Psychedelics

Oversoul by Alex Grey - An example of psychedelic artwork created by the renowned artist known as Alex Grey. This image is a representation of an experience report found within the 1901 book Cosmic Consciousness

Psychedelics (also known as serotonergic hallucinogens) are a class of psychoactive substances that produce profound alterations in perception, mood and numerous cognitive processes.^[1]

Psychedelics exert their effects primarily by binding to and activating the receptors for serotonin (5-hydroxytryptamine or 5-HT), particularly the 5-HT_2a receptor. Serotonin plays a number of critical roles all throughout the human body and is a key neurotransmitter involved in the functioning and regulation of sensory perception, behavior, mood, cognition and memory.^[2]

The term "psychedelic" was coined by the British psychiatrist Humphrey Osmond in 1956. It derives from the Greek words ψυχή (psyche, "soul, mind") and δηλείν (delein, "to manifest") which taken together mean "soul-manifesting," with the implication being that psychedelics can allow one to access the soul and develop unused potentials of the human mind.^[3][4]

Unlike most highly prohibited substances, psychedelics are generally considered to be physiologically safe and non-addictive by the scientific community.^[1]

The use of psychedelics predates written history, and they were employed by early cultures in many sociocultural and ritual contexts.^[1] In modern times, psychedelic substances are used in a range of contexts spanning from the shamanic, religious and "spiritual", or the transpersonal. They are sometimes referred to as entheogens (i.e. "generating the divine within")^[5] by those who use them for these purposes, although they are also used in purely recreational settings.

Etymology

The term "psychedelic" was first coined in 1956 by psychiatrist Humphry Osmond as an alternative descriptor for hallucinogenic substances in the context of psychedelic psychotherapy.^[6] Seeking a name for the experience induced by LSD, Osmond contacted Aldous Huxley, a personal acquaintance and advocate for the therapeutic use of the substance. Huxley coined the term "phanerothyme," from the Greek terms for "manifest" (φανερός) and "spirit" (θύμος). In a letter to Osmond, he wrote:

To make this mundane world sublime,

Take half a gram of phanerothyme

To which Osmond responded:

To fathom Hell or soar angelic,
Just take a pinch of psychedelic^[7]

It was on this term that Osmond eventually settled, because it was "clear, euphonious and uncontaminated by other associations."^[8] This mongrel spelling of the word 'psychedelic' was loathed by American ethnobotanist Richard Evans Schultes, but championed by Timothy Leary, who thought it sounded better.^[9] Due to the expanded use of the term "psychedelic" in pop culture and a perceived incorrect verbal formulation, Carl A.P. Ruck, Jeremy Bigwood, Danny Staples, Jonathan Ott, and R. Gordon Wasson proposed the term "entheogen" to describe the religious or spiritual experience produced by such substances.^[10]

Method of action

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^[11]

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.^[12]

Figure 1 - Activation of the prefrontal network and glutamate release by psychedelics. The figure shows a model in which hallucinogens, such as psilocin, lysergic acid diethylamide (LSD) and dimethyltryptamine (DMT), increase extracellular glutamate levels in the prefrontal cortex through stimulation of postsynaptic serotonin (5-hydroxytryptamine) 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 (α-amino-3-hydroxy-5-methyl-4- isoxazole propionic acid) and NMDA (N-methyl-d-aspartate) 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).^[13]

Psychedelics act on serotonin receptors (also referred to as 5-HT receptors) via the way in which they act as full or partial agonists through their structural similarity to the serotonin molecule. It has a higher affinity than serotonin itself for the receptors, therefore preventing serotonin from binding to the receptors by competing with it.

While the method of action behind psychedelics is not fully understood, serotonergic psychedelics are known to show affinities for various 5-HT receptors and may be classified by their activity at different 5-HT subsites, such as 5-HT_1A, 5-HT_1B, 5-HT_2A, etc.

Many serotonergic psychedelics share very close chemical and structural similarities to serotonin itself. There is a consensus that serotonergic psychedelics produce their effects by acting as uniquely effective partial agonists at 5-HT_2A receptor sites.^[14]

Subjective effects

The effects listed below are based upon the subjective effects index and personal experiences of PsychonautWiki contributors. These effects should be taken with a grain of salt and will rarely (if ever) occur all at once, but heavier doses will increase the chances of inducing a full range of effects. Likewise, adverse effects become much more likely on higher doses and may include serious injury or death.

Pharmacological classes

Psychedelic structural comparison diagram.

The "classical psychedelics" are all classed as serotonergic in nature.^[14] This means that they structurally mimic the endogenous neurotransmitter known as serotonin, the neurotransmitter that regulates higher-level brain functions such as mood, sensory perception, cognition, and memory.^[2]

The diagram to the right shows the structural similarities and differences between the various classes of psychedelics and the serotonin neurotransmitter. The three classes (phenethylamines, lysergamides and tryptamines) all contain the same chemical rings (which have been labeled).

• A represents the benzene ring, which all three classes contain.

• B represents the pyrrole ring in both tryptamines and lysergamides.

• A and B together form the indole ring.

• C (cyclohexane) and D are only contained in the lysergamides, possibly contributing to their potency.

Examples

Toxicity and harm potential

Radar plot showing relative physical harm, social harm, and dependence of LSD and psilocybin, which can tentatively be taken to apply psychedelics as a whole.^[16]

Psychedelics are considered to be non-addictive, do not cause brain damage, and tend to have an extremely low toxicity relative to dose.^[1]

Most psychedelics have very few physical side effects associated with acute exposure. Various studies have shown that in reasonable doses in a sufficiently prepared context, they are very unlike to present negative physical, cognitive, psychiatric or other toxic consequences. There is no evidence that any psychedelics causes damage to any human body organ.^[17]

However, they can act as a potential trigger for those with underlying psychiatric conditions, so those with a family history of mental illness are generally advised not to use these substances.

Lethal dosage

Psychedelics do not have established lethal dosages. There are no well-documented deaths attributable to the direct pharmacological action of any psychedelic, with the notable exception of the 25x-NBOMe series.

Tolerance and addiction potential

Psychedelics are not habit-forming and the desire to use them can actually decrease with use. They are generally considered to be self-regulating aspect, although cases of dependence and addiction have been recorded.^{[citation needed]} Notably, there is virtually no withdrawal syndrome when the chronic use of these substances have ceased.^[18]

Tolerance to the effects of most psychedelics is built almost immediately after ingestion and hits peak once the effects wear off. After that, it takes about 5-7 days for the tolerance to be reduced to half and 1-2 weeks to be back at baseline (in the absence of further consumption). Most psychedelics present cross-tolerance with one another, meaning that after the use of certain psychedelics all will have a reduced effect.

Notable exceptions to this include DMT and related tryptamines like DPT and MET, which are thought to produce little to no tolerance or cross-tolerance.

Another exception includes psychedelic phenethylamines like 2C-B. While the exact mechanism is not understood, generally tolerance is thought to rise immediately, but does not reach a peak unless with prolonged and repeated use. This means that the immediate tolerance does not rise as high as with lysergamides or tryptamines and can wear off faster and can be reduced to half within 1-2 days in the absence of further consumption. Mostly there will be less psychedelic and more stimulating effects.

Extremely high doses of psychedelics can also produce a tolerance which can last a significantly longer time than expected.

Dangerous interactions

Although many psychoactive substances are safe to use on their own, they can become dangerous or even life-threatening when taken with other substances. The list below contains some potentially dangerous combinations, but may not include all of them. Certain combinations may be safe in low doses but still increase the possibility of injury of death. Independent research should always be conducted to ensure that a combination of two or more substances is safe before consumption.

• Lithium - Lithium is often used as treatment for bipolar disorder. It can dangerously amplify the intensity of psychedelics and has been strongly linked with psychosis and seizures. The causes are poorly understood, but it may be due to its glutaminergic and GABAergic properties.^{[citation needed]}
• Stimulants - Stimulants affect many parts of the brain. Combined with psychedelics, stimulation can turn into uncontrollable anxiety, panic, thought loops and paranoia. This interaction may cause elevated risk of psychosis.^{[citation needed]}
• Tramadol - Tramadol lowers the seizure threshold^[19] and psychedelics may act as triggers for seizures, particularly in those who are predisposed to them.^{[citation needed]}

Responsible use

The information below describes and explains various concepts regarding the responsible use of psychedelic substances. These should be read over and carefully considered before one decides whether or not the potential benefits of experimenting with psychedelics outweighs the potential risks.

See also

• Hallucinogen
• Dissociative
• Deliriant
• Serotonin

External links

• Psychedelics (Wikipedia)

Literature

• Nichols, D. E. (2016). Psychedelics. Pharmacological Reviews, 68(2), 264-355. https://doi.org/10.1124/pr.115.011478
• Geyer, M. A., Nichols, D. E., & Vollenweider, F. X. (2009). Serotonin-Related Psychedelic Drugs. Encyclopedia of Neuroscience. https://doi.org/10.1016/b978-008045046-9.01160-8
• Preller, K. H., & Vollenweider, F. X. (2016). Phenomenology, Structure, and Dynamic of Psychedelic States. https://doi.org/10.1007/7854_2016_459
• 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., & Goodwin, G. M. (2017). The Therapeutic Potential of Psychedelic Drugs: Past, Present, and Future. Neuropsychopharmacology. https://doi.org/10.1038/npp.2017.84
• 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
• Johansen, P. Ø., & Krebs, T. S. (2015). Psychedelics not linked to mental health problems or suicidal behavior: A population study. Journal of Psychopharmacology, 29(3), 270-279. https://doi.org/10.1177/0269881114568039

References