Definitions And Scope- PSYCH: The Psychedelics As Medicine Report 3rd Edition

Serotonin (5-HT)

Serotonin is a crucial hormone found in the brain, gut, and throughout the central nervous system (CNS). In the brain, it serves a role as a neurotransmitter, or neuromodulator, and is involved in functions related to mood, cognition, learning, memory and happiness. Many conventional antidepressant drugs work by selectively inhibiting the reuptake of serotonin (SSRIs). Through that process, there is more serotonin available to improve the transition of messages between neurons. Many psychedelics work by agonising, binding to serotonin receptors, especially in neocortical pyramidal cells, and through that mechanism changing how the serotonergic system works. The complex effects of serotonin are mediated through 7 receptor types and at least 14 subtypes. Psychedelics usually influence either the 5-HT2a or 5-HT1a receptors.

Indole alkaloid

An alkaloid is a naturally occurring, organic, nitrogen-containing compound found in more than 4,000 species of plants, which has diverse physiological effects on humans. An indole alkaloid is a particular classification of alkaloid that has a chemical structure containing a ring system called indole. Examples of indole alkaloids include serotonin, and psychedelics such as psilocybin mushrooms, iboga, LSD and tryptamines such as DMT (dimethyltryptamine). Codeine and morphine (as well as nicotine) are well-known commonplace examples of pharmaceuticals derived from plant alkaloids.

Psychedelics

Psychedelics, or hallucinogens, are psychoactive substances that powerfully alter perception, mood, and a host of cognitive processes. They are considered physiologically safe and do not produce dependence or addiction. Psychedelics can cause changes in perception, thought and feeling, ranging from visual distortions (illusions) to imagining things that are not there (hallucinations). Psychedelics heighten sensory inputs (bottom-up) and lower the influence of preconceived ideas (top-down). Most psychedelics profiled in this report are serotonergic psychedelics, exerting their influence via the serotonergic pathways in the brain. MDMA (an empathogen), ibogaine, ketamine, and salvinorin A being notable exceptions that mainly work via changing other systems.

Psilocybin (‘magic’ mushrooms)

Psilocybin is a psychoactive substance derived from psilocybe mushrooms (such as Psilocybe Mexicana). It is an indole alkaloid that, when converted to psilocin, has psychedelic properties. It is thought that psilocin acts mainly by activating the 5-HT2a receptors. Psilocybin can be synthetically manufactured and was first isolated in a laboratory in the 1950s. The mental health care company COMPASS Pathways has successfully patented a synthetically derived psilocybin derivative known as COMP360.

Ibogaine

Ibogaine is a psychoactive substance extracted from the bark of the root of an African rainforest shrub called Tabernanthe Iboga. Ibogaine is an indole alkaloid that has psychedelic properties. Ibogaine was isolated from the plant in 1901 and was synthesised in 1966. In small doses, it acts as a general stimulant. A synthetically derived substance similar to ibogaine, called 18-MC, is also being investigated for its anti-addictive properties.

Mescaline (peyote)

Mescaline is a naturally occurring psychoactive substance derived from the flowering heads of the peyote cactus and is found in Mexico and in southwestern United States. San Pedro and Peruvian Torch are examples of other cacti that contain mescaline. Mescaline is an alkaloid that has psychedelic properties. The mescaline molecule is of similar structure to two hormones produced in the human adrenal gland, adrenaline and noradrenaline. Mescaline can also be synthetically manufactured. It was first isolated from the peyote plant in 1896.

Ayahuasca

Ayahuasca is a brew made from a blend of different plants, primarily the Banisteriopsis caapi (ayahuasca or yagé) vine and Psychotria viridis (chacruna) shrub, which contains DMT. So, unlike DMT, which is most commonly smoked, ayahuasca is a liquid preparation, consumed orally as a ‘tea’. Ayahuasca contains chemicals (MAOIs – monoamine oxidase inhibitors) that prevent the stomach from breaking down DMT and which prolong the effect of DMT. If ayahuasca is synthesised it is sometimes named pharmahuasca.

DMT

DMT (dimethyltryptamine) is a naturally occurring chemical found at low concentrations in many plants, animals and humans. When taken in concentrated doses, it is a powerful psychedelic. It is ordinarily the central active ingredient in ayahuasca. DMT is thought to act by activating 5-HT2a receptors. It can also be synthetically manufactured.

5-MeO-DMT

5-MeO-DMT is a tryptamine alkaloid that was first synthesised in 1936. The compound is found in both plant and animal sources, including high concentrations in the parotid gland secretions of the Colorado River toad, Bufo alvarius. The psychedelic effects of oral ingestion are both fast-acting and short-lived. A UK-based company, Beckley Psytech, is exploring the use of 5-MeO-DMT for the treatment of a variety of neuropsychiatric disorders.

LSD

LSD belongs to a chemical group named lysergamides, which have both phenethylamine and tryptamine (such as psilocybin) groups embedded within their structure.

MDMA

MDMA is a synthetic stimulant of the central nervous system (CNS) derived from amphetamine. It is closely related in structure to another stimulant, methamphetamine. MDMA shares a similar chemical structure to mescaline, which is found in the peyote cactus and is referred to as an ‘entactogen’ (this translates as ‘touching within’) and as an ‘empathogen’ (which means it can generate empathy).

Ketamine

Ketamine was first synthesised in 1962 and is used most commonly in veterinary practice as an animal tranquilliser. However, it has practical medical applications as a general anaesthetic and sedative in human patients, especially in children and in patients who have compromised respiratory systems. Ketamine is also a powerful psychoactive substance and antidepressant. It is available in liquid-soluble form as ketamine hydrochloride and is marketed in both Europe and North America by numerous companies, including Endo Pharmaceuticals and Pfizer, under the brand names Ketalar/Ketanest.

Esketamine

Esketamine is the S(+) enantiomer of ketamine, which is one half of the two mirror images that make up (racemic) ketamine. It is currently unknown if esketamine is superior to ketamine or arketamine (R(–) enantiomer) for the treatment of depression. A subsidiary of Johnson & Johnson has received FDA (Food and Drug Administration) approval to manufacture a nasal spray to treat treatment-resistant depression (TRD) under the brand name Spravato.

Salvia divinorum

Salvia divinorum is a species of plant native to Mexico. Little is known about the toxicology, adverse events, and safety, as little clinical research has been undertaken with salvia. It has psychedelic effects when consumed by chewing, smoking, or when drunk as tea. The chemical structure of salvia is distinct from other psychedelics, and it is a potent k-opioid receptor, so not a serotonin receptor agonist. Revixia Life Sciences, an entity of clinical-stage biopharmaceutical company atai Life Sciences, is developing a proprietary formulation of Salvinorin A, RLS-01, as a medication for TRD.

Breakthrough Therapy Designation

If the United States FDA awards a substance/treatment Breakthrough Therapy designation (BTD), this means the FDA will expedite the substance’s development and review process because clinical evidence has shown that it may offer a substantial improvement over existing therapies. BTD has been given to COMPASS Pathways and Usona Institute to develop psilocybin to treat depression, to the Multidisciplinary Association for Psychedelic Studies (MAPS) which is developing MDMA to treat post-traumatic stress disorder (PTSD), and to Janssen & Janssen for the treatment of TRD with Spravato.