A glossary of terms you may come across in the psychedelic space, including relevant regulatory and clinical trial terminology.
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A type of receptor in the brain that is responsive to serotonin. This specific subtype of receptor is thought to play a pivotal role in engendering the psychedelic experience, as it is the target of serotonergic or ‘classic’ psychedelics such as LSD and psilocybin. You may see these psychedelics described as 5-HT2A agonists, which means they bind to the receptor, generating a biological response. As such, 5-HT2A receptors are of great interest to psychedelic researchers in particular (see this piece in Psychology Today for further information).
A psychedelic drug that is found in the secretions of the Sonoran Desert Toad, and a number of plant species. The psychedelic experience precipitated by ingestion of 5-MeO-DMT is brief in comparison to others psychedelics, often lasting for just 20 minutes, for example. Beckley Psytech is seeking to advance development of the drug for neuropsychiatric diseases.
Ibogaine derivative invented in 1996, which shows potential as a treatment for various types of drug abuse. MindMed is exploring the derivative in clinical trials, as a treatment for opioid use disorder.
A set of regulations instituted in 1992 by the FDA. The process allows for expedited approval of drugs that treat serious conditions, “and that fill an unmet medical need based on a surrogate endpoint. A surrogate endpoint is a marker, such as a laboratory measurement, radiographic image, physical sign or other measure that is thought to predict clinical benefit, but is not itself a measure of clinical benefit (i.e., a proxy of sorts). The use of a surrogate endpoint can considerably shorten the time required prior to receiving FDA approval” (FDA). Phase 4 confirmatory trials are still required (see Phase IV, below). Should these trials confirm the drug provides the expected clinical benefit, the FDA approves the drug in the conventional manner. However, should the confirmatory trials fail to demonstrate clinical benefit, the FDA may remove the drug from the market.
Active placebos are designed to trick a study participant into believing they have received the psychoactive drug under investigation. Niacin is a popular choice among psychedelic researchers, as it produces a tingling sensation. Active placebos are particularly useful in trials and studies involving the use of psychedelics, as otherwise the very existence of psychoactive effects would likely compromise the blinding of the trial.
A state characterized by positive physical and mental effects that persists after the primary effects of a drug have subsided, described by Walter Pahnke as period of ‘elevated and energetic mood with a relative freedom from concerns of the past and from guilt and anxiety.’ During the afterglow period, the effectiveness of psycho-therapeutic interventions is reported to be enhanced until the afterglow gradually subsides after a period of between two weeks and a month (see Majić et al., 2015 for discussion).
Partial – A partial agonist will activate a receptor, but only have partial efficacy compared to a full agonist. For example, fentanyl is a full mu opioid receptor agonist that can elicit maximal receptor response, while buprenorphine (an opioid use disorder management drug) is a partial mu opioid receptor agonist.
Inverse – An inverse agonist will bind to a receptor at the same site as an agonist but induce a pharmacological response that is opposite to that of the agonist. One requisite is that the receptor must have basal levels of activity, such that an agonist will increase activity, and an inverse agonist will decrease activity. Note that the effects of both can be blocked with an antagonist.
A medication (or other intervention) that reduces anxiety. The antonym is anxiogenic; agents that increase anxiety.
A brew made from a mixture of plants native to the Amazon basin, which is used by indigenous peoples of South America as a sacrament. The brew typically contains Banisteriopsis caapi vine and the Psychotria viridis shrub, also known as chacruna. The former contains MAOIs, which orally activate the DMT in the latter. A broad range of other species of plant contain DMT, so the mixture is not always as such.
In a landmark 2006 decision (Gonzales v. O Centro Espírita Beneficente União do Vegetal; notes on the case) the U.S. Supreme Court allowed the use of ayahuasca by the União do Vegetal, or Union of the Plants, a religious society founded in 1961. The decision was made in light of the Religious Freedom Restoration Act, and a Santo Daime Church in both Orgeon and Montreal have since received exemptions to use ayahuasca.
The Beckley Foundation
Psychedelics-focused drug policy reform think tank and NGO founded in 1998, based in Oxford, UK (website).
Breakthrough Therapy Designation
A process designed to expedite the development and review of drugs intended to treat a serious condition. Awarded when preliminary clinical evidence indicates that the new therapy has the potential to provide substantial improvement over available therapies (FDA).
Psilocybin-assisted therapy (twice: COMPASS Pathways and Usona Institute) and MDMA-assisted therapy (MAPS) have both received this designation. Spravato, an esketamine nasal spray product for the treatment of depression, received a Breakthrough Therapy designation, and was approved in 2019 (FDA).
Center for Drug Evaluation and Research (CDER)
FDA Division tasked with ensuring “that safe and effective drugs are available to improve the health of people in the United States”. CDER’s remit covers all prescription, generic, and over-the-counter drugs – including fluoride toothpaste, sunscreen, etc. (FDA).
Centre for Psychedelic Research, Imperial College London
A research Centre based at Imperial College London that seeks to explore the use of psychedelics in mental health care, and to harness psychedelics “as tools to probe the brain’s basis of consciousness.” The Centre is led by Dr Robin Carhart-Harris.
Short, but incredibly painful headaches that can occur on a daily basis for weeks, or even months, at a time. Unlike a typical headache, cluster headaches are concentrated on one side of the head and are often accompanied by other symptoms including, but not limited to, irritated eyes, runny nose, and facial sweating.
Psychedelics, including psilocybin and LSD, are being examined as possible treatments (see, for example, Andersson et al., 2017; see also Cluster Busters, a nonprofit supporting research for better treatment for cluster headaches, including psychedelics).
Controlled Drugs and Substances Dealer’s License (Canada)
Certification provided by Health Canada under the Controlled Drugs and Substances Act (CDSA). A dealer’s license allows for the procurement (through synthesis, importation, cultivation, and harvest), research and manufacture, business to business sale, and the pharmaceutical sale of controlled substances.
Controlled Substances Act (CSA)
Statute, signed into law in 1970 by Nixon, establishing federal U.S. drug policy regulating certain substances according to five schedules (or, classifications). Each schedule carries associated restrictions and penalties, with Schedule I being the most severe. LSD, psilocybin, psilocin, mescaline, peyote, MDMA, cannabis, and DMT became Schedule I drugs, labeling them as ‘drugs with no currently accepted medical use and a high potential for abuse.’
Default Mode Network (DMN)
A brain network most active when the brain is in a state of wakeful rest: daydreaming, for example. The network is also active when an individual is engaging in self-reflection, thinking about the past, planning for the future, etc. (see Andrews-Hanna, 2011). Research has linked both a hyperactive and less active DMN to mental health conditions.
Some psychedelics, including psilocybin, have a significant effect on the DMN. Research by Lebedev et al. (2015) suggests that the consumption of psilocybin causes a rapid dissolution of the connections that characterize the DMN. This has been associated with the common experience of ego-dissolution when using psychedelics.
Digital Therapeutics (DTx)
A broad category encompassing treatments or therapies that employ digital health technologies to improve health outcomes. According to the Digital Therapeutics Alliance: “Digital therapeutics deliver evidence-based therapeutic interventions to patients that are driven by high quality software programs to prevent, manage, or treat a broad spectrum of physical, mental, and behavioral conditions.” See this Nature article for further context.
Dissociative anaesthetics are a class of hallucinogens that produce notable effects such as depersonalization (separation of the self from the body), derealization (belief that the natural world is not real), hallucinations and sensory deprivation. NMDAR antagonists such as ketamine and PCP induce dissociative anaesthesia. While these drugs have been preferentially used as general anaesthetics, they have also been investigated for their antidepressant properties in the treatment of suicide ideation and major depressive disorder (MDD).
A hallucinogenic compound found in many plants and animals, and included in ayahuasca brews (see above). A DMT trip is considerably shorter than that of other psychedelics, often lasting just 15 minutes (see Kaplan et al., 1974). While short, the effects are often intense (see Carbonaro and Gatch, 2016).
Dopamine is a neurotransmitter released by axon terminals that has widespread regulatory function in the brain. The molecule contributes to movement, learning, reward valence, motivation, mood states, and predicting internal states.
While dopamine is most attributed to pleasure by the media and public, the more nuanced pharmacological view is that it contributes to motivational salience – the neurotransmitter will modulate how an organism views predictors of an outcome (whether it was desirable or aversive) and thus, either propel it to further achieve or avoid the predictor that achieves the outcome. This theory of dopamine can be applied to drug-taking behaviour, but also to other facets of learning.
Psychoactive drugs that generate feelings of empathy or sympathy in the subject, such as feelings of oneness, emotional openness, etc. MDMA is the drug most commonly associated with this class.
A word for psychedelics, coined in 1979 (Ruck et al., 1979), that is generally reserved for their use in spiritual, sacred contexts. The word was coined in an attempt to rebrand psychedelics, and place it in its historical context as a ceremonial, spiritual tool.
Fast Track (FDA Designation)
“A process designed to facilitate the development, and expedite the review of drugs to treat serious medical conditions and fill an unmet medical need.” In order to fill an unmet medical need, one must provide a therapy where none exists, or provide a therapy that may be potentially better than available therapy (FDA).
Forced Swim Test (FST)
The forced swim test is a preclinical behavioural test employed in rodents to study motivation and apathy. In this paradigm, rodent behaviour is manipulated via either a drug, surgical ablation or device and placed in a bucket of water. It is thought that the amount of time animals spend immobile correlates to levels of apathy, reduced motivation, and depressive behaviour. Many anti-depressive drugs for example, such as SSRIs, have increased the amount of time depressed rodents swim in the forced swim test, further validating the drug’s efficacy in reducing depressive states or behaviours.
GMP/cGMP (Good Manufacturing Practices)
A series of practices devised to ensure coherence to guidelines recommended by agencies that control the manufacture and sale of items including pharmaceuticals and medical devices, such as the FDA. These regulations work to ensure the identity, strength, quality, and purity of drug products. Designed to be flexible, GMP regulations are minimum requirements, and many drug development companies use innovative approaches and technologies that surpass given GMP standards.
A subclass of psychoactive drugs that generally causes hallucinations.
Head-Twitch Response (HTR)
A rapid side-to-side head movement observed in rats and mice when the 5-HT2A receptor (see above) is activated. As such, the HTR is often observed following the administration of serotonergic hallucinogens (see Halberstadt and Geyer, 2013).
A naturally occurring psychoactive substance with dissociative properties found in plants such as Tabernanthe iboga. While it has historical roots in healing ceremonies and initiations in West Africa, the psychoactive is also used in efforts to overcome substance misuse and addiction via the temporary elimination of cravings.
A medical condition that makes a particular treatment or procedure advisable. Examples include major depressive disorder, treatment-resistant depression, cluster headaches, and PTSD.
Investigational New Drug (IND)
A request for authorization from the Food and Drug Administration (FDA) to administer an investigational drug or biological product to humans (see FDA). This is the process through which companies obtain permission to initiate human clinical trials, and to facilitate interstate shipment of experimental drugs (e.g., to trial sites).
A synthetic compound generally used as a dissociative anesthetic. Its fast-acting pain relief and short-term memory loss properties make it a popular anesthetic for medical procedures and injuries sustained in combat environments. More recently, lower doses of ketamine are being used to tackle treatment-resistant depression, with one of its enantiomers (esketamine) approved as a nasal spray for this indication in the United States.
LSD (lysergic acid diethylamide)
A psychedelic compound first synthesized by Albert Hofmann in 1938. Hofmann accidentally ingested a small quantity of the drug while resynthesizing it five years after shelving it, and discovered its hallucinogenic properties. This marked the first intentional ingestion of LSD, with the day—April 19, 1943—now celebrated annually as Bicycle Day. LSD is colloquially known as acid.
LSD was used to assist psychotherapy in the 1950s and 1960s, but studies conducted at the time lacked rigour. More recently, MAPS completed a Phase 2 double-blind placebo-controlled study of LSD-assisted psychotherapy for anxiety (n=12), with positive results (Gasser et al., 2014). In 2020, MindMed launched Project Lucy, focused on LSD-assisted therapy for the treatment of anxiety disorders.
The psychoactive Sclerotia of psilocybin mushrooms. Sclerotia is a dense mass of hardened fungal mycelium which contains food reserves. They contain a lower dose of psilocybin than magic mushrooms, resulting in a short, yet impactful trip. Magic truffles may be purchased legally in the Netherlands.
Major Depressive Disorder (MDD)
Often referred to as ‘depression’. MDD is one of the most common mental health disorders in the United States, and across the world. Where pervasive low mood persists for at least two weeks, a diagnosis may be made. Affecting over 165 million people annually, MDD is onset by a combination of genetic, environmental, and physiological factors.
A particularly relevant clinical study examining the ability of psilocybin-assisted therapy to treat MDD was released in 2020 by the Center for Psychedelic and Consciousness Research at Johns Hopkins (Davis et al., 2020).
MAPS (Multidisciplinary Association for Psychedelic Studies)
Founded by Rick Doblin in 1986, MAPS is a nonprofit seeking to raise awareness and understanding of psychedelics. MDMA has been the primary focus of MAPS in recent years, specifically in the treatment of PTSD. To this end, MAPS received FDA approval to initiate Phase 3 trials in 2016, before the Agency went on to designate MDMA as a breakthrough therapy for PTSD.
MDMA was first synthesized by pharmaceutical juggernaut Merck in 1912, but never came to market. Sixty years later, in the 1970s, Sasha Shulgin resynthesized it in his Bay Area home. This time, its empathogenic qualities (see empathogen above) were harnessed to augment psychotherapy, assisting in the building of trust between the therapist and the therapised. Despite the fact that the drug has been Schedule 1 in the United States since the late 1980s, MAPS (see above) has demonstrated its efficacy in the treatment of PTSD, landing MDMA a Breakthrough Therapy designation from the FDA.
A naturally-occurring psychedelic, found in the peyote and San Pedro cactus (among other cactus species). Arthur Heffter first isolated and identified the compound in 1897, and it was first synthesized by Ernst Späth in 1918. Writer and philosopher Aldous Huxley recounted his experience with mescaline in The Doors of Perception (1954).
The ingestion of a sub-perceptual dose of a psychedelic (often psilocybin or LSD) with the aim of augmenting mental performance and/or mental health.
Mystical Experience Questionnaire
A self-reported measure, in the form of a survey, used by researchers to understand whether a participant had a mystical experience (e.g., after ingesting psychedelics in a trial). The conventional version, which has 43 items, was developed by Walter Pahnke and William Richards in the 1960s. A revised version, including 30 items, was validated in 2015 (Barrett et al., 2015) and is often used in contemporary research.
Neuroplasticity is the brain’s ability to adapt, modify, and change structure through the growth and reorganisation of neural networks in the organ. Psychedelics such as LSD, DMT, ketamine, and psilocybin have been found to promote neuroplasticity (Ly et al., 2018), one of the reasons why they may provide a novel means of treating mood and anxiety disorders.
New Drug Application (NDA)
The NDA is the vehicle through which drug sponsors formally propose that the FDA approve a new pharmaceutical for sale and marketing in the United States (FDA). The NDA should provide sufficient information to convince the FDA that the drug is safe and effective; that the labeling is appropriate; and that the methods of manufacture, and quality control, are adequate.
NMDA Receptor (NMDAR)
The N-Methyl-D-aspartic acid receptor (NMDAR) requires coactivation of glutamate and glycine as well sufficient neuronal excitation to remove the magnesium blocking the pore. Indeed, its activation is mechanistically complex.
NMDARs play a significant role in memory, learning, and synaptic plasticity. The activity of this receptor is affected by many psychoactive drugs such as alcohol, PCP, and ketamine. Notably, NMDAR antagonists like ketamine, PCP and NO are thought to have anaesthetic properties through this mode of action.
Observational studies or investigations are frequently used in the social sciences to understand relationships or associations in a target sample population where the independent variable is not under the control of the researcher. This method is typically employed when studying human psychology or behaviour in a naturalistic environment, for example.
Open Field Test (OFT)
The open field test (OFT) is a preclinical behavioural test where rodents are placed in an open and novel environment. Since rodents are naturally exploratory animals, the amount of time they spend immobile with a preference near to walls (thigmotaxis), is thought to correlate to greater levels of anxiety and stress.
Open label clinical trials are designed when both the researcher and the participant are aware of the treatment to be received (control/placebo or test drug in a two-arm clinical design). This type of trial design is converse to double blind studies in which neither the researcher nor the participant are aware of the treatment to be received. It is notable that regardless of the trial design, the type of treatment to be received can still be randomized.
Orphan Drug Designation
A special status granted to a drug or biological product under the Orphan Drug Act (ODA). In order to receive orphan designation, a drug must be intended for the treatment, prevention or diagnosis of a rare disease or condition – one that affects less than 200,000 persons in the US or meets cost recovery provisions of the act (FDA).
Phase I (Clinical Trial)
Phase I clinical trials are intended to establish initial safety in humans. The drug is given to a small number of healthy volunteers to test for possible side effects and determine what the safe dosing range is.
Phase II (Clinical Trial)
Phase II clinical trials are the first in which the drug is tested in a small group of patient volunteers with the disease it is meant to treat. Phase II studies assess the safety and efficacy of the drug across a range of doses. Due to the small number of patients involved, conclusions about overall efficacy cannot be drawn, however Phase II trials provide guidance on how to optimally design larger Phase III trials to confirm the drug’s safety and efficacy.
Phase III (Clinical Trial)
Phase III trials, also known as pivotal trials, demonstrate a drug’s safety and efficacy in a large group of patients. Typically, at least two successful Phase III trials are required in order to provide sufficient evidence of efficacy. Given the large number of patients required, Phase III trials are most often multi-centre, international trials.
Phase IV (Clinical Trial)
Following the approval of a drug by the FDA, post marketing surveillance is conducted with the primary goal of monitoring long-term effects.
Compounds that act as central nervous system stimulants, and have psychedelic effects. Well-known phenethylamines include mescaline and MDMA. Alexander Shulgin pioneered synthetic work in phenethylamines, documenting his efforts (which resulted in drugs such as 2C-B) in his book PiHKAL, which stands for Phenethylamines I Have Known And Loved.
In a clinical drug trial with multiple treatment arms, it is necessary to test the drug efficacy against a control. The control group will typically receive a placebo, which could be, for example, an intravenous injection of saline or a sugar pill in place of the drug. Indeed, placebos have no therapeutic value and thus, serve as a comparison to the test drug. See Active Placebo for more.
Post-Traumatic Stress Disorder (PTSD)
A mental disorder that may develop following exposure to a traumatic event. MAPS is working to achieve FDA approval for MDMA-assisted psychotherapy for PTSD (see MAPS).
Pre-Investigational New Drug (IND) Meeting
An opportunity for the sponsors of a drug to meet with the FDA prior to formally filing an IND application. Pre-IND meetings allow sponsors to incorporate FDA feedback into their drug development (FDA).
The metabolite of psilocybin (see below), which produces psychedelic effects.
A naturally-occurring psychedelic drug found in over 200 species of fungus. Psilocybin is a prodrug, which the body converts to psilocin.
Psychedelic-Assisted Therapy (PAT)
Psychedelic-Assisted Therapy (PAT) is a therapeutic practice led by a registered clinician that employs traditional “talk therapy” (psychotherapy) while the patient is administered a psychedelic. It is thought that psychedelics can increase patient suggestibility and allow them to be more receptive to talk therapy, which can be reflected in everlasting changes in both attitudes and beliefs. PAT has been demonstrated to be effective for a range of mental health indications such as substance use disorder (SUD) and major depressive disorder (MDD).
Randomized Control Trial (RCT)
A randomized control trial is a type of clinical or basic science investigation that randomly assigns whether the participant is to receive a treatment or placebo/control. Therefore, it is thought that in a clinical the only observed differences between the two clinical arms must be attributed to the efficacy of the treatment intervention.
Salvia divinorum is a plant species that is a relative of sage which can be found growing in the wild in areas of Mexico. Mazatec shamans have used the leaves of the plant in healing rituals, and for medicinal purposes. The primary psychoactive in Salvia is salvinorin A, and ingestion of the plant results in a short, potent, psychedelic experience.
See magic truffle.
Section 56 (Exemption)
Section of the Canadian Controlled Drugs and Substances Act (CDSA) that allows the Minister of Health to provide individual exemptions to the Act “if, in the opinion of the Minister, the exemption is necessary for a medical or scientific purpose or is otherwise in public interest” (Government of Canada). On August 4, 2020, four Canadians with incurable cancer were granted Section 56 exemptions, allowing them to receive psilocybin-assisted therapy. Since then, a non-palliative Canadian, and seventeen healthcare professionals, have been awarded the same exemption.
Serotonin is a neurotransmitter released by axon terminals that has widespread regulatory function in the brain. The molecule contributes to reward, mood states, and numerous physiological processes. It is produced in the raphe nucleus of the brainstem. It is through the serotonin-binding receptor (5-HT2) that the hallucinogenic effects are produced with classic psychedelics LSD, mescaline, and psilocin.
Set and Setting
Refers to the participant’s mindset (‘set’) and physical and social environment (‘setting’) during a psychedelic experience. Supportive set and setting is thought to be central to a positive psychedelic experience.
Special Access Program (SAP)
In Canada, this is the formal means through which Canadian health care professionals can request access to drugs not available in Canada. The request can be made when treating a patient with a serious or life-threatening condition when conventional treatments have failed, are unsuitable, or are not available in Canada. In December 2020, Health Canada announced their intent to amend the SAP to restore potential access to restricted drugs under the program.
SSRI (Selective Serotonin Reuptake Inhibitor)
A class of drugs that represent the most widely prescribed antidepressants in many societies. They are typically prescribed to individuals suffering major depressive disorder, anxiety disorders, and related mental health indications. Serotonin is a neurotransmitter, meaning it carries signals between nerve cells in the brain. Usually, when serotonin has carried a message, it is then reabsorbed by the nerve cells (reuptake). SSRIs, however, inhibit this reuptake, resulting in greater availability of serotonin in the brain.
Tail Suspension Test (TST)
The tail suspension test (TST) is similar in concept to the forced swim task (FST) but has a much greater sensitivity. In this preclinical behavioural test, rodents are suspended by the tail and are observed for the duration spent mobile versus immobile. Animals that spend more time immobile are thought to have greater apathy and depressed mood. Acute administration of antidepressants has been shown to reduce the amount of time the animal spends immobile.
Treatment-Resistant Depression (TRD)
A condition affecting those with Major Depressive Disorder (MDD, see above) who show little positive response to a course of an appropriate antidepressant. The definition and measurement of an ‘inadequate response’ varies, however. Compass Pathways is conducting clinical trials to investigate the efficacy of psilocybin therapy for TRD.
A family of compounds which includes the neurotransmitter serotonin (see SSRIs) and psychedelics such as psilocybin, LSD, and DMT.