higher (and very different) in the psilocybin group, suggesting greater integration<ref>Petri, G., Expert, P., Turkheimer, F., Nutt, D., Hellyer, P. J., & Vaccarino, F. (2014). Homological scaffolds of brain functional networks, 14–18. https://doi.org/10.1098/rsif.2014.0873</ref>]]
[[File:NeuroPsychDiagram.png|thumbnail|315px|right|Figure 1 - The figure shows a model in which hallucinogens, such as [[psilocin]], [[LSD]] and [[DMT]], increase extracellular glutamate levels in the prefrontal cortex through stimulation of postsynaptic serotonin 2A (5-HT 2A) receptors that are located on large glutamatergic pyramidal cells in deep cortical layers (V and VI) projecting to layer V pyramidal neurons. <p>This glutamate release leads to an activation of [[AMPA]] and [[NMDA]] receptors on cortical pyramidal neurons. In addition, hallucinogens directly activate 5-HT2A receptors located on cortical pyramidal neurons. This activation is thought to ultimately lead to increased expression of brain-derived neurotrophic factor (BDNF).<ref>Vollenweider, F. X., & Kometer, M. (2010). The Neurobiology of Psychedelic Drugs: Implications for the Treatment of Mood Disorders. Nature Publishing Group, 11(9), 642–651. https://doi.org/10.1038/nrn2884</ref>]]
[[File:Lsd brain scan.jpg|thumbnail|315px|right|This image shows how, with eyes-closed, much more of the brain contributes to the visual experience under LSD (right image) than under placebo (left image). The magnitude of this effect correlates with participants’ reports of complex, dreamlike visions.<ref>Carhart-Harris, R. L., Muthukumaraswamy, S., Roseman, L., Kaelen, M., Droog, W., Murphy, K., … Nutt, D. J. (2016). Neural correlates of the LSD experience revealed by multimodal neuroimaging. Proceedings of the National Academy of Sciences. https://doi.org/10.1073/pnas.1518377113</ref>]]
While the full mechanism of action is not understood, serotonergic psychedelics are known to exhibit [[partial agonism|partial agonist activity]] for various 5-HT receptors in a range of affinities and efficacies. As a result, they may be classified by their activity at different 5-HT sub-sites, such as 5-HT<sub>1A</sub>, 5-HT<sub>1B</sub>, 5-HT<sub>2A</sub>, etc.
Many serotonergic psychedelics, such as the family of [[tryptamines]], have very strong structural similarities to serotonin itself. This partially explains the affinity they have for certain 5-HT sites. Most research suggests that the signature psychedelic effect is due to strong partial [[agonist]] activity at the 5-HT<sub>2A</sub>, and to a lesser extent, 5-HT<sub>2C</sub> and 5-HT<sub>1A</sub> receptors.{{citation needed}}
The cortico-striato-thalamo-cortical loops (also known as CSTC-loops) appear to be central to the function of psychedelics,<ref>Taylor, S. B., Lewis, C. R., & Olive, M. F. (2013). The neurocircuitry of illicit psychostimulant addiction: acute and chronic effects in humans. Substance Abuse and Rehabilitation, 4, 29–43. https://doi.org/10.2147/SAR.S39684; [..] The overall output of the basal ganglia is predominantly via the thalamus, which then projects back to the PFC to form cortico-striatal-thalamo-cortical (CSTC) loops. [..]</ref> which are also regulated by the serotonergic system. These control loops connect brain areas like the frontal lobe, the striatum and the thalamus; they aggregate, process and forward internal and external information.
The disruption of the neurotransmitter balance causes these control loops to collapse overwhelmed, leading to the flooding of the frontal lobe with neuronal excitatory glutamate; internal and external stimuli as well as all kinds of non-conscious contents can freely move up to the cerebral cortex and appear as visions in consciousness.<ref>Vollenweider, F. X. (2001). Brain mechanisms of hallucinogens and entactogens. Dialogues in Clinical Neuroscience, 3(4), 265–79. Retrieved from https://doi.org/10.31887/DCNS.2001.3.4/fxvollenweider</ref><ref>[http://archive.today/jcBm Edelrausch im Labor] – ''Neuro Culture Lab'' (German)</ref>
Furthermore, over-activation of the ''locus coeruleus'' and subsequent widespread [[norepinephrine]] secretion may occur, causing a perceived state of sensory transcendence and sometimes even intense spiritual or [[transpersonal]] experiences.
It is worth noting that [[selective serotonin reuptake inhibitors]] (a class of [[antidepressants]] including Paroxetine, Fluoxetine and Sertraline) can increase the dosage required for hallucinogenic effects in some people (based on anecdotal reports). Some users, however, have found this to be entirely untrue for them, so those who are using daily antidepressants should, at first, only attempt a common dosage.
==Examples==
==Examples==
Examples of serotonergic psychedelics include [[Dimethyltryptamine|DMT]], [[Lysergic acid diethylamide|LSD]], [[psilocybin]], and [[mescaline]]. The [[tryptamine]] psychedelics, such as [[Dimethyltryptamine|DMT]] and [[psilocybin]], structurally resemble [[serotonin]] itself. The [[phenethylamine]] psychedelics on the other hand, such as compounds of the [[2C (psychedelics)|2C]] family, more closely resemble the [[neurotransmitter]] [[dopamine]].
*Nichols, C. D., & Sanders-Bush, E. (2001). "Serotonin Receptor Signaling and Hallucinogenic Drug Action". Heffter Rev Psychedelic Res, 2, 73-79. https://web-beta.archive.org/web/20170110205041/https://heffter.org/docs/hrireview/02/chap5.pdf
*{{cite journal|last1=Halberstadt|first1=Adam L.|title=Recent advances in the neuropsychopharmacology of serotonergic hallucinogens|journal=Behavioural Brain Research|volume=277|year=2015|pages=99–120|issn=01664328|doi=10.1016/j.bbr.2014.07.016}}
*{{cite journal|last1=Beique|first1=J.-C.|last2=Imad|first2=M.|last3=Mladenovic|first3=L.|last4=Gingrich|first4=J. A.|last5=Andrade|first5=R.|title=Mechanism of the 5-hydroxytryptamine 2A receptor-mediated facilitation of synaptic activity in prefrontal cortex|journal=Proceedings of the National Academy of Sciences|volume=104|issue=23|year=2007|pages=9870–9875|issn=0027-8424|doi=10.1073/pnas.0700436104}}
*{{cite journal|last1=Winter|first1=J.C|last2=Fiorella|first2=D.J|last3=Timineri|first3=D.M|last4=Filipink|first4=R.A|last5=Helsley|first5=S.E|last6=Rabin|first6=R.A|title=Serotonergic Receptor Subtypes and Hallucinogen-Induced Stimulus Control|journal=Pharmacology Biochemistry and Behavior|volume=64|issue=2|year=1999|pages=283–293|issn=00913057|doi=10.1016/S0091-3057(99)00063-5}}
*Canal, C. E., & Murnane, K. S. (2017). The serotonin 5-HT2C receptor and the non-addictive nature of classic hallucinogens. Journal of Psychopharmacology, 31(1), 127-143. https://doi.org/10.1177/0269881116677104
==References==
==References==
<references/>
<references />
[[Category:Psychedelic]]
Latest revision as of 07:12, 10 March 2024
Psychedelic structural comparison diagram
Serotonergic psychedelics (also known as serotonergic hallucinogens) are a class of hallucinogenic substances with a method of action strongly tied to modifying the normal neurotransmission of serotonin in the central nervous system (CNS).
Serotonin, which is also referred to as 5-HT (from its chemical name 5-hydroxy-tryptamine), is a naturally-occurring monoamine neurotransmitter that is tied to functions including developmental, cardiovascular, gastrointestinal, and endocrine function, sensory perception, behaviors such as aggression, appetite, sex, sleep, mood, cognition, and memory, many of which have yet to be fully understood.[1]
The diagram above demonstrates the neural connections associated with sobriety in comparison to being under the influence of psilocybin as demonstrated through the use of MRI scans.
The width of the links is proportional to their weight and the size of the nodes is proportional to their strength. Note that the proportion of heavy links between communities is much higher (and very different) in the psilocybin group, suggesting greater integration[2]
Figure 1 - The figure shows a model in which hallucinogens, such as psilocin, LSD and DMT, increase extracellular glutamate levels in the prefrontal cortex through stimulation of postsynaptic serotonin 2A (5-HT 2A) receptors that are located on large glutamatergic pyramidal cells in deep cortical layers (V and VI) projecting to layer V pyramidal neurons.
This glutamate release leads to an activation of AMPA and NMDA receptors on cortical pyramidal neurons. In addition, hallucinogens directly activate 5-HT2A receptors located on cortical pyramidal neurons. This activation is thought to ultimately lead to increased expression of brain-derived neurotrophic factor (BDNF).[3]
This image shows how, with eyes-closed, much more of the brain contributes to the visual experience under LSD (right image) than under placebo (left image). The magnitude of this effect correlates with participants’ reports of complex, dreamlike visions.[4]
While the full mechanism of action is not understood, serotonergic psychedelics are known to exhibit partial agonist activity for various 5-HT receptors in a range of affinities and efficacies. As a result, they may be classified by their activity at different 5-HT sub-sites, such as 5-HT1A, 5-HT1B, 5-HT2A, etc.
Many serotonergic psychedelics, such as the family of tryptamines, have very strong structural similarities to serotonin itself. This partially explains the affinity they have for certain 5-HT sites. Most research suggests that the signature psychedelic effect is due to strong partial agonist activity at the 5-HT2A, and to a lesser extent, 5-HT2C and 5-HT1A receptors.[citation needed]
The cortico-striato-thalamo-cortical loops (also known as CSTC-loops) appear to be central to the function of psychedelics,[5] which are also regulated by the serotonergic system. These control loops connect brain areas like the frontal lobe, the striatum and the thalamus; they aggregate, process and forward internal and external information.
The disruption of the neurotransmitter balance causes these control loops to collapse overwhelmed, leading to the flooding of the frontal lobe with neuronal excitatory glutamate; internal and external stimuli as well as all kinds of non-conscious contents can freely move up to the cerebral cortex and appear as visions in consciousness.[6][7]
Furthermore, over-activation of the locus coeruleus and subsequent widespread norepinephrine secretion may occur, causing a perceived state of sensory transcendence and sometimes even intense spiritual or transpersonal experiences.
It is worth noting that selective serotonin reuptake inhibitors (a class of antidepressants including Paroxetine, Fluoxetine and Sertraline) can increase the dosage required for hallucinogenic effects in some people (based on anecdotal reports). Some users, however, have found this to be entirely untrue for them, so those who are using daily antidepressants should, at first, only attempt a common dosage.
Halberstadt, Adam L. (2015). "Recent advances in the neuropsychopharmacology of serotonergic hallucinogens". Behavioural Brain Research. 277: 99–120. doi:10.1016/j.bbr.2014.07.016. ISSN0166-4328.
Beique, J.-C.; Imad, M.; Mladenovic, L.; Gingrich, J. A.; Andrade, R. (2007). "Mechanism of the 5-hydroxytryptamine 2A receptor-mediated facilitation of synaptic activity in prefrontal cortex". Proceedings of the National Academy of Sciences. 104 (23): 9870–9875. doi:10.1073/pnas.0700436104. ISSN0027-8424.
Nichols, David E.; Nichols, Charles D. (2008). "Serotonin Receptors". Chemical Reviews. 108 (5): 1614–1641. doi:10.1021/cr078224o. ISSN0009-2665.
Canal, C. E., & Murnane, K. S. (2017). The serotonin 5-HT2C receptor and the non-addictive nature of classic hallucinogens. Journal of Psychopharmacology, 31(1), 127-143. https://doi.org/10.1177/0269881116677104
References
↑David E. Nichols and Charles D. Nichols, Serotonin Receptors. Chemical Reviews. 2008. 108 (5), 1614-1641. https://doi.org/10.1021/cr078224o
↑Petri, G., Expert, P., Turkheimer, F., Nutt, D., Hellyer, P. J., & Vaccarino, F. (2014). Homological scaffolds of brain functional networks, 14–18. https://doi.org/10.1098/rsif.2014.0873
↑Vollenweider, F. X., & Kometer, M. (2010). The Neurobiology of Psychedelic Drugs: Implications for the Treatment of Mood Disorders. Nature Publishing Group, 11(9), 642–651. https://doi.org/10.1038/nrn2884
↑Carhart-Harris, R. L., Muthukumaraswamy, S., Roseman, L., Kaelen, M., Droog, W., Murphy, K., … Nutt, D. J. (2016). Neural correlates of the LSD experience revealed by multimodal neuroimaging. Proceedings of the National Academy of Sciences. https://doi.org/10.1073/pnas.1518377113
↑Taylor, S. B., Lewis, C. R., & Olive, M. F. (2013). The neurocircuitry of illicit psychostimulant addiction: acute and chronic effects in humans. Substance Abuse and Rehabilitation, 4, 29–43. https://doi.org/10.2147/SAR.S39684; [..] The overall output of the basal ganglia is predominantly via the thalamus, which then projects back to the PFC to form cortico-striatal-thalamo-cortical (CSTC) loops. [..]
