Psychedelics

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

Psychedelics (also known as serotonergic hallucinogens) are a class of psychoactive substances that produce an altered state of consciousness marked by unusual changes in perception, mood, and cognitive processes.^[1] While their precise mechanism of action is not known, psychedelics are thought to produce their characteristic effects by binding to serotonin receptors (5-hydroxytryptamine or 5-HT), particularly the 5-HT_2a subtype. Serotonin plays a number of critical roles throughout the human body and is a key neurotransmitter involved in the functioning and regulation of sensory perception, behavior, mood, cognition and memory.^[2]

Human usage of psychedelics predates written history, and there is growing evidence that they were employed by early cultures in a variety of sociocultural and ritual contexts.^[1] In modern times, psychedelic substances are used for a number of purposes that span from the traditional shamanic forms (such as the use of ayahuasca in the Amazon jungle, or peyote among Native Americans) to more modern forms of New Age spiritual, transpersonal, or religious practices. Psychedelics, particularly those in the traditional or herbal forms, are sometimes referred to as entheogens (i.e. "generating the divine within")^[3] by those who use them for these purposes, although they are also often used in purely recreational settings.

Subjective effects can vary significantly depending on class, but generally include some form of open and closed-eye visuals, time distortion, enhanced introspection, conceptual thinking, euphoria, and ego loss. The so-called classical psychedelics, which consist of LSD, psilocybin mushrooms, mescaline, and DMT (ayahuasca) are considered to produce the archetypal psychedelic effects and also have the most established safety profiles. Psychedelics can be divided into three major sub-classes: tryptamines, lysergamides, and phenethylamines. Psychedelic tryptamines are based on, or derive from, dimethyltryptamine (DMT), lyergamides on LSD, and phenethylamines on mescaline.

Unlike other highly prohibited substances, most psychedelics have not been shown to be physiologically toxic and none have been shown to be addictive.^[1] However, adverse psychological reactions such as severe anxiety, paranoia, delusions, and psychosis are always possible, particularly for those predisposed to mental disorders.^[4] As a result, it is highly advised to use harm reduction practices if using these substances.

Etymology

The term "psychedelic" was coined by psychiatrist Humphry Osmond in 1956 as an alternative descriptor for hallucinogens in the context of psychedelic psychotherapy.^[5] 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^[6]

"Psychedelic" derives from the Greek words ψυχή (psyche, "soul, mind") and δηλείν (delein, "to manifest") which taken together mean "soul-manifesting." The implication was that psychedelics can allow one to access the soul and develop unused potentials of the human mind.^[7][8] It was on this term that Osmond eventually settled, because it was "clear, euphonious and uncontaminated by other associations."^[9] 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.^[10]

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 later proposed the term "entheogen" to describe the religious or spiritual experience produced by such substances.^[11]

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^[12]

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.^[13]

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 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).^[14]

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.^[15]

Subjective effects

Disclaimer: The effects listed below cite the Subjective Effect Index (SEI), a research literature based on anecdotal reports and the personal experiences of PsychonautWiki contributors. As a result, they should be regarded with a healthy degree of skepticism. It is worth noting that these effects will not necessarily occur in a predictable or reliable manner, although higher doses are more liable to induce the full spectrum of effects. Likewise, adverse effects become much more likely with higher doses and may include addiction, serious injury, or death.

Chemical classes

Psychedelic structural comparison diagram.

The "classical psychedelics" are all classed as serotonergic in nature.^[15] 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.^[17]

While more research is needed, most psychedelics (and especially classical psychedelics) appear to be physiologically well-tolerated and have very 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 unlikely to present negative physical, cognitive, psychiatric or other toxic consequences. There is no evidence that classical psychedelics cause damage to any human body organ.^[18] However it should be noted that some exceptions exist, such as some members of the 25x-NBOMe, 2C-T-x, DOB and 5-MeO series.

However, while psychedelics may not be capable of causing direct bodily harm or death, they can still have serious negative consequences. For example, they are capable of impairing the judgment and attention of users which may cause erratic or high-risk behaviors. In extreme cases, users may fall under the delusion that they are a character in a dream or physically invincible which may cause them to jump off of a building or run into a busy road.^[19] Additionally, intense negative experiences and psychotic episodes ("bad trips") can cause psychological trauma if not properly managed or treated. This is particularly a concern in non-supervised settings or when heavy doses are used.

Psychedelics may trigger or exacerbate symptoms (e.g. delusions, mania, psychosis) in those who have or are predisposed to mental illness such as bipolar disorder or schizophrenia.^[20] Those with a personal or family history of mental illness (including anxiety and depression) should not use LSD without the advice of a qualified medical professional.

Lethal dosage

Unlike many other illicit substances, psychedelics typically 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, 2C-T-x, and 5-MeO series.

Dependence and abuse potential

Psychedelics are considered to have low abuse potential.^[20] There are no literature reports of successful attempts to train animals to self-administer psychedelics — an animal model predictive of abuse liability — indicating that it does not have the necessary pharmacology to either initiate or maintain dependence.^[20] Likewise, there is no human clinical evidence that psychedelics cause addiction. Finally, there is virtually no withdrawal syndrome when chronic use of these substances is stopped.^[21]

Tolerance to the effects of most psychedelics builds almost immediately after ingestion and hits a 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 all psychedelics, meaning they 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 reasonably safe to use on their own, they can suddenly become dangerous or even life-threatening when combined with other substances. The following list includes some known dangerous combinations (although it is not guaranteed to include all of them). Independent research (e.g. Google, DuckDuckGo) should always be conducted to ensure that a combination of two or more substances is safe to consume. Some of the listed interactions have been sourced from TripSit.

• Lithium - Lithium is commonly prescribed for the treatment of bipolar disorder. There is a large body of anecdotal evidence that suggests taking it with psychedelics significantly increases the risk of psychosis and seizures. As a result, this combination is strictly discouraged.
• Cannabis - Cannabis may have an unexpectedly strong and unpredictable synergy with the effects of Psychedelics. Caution is advised with this combination as it can significantly increase the risk of adverse psychological reactions like anxiety, paranoia, panic attacks, and psychosis. Users are advised to start off with only a fraction of their normal cannabis dose and take long breaks between hits to avoid unintentional overdose.
• Stimulants - Stimulants like amphetamine, cocaine or methylphenidate affect many parts of the brain and alter dopaminergic function. This combination can increase the risk of anxiety, paranoia, panic attacks, and thought loops. This interaction may also result in an elevated risk of mania and psychosis.^{[citation needed]}
• Tramadol - Tramadol is well-documented to lower the seizure threshold^[22] and psychedelics may act to trigger seizures in susceptible individuals.^{[citation needed]}

See also

• Responsible use
• 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
• Elsey, J. W. (2017). Psychedelic drug use in healthy individuals: A review of benefits, costs, and implications for drug policy. Drug Science, Policy and Law, 3, 2050324517723232. https://doi.org/10.1177/2050324517723232

References