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115
From Venerable Cultural Practices to Modern Psychological Solutions:
Enter Entheogens into Mainstream Medicine
Nicholas A. Kerna†
Independent Global Medical Researchers Consortium;
First InterHealth Group, Thailand
Kevin D. Pruitt†
Kemet Medical Consultants, USA;
PBJ Medical Associates, LLC, USA
N.D. Victor Carsrud
Lakeline Wellness Center, USA
Kyle Kadivi
Global Health Group LLC, USA
Dabeluchi C. Ngwu
FMC Umuahia with King Abdullah Hospital, Bisha, Saudi Arabia;
Earthwide Surgical Missions, Nigeria
Hilary M. Holets
Orange Partners Surgicenter, USA
John V. Flores
Orange Partners Surgicenter, USA
Ijeoma Nnake
Simplex Care Inc., USA
Cornelius I. Azi
Northern Care Alliance NHS Foundation Trust, UK
Joseph Anderson II
International Institute of Original Medicine, USA
Fatimah A. Olunlade
Obafemi Awolowo College of Health Sciences, Sagamu, Ogun State, Nigeria
Uzoamaka Nwokorie
Howard University, USA
† indicates co-first author
Abstract
Entheogens, a class of psychoactive substances with profound cultural and religious significance, have
been utilized for centuries across diverse traditions for healing, spiritual exploration, and communication
with the divine. Their historical usage spans continents, from the pre-Columbian Americas to traditional
African practices and Ayurvedic medicine in India. While entheogens offer potential therapeutic benefits,
their use entails inherent risks, including physiological and psychological adverse effects.
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Recent research has increasingly focused on elucidating the mechanisms of action and therapeutic
potential of entheogens such as psilocybin, N,N-dimethyltryptamine (DMT), mescaline, lysergic acid
diethylamide (LSD), ayahuasca, ibogaine, and Salvia divinorum. These substances exhibit diverse
pharmacological profiles, acting primarily on serotonin receptors and other neurotransmitter systems,
resulting in alterations in perception, mood, and cognition.
Clinical studies have demonstrated promising results for entheogens in the treatment of psychiatric
disorders, including depression, anxiety, addiction, and post-traumatic stress disorder (PTSD), and, to a
lesser extent, pain management and cluster headaches. However, regulatory constraints, limited
participant numbers, and ethical considerations hinder comprehensive research.
Safety considerations are paramount in administering entheogens, necessitating proper dosing, individual
risk assessment, supportive set and setting, and medical supervision. Adherence to rigorous clinical trial
standards and transparent methodologies is essential for advancing research and harnessing the
therapeutic potential of entheogens.
Despite obstacles, continued investigation into entheogens is imperative for unlocking their therapeutic
potential and developing safe and effective mental health treatments. Key research avenues include
elucidating mechanisms of action, standardizing administration protocols, determining optimal dosages,
and assessing long-term effects and associated risks.
While cannabis is commonly recognized as an entheogen, it was not encompassed in this review. The
authors omitted it due to its unique status, ongoing discourse, and the need for a separate dedicated
analysis.
Keywords: Addiction, Bad Trips, Cluster Headaches, Flashbacks, Psychiatric Disorders, Psychoactive.
Abbreviations: CNS: Central Nervous System; DMT: N,N-Dimethyltryptamine; DMN: Default Mode
Network; IM: Intramuscular; IP: Intraperitoneally; IV: Intravenously; LSD: Lysergic acid diethylamide;
MAO: Monoamine Oxidase; NMDA: N-methyl-D-aspartate; PNS: Peripheral Nervous System; PTSD:
Post-Traumatic Stress Disorder; Tmax: Time to Maximum Plasma Concentration; VTA: Ventral
Tegmental Area
Suggested citation: Kerna, N.A., Pruitt, K.D., Carsrud, N.D.V., Kadivi, K., Ngwu, D.C., Holets, H.M.,
Flores, J.V., Nnake, I., Azi, C.I., Anderson II, J., Olunlade, F.A., & Nwokorie, U. (2024). From Venerable
Cultural Practices to Modern Psychological Solutions: Enter Entheogens into Mainstream Medicine.
European Journal of Arts, Humanities and Social Sciences, 1(3), 115-129. DOI: 10.59324/ejahss.2024.1(3).10
Copyright © 2024 Nicholas A. Kerna, et al. All rights reserved
Introduction
Entheogens are a class of psychoactive substances that have been used for centuries in various cultures
and religious practices to produce altered states of consciousness and spiritual experiences. The term
“entheogen” was first coined in the late 1970s by botanists and scholars who wanted to distinguish these
substances from recreational drugs and emphasize their spiritual and religious significance (Kime, 2018;
Thoricatha, 2015).
Entheogens play vital roles in diverse cultural and religious traditions. They have been used as tools for
healing, divination, communication with spirits and ancestors, and connecting with the divine or
experiencing mystical states of consciousness. In many traditional cultures, the use of entheogens is
deeply intertwined with their cultural and spiritual heritage (Arce & Winkelman, 2021).
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The earliest reported usage of entheogens dates back thousands of years and includes substances such as
cannabis, opium, and the peyote cactus. In pre-Columbian America, entheogens were widespread and
included sacred plants such as ayahuasca, San Pedro, and psilocybin-containing mushrooms (Carod-Artal,
2015). In Africa, iboga has been used for healing and spiritual purposes for centuries (Corkery, 2018). In
India, Ayurvedic medicine has long used a variety of psychoactive plants (Alrashedy & Molina, 2016).
The use of ayahuasca by indigenous people in South America has spread to the West and other parts of
the world, where it is used in spiritual communities and by individuals seeking healing and personal
transformation (Frecska, Bokor, & Winkelman, 2016). The use of peyote by Native American
communities has a controversial history, including persecution by the US government and struggles for
religious freedom (Calabrese, 2013).
While entheogens offer potential therapeutic benefits, their usage also entails inherent risks. These risks
include panic attacks, psychotic episodes, dehydration, heat stroke, or interactions with other medications
(Schifano, Vento, Scherbaum, & Guirguis, 2023). However, recent research has shown that some of these
substances may have therapeutic potential, particularly in the treatment of mental health disorders such
as depression, anxiety, and addiction (Tupper, Wood, Yensen, & Johnson, 2015).
Studies on entheogens have increased in recent years, with a focus on substances such as psilocybin,
ayahuasca, and lysergic acid diethylamide (LSD). Research on psilocybin has shown promising results in
the treatment of depression and anxiety, with some studies showing that a single dose can produce lasting
improvements in mood and well-being. Ayahuasca has been studied for its potential to treat addiction
and has been shown to have antidepressant effects. LSD has also been studied for its potential therapeutic
applications, particularly in the treatment of anxiety and end-of-life distress (Nichols, 2016).
The term “entheogen” is derived from the Greek words “entheos,” meaning “full of the divine,” and
“genesthai,” meaning “to generate” or “to bring forth.” Entheogens are believed to facilitate experiences
perceived as sacred or transcendent, leading to a deeper understanding of oneself, the universe, or
spiritual realms (Thoricatha, 2015).
Discussion
Entheogens Trending in Medical Research
The most commonly reported entheogens include psilocybin, N,N-dimethyltryptamine (DMT),
mescaline, lysergic acid diethylamide (LSD), ayahuasca, ibogaine, and Salvia divinorum (Garcia-Romeu et
al., 2016). These substances vary widely in their chemical structure and pharmacological properties.
Psilocybin is the primary psychoactive compound found in certain species of mushrooms, particularly
those in the genus Psilocybe. It is classified as a tryptamine alkaloid and has structural similarities to the
neurotransmitter serotonin—carrying messages between nerve cells in the brain (central nervous system
[CNS]) and throughout the peripheral nervous system (PNS). Psilocybin is rapidly dephosphorylated to
psilocin, which produces its characteristic effects by acting as an agonist at serotonin receptors in the
brain (Lowe et al., 2021). These effects are alterations in consciousness, mood, and perception, resulting
in subjective experiences characterized by visual distortions and enhanced emotional processing.
DMT is a tryptamine alkaloid that occurs naturally in many plants and animals, including humans. It is a
highly potent psychedelic compound that is typically smoked or brewed in a tea known as ayahuasca.
DMT produces its effects by acting as a partial agonist at serotonin receptors, particularly the 5-HT2A
receptor, widely distributed in the CNS, especially in the brain region. DMT elicits rapid and intense
alterations in consciousness characterized by vivid visual hallucinations, dissociative experiences, and
profound changes in perception (Barker, 2018).
Mescaline is a psychoactive alkaloid found in the peyote cactus and certain other cactus species. It is
structurally similar to amphetamines and produces its effects by acting as an agonist at several serotonin
receptor subtypes, as well as at the dopamine receptor. Mescaline has a long history of use in Native
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American religious traditions. Mescaline alters perception, mood, and cognition, often accompanied by
sensory enhancement, synesthesia, and profound introspection (Dinis-Oliveira, Pereira, & Da Silva,
2019).
LSD is a synthetic compound derived from ergot fungus. It belongs to the class of compounds known
as lysergamides. LSD acts as an agonist at serotonin receptors, particularly the 5-HT2A receptor. It is
recognized for inducing profound changes in perception and thought (Jastrzębski, Kaczor, & Wróbel,
2022; Passie, Halpern, Stichtenoth, Emrich, & Hintzen, 2008).
Ayahuasca is a traditional South American brew made from the Amazonian vine Banisteriopsis caapi and
the leaves of the Psychotria viridis (chacruna) or Diplopterys cabrerana (chaliponga) plants. The active
compounds in ayahuasca are DMT and beta-carboline alkaloids. Beta-carbolines are believed to inhibit
the action of monoamine oxidase (MAO), allowing DMT to be orally active. Ayahuasca has been
associated with alterations in serotonin receptor activity, modulation of brain connectivity, and subjective
experiences encompassing heightened introspection, emotional processing, and potential therapeutic
effects on mood disorders (Frecska et al., 2016; White, Kennedy, Ruffell, Perkins, & Ruffell, 2024).
Ibogaine is a psychoactive and indole alkaloid found in the roots of the iboga plant, which is native to
Africa. It is used in traditional African religious practices and has gained attention in recent years for its
potential to treat addiction. Ibogaine produces its effects by acting as an antagonist at the kappa-opioid
receptor and a partial agonist at the serotonin 5-HT2 receptor. Ibogaine alters mood, perception, and
cognitive processes. Additionally, it has been shown to stimulate the production of growth factors that
may contribute to its anti-addictive effects (Bouso et al., 2020; Corkery, 2018; Obembe, 2012).
Salvia divinorum is a plant native to Mexico that contains the psychoactive compound salvinorin A.
Salvinorin A is a potent kappa-opioid receptor agonist and produces dissociative and often intense
hallucinogenic effects. Salvia divinorum has been used in traditional Mazatec shamanic practices and has
gained popularity in recent years as a recreational drug (Maqueda et al., 2015).
Table 1 provides an overview of where the receptors mentioned above are distributed in the human body.
Table 1. Specific Receptors and Their Distributions in the Human Body
Receptor
Distribution in Human Body
Serotonin
Central Nervous System (CNS): Found in various brain regions including the cortex, hippocampus,
amygdala, and basal ganglia. Also present in the spinal cord.
Peripheral Nervous System (PNS): Found in the gastrointestinal tract, blood vessels, platelets, and
various other organs such as the liver, kidneys, and lungs.
5-HT
2A
Predominantly located in the cerebral cortex, particularly in areas associated with sensory perception,
cognition, and mood regulation.
Dopamine
Central Nervous System (CNS): Concentrated in the substantia nigra and ventral tegmental area (VTA),
with projections to various brain regions including the striatum.
Peripheral Nervous System (PNS): Present in sympathetic ganglia and adrenal medulla, influencing
functions such as heart rate, blood pressure, and renal blood flow.
5-HT
2
Mainly distributed in the brain, particularly in areas associated with mood regulation, such as the limbic
system and frontal cortex.
Kappa-opioid
Central Nervous System (CNS): Found in regions involved in pain modulation, including the spinal cord
and brain areas such as the periaqueductal gray and amygdala.
Peripheral Nervous System (PNS): Present in peripheral sensory neurons and immune cells, contributing
to analgesic effects and modulation of inflammatory responses.
Mechanisms of Action and General Psychological Effects
Psilocybin
Psilocybin is commonly ingested orally by eating the mushrooms directly or brewing them in tea.
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After ingestion, psilocybin is primarily metabolized in the liver by cytochrome P450 enzymes, particularly
CYP2D6, to the active metabolite psilocin—the actual active compound responsible for the effects of
psilocybin—which then undergoes further metabolism by MAO enzymes before being excreted in the
urine. Psilocybin and psilocin bind primarily to serotonin receptors in the brain, inducing a wide range of
perceptual, cognitive, and emotional alterations (Dinis-Oliveira, 2017; Lowe et al., 2021).
The onset of action of psilocybin is typically 20 to 40 minutes after oral administration, with peak effects
occurring within 60 to 90 minutes. The duration of effects is usually 4 to 6 hours, depending on the dose
and route of administration. Psilocin and other metabolites have a half-life of approximately 50 minutes
and are cleared from the body within 24 hours after ingestion (MacCallum, Lo, Pistawka, & Deol, 2022).
The clearance of psilocybin and its metabolites occurs mainly through the kidneys via excretion in urine,
followed by bile and stool. The ratio of unchanged psilocybin to psilocin varies depending on the dose
and route of administration, with psilocin being the dominant metabolite after oral administration
(Matsushima, Eguchi, Kikukawa, & Matsuda, 2009).
Psilocybin is mainly administered orally in capsules or tablets under medical supervision. The doses range
from 10 to 30 mg, with most of the trials using a standard dose of 25 mg (MacCallum et al., 2022;
Matsushima et al., 2009; Ziff, Stern, Lewis, Majeed, & Gorantla, 2022).
DMT
DMT is most commonly self-administered through inhalation; other routes are injection, oral ingestion,
and sublingual absorption. Inhalation is considered the most common and effective route, providing the
most rapid onset of effects and the highest bioavailability (Barker, 2018). After inhalation, DMT is readily
absorbed into the bloodstream and rapidly crosses the blood-brain barrier to reach the CNS (Barker,
2018).
The mechanisms of action of DMT are not yet fully understood. However, it is thought to act through
multiple receptors, including 5-HT2A, sigma-1, and trace amine-associated receptors, causing a wide range
of perceptual, cognitive, and emotional changes (Barker, 2018).
DMT has a rapid onset of action, typically within seconds to minutes. Peak effects occur 5 to 10 minutes
after inhalation and last less than one hour, depending on dose and route. DMT has a short half-life of 9
to 12 minutes, and the metabolites are eliminated mainly via renal excretion (Barker, 2018; Brito-Da-
Costa, Da Silva, Gomes, Dinis-Oliveira, & Madureira-Carvalho, 2020; Good et al., 2022).
The clearance rate of DMT is rapid, estimated to be 26 L/min, suggesting that the elimination of DMT
is independent of blood flow (Eckernäs, Timmermann, Carhart‐Harris, Röshammar, & Ashton, 2022).
In medical trials, DMT has been mainly administered intravenously (IV) via bolus or infusion or
intraperitoneally (IP) under medical supervision. IV doses range from 0.2 to 0.4 mg/kg, with most trials
using 0.4 mg/kg as the highest dose (Vogt et al., 2023). In animal studies, the IP dose was 10 mg/kg
(Barker, 2018).
Mescaline
Mescaline is commonly ingested orally by chewing the dried cactus buttons or brewing them in tea. After
oral administration, mescaline is slowly absorbed from the gastrointestinal tract and metabolized mainly
in the liver afterward.
Mescaline is a partial agonist of serotonin 5-HT2A and 5-HT2C receptors, resulting in cognitive, sensory,
and affective alterations.
The onset of mescaline’s effects is within 30 minutes after ingestion, with peak effects occurring within
about 2 hours and a duration of up to 12 hours. Mescaline has a relatively long half-life of 6 hours.
It is metabolized mainly by oxidation and excreted in the urine. The majority of the dose is eliminated
unchanged. The remaining dose is converted into inactive metabolites, primarily 3,4,5-
trimethoxyphenylacetic acid.
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In medical studies, there are no standardized routes of administration for mescaline. However, synthetic
mescaline is usually administered orally. It has an effective oral dosage range of 200 to 400 mg, with most
studies using a standard dose of 200 mg (Dinis-Oliveira et al., 2019; Thomann, Ley, Klaiber, Liechti, &
Duthaler, 2022).
LSD
LSD is commonly ingested orally in a tablet, capsule, or blotter paper (Couper, 2016). Following oral
administration, LSD is rapidly absorbed from the gastrointestinal tract and then distributed throughout
the body with concentrations in organs such as the liver, gallbladder, lungs, kidneys, adipose tissue, blood
plasma, and brain (Passie et al., 2008).
The brain stem and cortex contain LSD concentrations similar to each other, and LSD is equally
distributed between white and gray matter in the brain (Passie et al., 2008).
LSD is thought to act primarily through binding to serotonin 5-HT2A receptors, leading to altered sensory,
emotional, and cognitive experiences (Jastrzębski et al., 2022; Passie et al., 2008).
The onset of effects of LSD is usually within 30 to 45 minutes after ingestion, with peak effects occurring
within 1 to 2 hours and lasting up to 12 hours. LSD has a plasma half-life of 3 to 4 hours and is
metabolized primarily in the liver. The major metabolite in urine is 2-oxylysergide (Okumuş, Metin, &
Kariper, 2023; Passie et al., 2008).
LSD is excreted in urine within 24 hours, depending on dose, with only a small amount of LSD (1% or
less) eliminated unchanged. The majority of LSD is metabolized to inactive compounds, such as O-H-
LSD, and then excreted in the urine. However, it is reported that metabolites can still be detected in the
urine after 4 days after ingestion (Passie et al., 2008).
In clinical research, LSD is administered through various routes, such as oral, IV, and intramuscular (IM)
injection. Most studies using LSD involved oral administration of the drug, usually in a tablet or capsule.
The dosage of LSD in these studies ranges from 20 to 800 mcg, with most studies using a standard dose
of 100 to 200 mcg (Fuentes, Fonseca, Elices, & Farré, 2020; Liechti, 2017).
Ayahuasca
Ayahuasca is commonly ingested orally and contains compounds such as DMT and harmine, which can
interact with different neurotransmitter systems in the human body.
After oral ingestion of ayahuasca, DMT and harmine are rapidly absorbed from the gastrointestinal tract
and distributed throughout the body. DMT acts on serotonin 5-HT2A and sigma-1 receptors, leading to
psychedelic and clinically significant psychoactive effects. Harmine acts as an MAO inhibitor and
increases the bioavailability of DMT, thus potentiating its pharmacological effects (Frecska et al., 2016;
White et al., 2024).
DMT and harmine affect various target organs, such as the brain, heart, liver, and kidneys. Ayahuasca
can modulate neuronal activity by activating the default mode network (DMN) and other cortical and
subcortical regions. Ayahuasca’s psychoactive effects include changes in mood, perception, and ego-
death experiences (Frecska et al., 2016; White et al., 2024).
The onset of effects of ayahuasca is usually within 30 to 60 minutes after ingestion, with peak effects
occurring within 1.5 to 2 hours. The duration of action is approximately 4 to 6 hours. DMT and harmine
have a relatively short plasma half-life of 10 to 25 minutes and about 2 hours, respectively. After
metabolism in the liver, harmine is excreted through the kidneys, while DMT is rapidly metabolized to
inactive metabolites via MAOs and excreted in urine within 24 hours (Barker, 2018; Brito-Da-Costa et
al., 2020; Campagnoli, Pereira, & Bueno, 2020).
Ayahuasca is typically administered orally in medical research. The dose of ayahuasca used in research
can vary. According to specific reviews, the average ceremonial dose of DMT in ayahuasca preparations
is about 27 mg, with an average ritual/ceremonial oral dose of ayahuasca being 100-150 mL for a 70 kg
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person (Frecska et al., 2016; White et al., 2024). However, clinical studies have administered an oral dose
of ayahuasca of 2.2 mL/kg (De Morais Santos et al., 2023). In the first-in-human clinical trial, 50 mg of
DMT and harmine was administered as a capsule (Dornbierer et al., 2023).
Ibogaine
Ibogaine is commonly ingested orally in the form of capsules, tablets, or a crude extract. It is rapidly
absorbed from the gastrointestinal tract and has a time to maximum plasma concentration (Tmax) of
approximately 2 to 6 hours (Luz & Mash, 2021).
The exact mechanisms of ibogaine’s actions are not well understood, but it has been suggested to act on
various neurotransmitter systems, including dopamine, serotonin, and glutamate. It acts as a non-
competitive antagonist at the N-methyl-D-aspartate (NMDA) receptor, a partial agonist at the mu-opioid
receptor, and an agonist at the kappa-opioid receptor. Ibogaine alters mood, perception, and cognitive
processes (Luz & Mash, 2021).
The onset of effects of ibogaine is 1 to 3 hours and typically lasts from 24 to 72 hours, depending on the
dose and individual metabolism. The active metabolite noribogaine is formed by the O-demethylation of
ibogaine and has a considerably longer half-life than ibogaine, up to 30 hours (Dickinson et al., 2016; Luz
& Mash, 2021).
Ibogaine and its metabolites are mainly excreted in urine, with small amounts being eliminated in feces
and expired air. Ibogaine is primarily metabolized by oxidation through cytochrome P450 enzymes,
particularly the CYP2D6 isoform, into various metabolites, including noribogaine and O-
desmethylibogaine. Most of the dose of ibogaine is excreted in the urine and feces in 24 hours (Luz &
Mash, 2021; Martins et al., 2022; Mash, Duque, Page, & Allen-Ferdinand, 2018).
In clinical research studies, ibogaine has been administered through various routes, such as oral, IM, and
IV injection. The most common method of administration is oral ingestion, usually in the form of tablets,
capsules, or a crude extract. The dose of ibogaine used in clinical research studies ranges widely, from 1
to 29 mg/kg, but most studies use a dose of 10 mg/kg (Martins et al., 2022).
Salvia divinorum
Salvia divinorum is commonly smoked, vaporized, or chewed, with smoking being the most common route
of administration.
Salvinorin A, the primary psychoactive compound in Salvia divinorum, is rapidly absorbed through the oral
mucosa or the respiratory tract into the bloodstream through the lungs and then distributed throughout
the body and into the brain (Brito-Da-Costa, Da Silva, Gomes, Dinis-Oliveira, & Madureira-Carvalho,
2021).
Salvinorin A acts as a potent, selective agonist at the kappa-opioid receptor, producing dissociative and
hallucinogenic effects. The kappa-opioid receptor is widely distributed throughout the brain and is
involved in various processes, such as pain perception, mood regulation, and cognition (Brito-Da-Costa
et al., 2021).
The onset of the effects of Salvia divinorum occurs within minutes. The duration of the effects varies
depending on the dose and method of administration, with effects typically lasting about 30 to 60 minutes
after smoking and up to 2 hours after oral consumption. The half-life of Salvia divinorum is not well
documented in humans, but studies in rats suggest a half-life of approximately 10 minutes (Cunningham,
Rothman, & Prisinzano, 2011).
The liver plays a minor role in Salvia divinorum metabolism, and the compound is primarily eliminated
unchanged in the urine. The clearance pathways for Salvia divinorum’s metabolites remain unclear, but it
is posited that a small portion of the compound is excreted in the bile and feces (Brito-Da-Costa et al.,
2021).
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Medical research on Salvia divinorum is limited. Subsequently, no standard administration method has been
established for research purposes. Salvia divinorum is typically smoked or vaporized by study participants.
The dose and method of administration in research studies vary widely, with some studies using
standardized doses of Salvia divinorum preparations, while others rely on self-administration by
participants (Brito-Da-Costa et al., 2021; Cunningham et al., 2011).
Table 2 summarizes the administration routes, medical administration routes, target organs or systems,
target receptors, onset of effects, duration of effects, and type of effects for each entheogen.
Table 2. Administration Methods, Targets in the Human Body, and Effects
Substance
Administration
Routes
Medical
Administration
Routes
Target
Organs/Sys
tems
Target
Receptors
Onset of
Effects
Duration
of Effects
Type of Effects
Psilocybin
Oral (ingestion,
brewing in tea)
Oral (capsules,
tablets)
Central
Nervous
System
(CNS),
Peripheral
Nervous
System
(PNS)
Serotonin
(primarily)
20-40
minutes
4-6 hours
Perceptual,
cognitive,
emotional
alterations
DMT
Inhalation,
Injection, Oral,
Sublingual
IV, IP
(Intravenous,
Intraperitoneal)
Central
Nervous
System
(CNS)
5-HT
2A
,
sigma-1,
trace
amine-
associated
receptors
Seconds to
minutes
Less than 1
hour
Perceptual,
cognitive,
emotional
changes
Mescaline
Oral (ingestion,
brewing in tea)
Oral
Central
Nervous
System
(CNS)
Serotonin
5-HT2A, 5-
HT2C
30 minutes
Up to 12
hours
Cognitive,
sensory, affective
alterations
LSD
Oral (tablet,
capsule, blotter
paper)
Oral, IV, IM
(Intravenous,
Intramuscular)
Central
Nervous
System
(CNS),
Peripheral
Nervous
System
(PNS)
Serotonin
5-HT2A
30-45
minutes
Up to 12
hours
Altered sensory,
emotional,
cognitive
experiences
Ayahuasca
Oral (ingestion)
Oral
Central
Nervous
System
(CNS),
Peripheral
Organs
Serotonin
5-HT2A,
sigma-1
30-60
minutes
4-6 hours
Changes in
mood,
perception, ego-
death experiences
Ibogaine
Oral (capsules,
tablets, crude
extract)
Oral, IM, IV
(Intramuscular,
Intravenous)
Central
Nervous
System
(CNS),
Peripheral
Organs
NMDA,
mu-opioid,
kappa-
opioid
1-3 hours
24-72 hours
Altered mood,
perception,
cognitive
processes
Salvia
divinorum
Smoking,
Vaporization,
Chewing
Not established
Central
Nervous
System
(CNS)
Kappa-
opioid
Within
minutes
Up to 2
hours
Dissociative,
hallucinogenic
effects
Potential Therapeutic Benefits and Notable Medical Applications
Entheogenic substances have shown potential therapeutic benefits for several psychiatric disorders,
including addiction, anxiety, depression, and post-traumatic stress disorder (PTSD), as well as pain
management and cluster headaches (Table 3).
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Table 3. Overview of the Clinical Applications of Each Entheogen
Entheogen
Addiction
Anxiety
Depression
PTSD
Pain
Management
Cluster
Headaches
Psilocybin
✔
✔
✔
✔
DMT
✔
✔
Mescaline
✔
✔
✔
LSD
✔
Ayahuasca
✔
✔
✔
Ibogaine
✔
Salvia divinorum
✔
✔
Note: The data in the above table are derived the following sources: Bouso et al. (2020), Brito-Da-Costa
et al. (2021), Cunningham et al. (2011), Dinis-Oliveira (2017), Dornbierer et al. (2023,) Holze et al. (2022),
Krediet et al. (2020,) Liechti (2017), MacCallum et al. (2022), Nichols (2016), and Thomann et al. (2022).
Adverse Effects of Entheogens
There are several potential adverse effects associated with the use of entheogenic substances. Short-term
effects can include nausea, vomiting, anxiety, panic attacks, and psychotic symptoms such as paranoid
ideation, hallucinations, and thought disturbances. Long-term effects may include changes in mood,
perception, and cognition, as well as the development of persistent psychotic symptoms such as delusions
and mood disorders. (Refer to the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition
[DSM-5], Section II “Bipolar and Related Disorders” and “Depressive Disorders” for a review of specific
mood disorders).
Psilocybin exhibits a low potential for abuse and toxicity. Nonetheless, it can induce adverse reactions,
including nausea, vomiting, panic attacks, and mydriasis. Recent trials have demonstrated its efficacy in
reducing depressive symptoms, but some studies indicate potential long-term mood and behavioral
changes (Lowe et al., 2021).
DMT, while having low toxicity and abuse potential, may lead to persistent psychotic symptoms with
prolonged use. Adverse effects such as panic attacks, seizures, and psychotic symptoms have been
reported (Frecska et al., 2016; White et al., 2024).
Mescaline shares similar low toxicity and abuse potential traits. While it shows promise in anxiety and
depression treatment, there’s a risk of persistent psychotic symptoms (Dinis-Oliveira et al., 2019).
LSD presents potential addiction risks, with higher doses increasing the likelihood of a “bad trip” or
flashbacks post-discontinuation (Fuentes et al., 2020; Liechti, 2017).
Ayahuasca can elevate heart rate and blood pressure, posing risks for individuals with heart conditions
and potentially leading to complications such as heart failure or stroke. Additionally, it carries a potential
risk of developing psychotic symptoms (Brito-Da-Costa et al., 2020; Dornbierer et al., 2023).
Ibogaine, effective in addiction treatment, may cause vomiting, nausea, and bradycardia. Higher doses
can induce pharmacologic psychosis, necessitating specialized medical supervision (Mash et al., 2018).
Salvia divinorum’s adverse effects are not fully elucidated due to limited research, but studies suggest
potential adverse reactions, including nausea, vomiting, and persistent mood and behavioral changes
(Brito-Da-Costa et al., 2021; Zawilska & Wojcieszak, 2013).
The potential negative effects of entheogens may depend on several factors, including the method of
administration, dose, and individual factors (e.g., age, medical history, and co-occurring psychiatric
conditions). Adverse effects can be reduced through proper medical supervision and the use of
appropriate dosage.
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Safety Considerations
The safety and efficacy of entheogenic substances depend on several factors, including the set and setting
of use, dose, individual mental and physical health, and the quality of the substance administered.
The term “set” refers to an individual’s mindset, prior experience with drugs, and overall personality,
while “setting” refers to the physical and social environment in which the drug is consumed (Hartogsohn,
2017).
Some studies have suggested that the set and setting of entheogen use can significantly influence the
nature of the experience and associated psychological outcomes. Using entheogens with supportive
personnel and integrated practices in a therapeutic setting can lead to positive and lasting outcomes.
However, adverse outcomes can occur if the setting is unsupportive or non-therapeutic (Dos Santos,
Bouso, Rocha, Rossi, & Hallak, 2021; Hartogsohn, 2017).
The dose of entheogenic substances is another crucial factor, as many adverse effects can be the result
of taking excessively high doses. Studies have suggested that appropriate dosing regimens with
entheogens, administered under proper medical supervision, can lead to positive therapeutic outcomes
with a low likelihood of abuse or clinically significant adverse effects (Dos Santos et al., 2021; Elsey,
2017).
The mental and physical health of individuals should be assessed before the administration of
entheogenic substances to ensure their safety. Certain health conditions, such as heart or lung disease or
a history of psychiatric disorders, may make individuals more vulnerable to developing adverse reactions.
Medical supervision of entheogen use minimizes negative outcomes (Marrocu et al., 2024; Schlag, Aday,
Salam, Neill, & Nutt, 2022).
The quality of the substance being ingested is also critical, as some entheogenic compounds adulterated
with other substances can lead to severe consequences. Toxic substances can cause liver damage, while
impure substances can cause gastrointestinal distress, muscle tremors, and other negative symptoms
(Baumeister, Tojo, & Tracy, 2015; Jo, Hossain, & Park, 2014). Obtaining these compounds from a reliable
source and testing them for purity can minimize the risk of unwanted effects.
The safety of entheogenic substances requires proper dosing, individual risk assessment, mental support,
and medical supervision, as well as set and setting considerations.
Limitations of Research
The scientific exploration of entheogenic compounds is nascent, accompanied by various challenges and
constraints. These include issues such as the breaking blind problem, placebo effects, and the absence of
a well-defined mechanism of action for many of these agents.
Entheogenic substances often induce profound perceptual alterations, complicating clinical trials to
demonstrate therapeutic efficacy. Moreover, limited participant numbers in such trials hinder conclusive
safety and efficacy determinations (Barker, 2018; Vogt et al., 2023).
Regulatory skepticism and funding hurdles further impede entheogenic research progress. Ethical
complexities demand meticulous participant safeguarding (Pilecki, Luoma, Bathje, Rhea, & Narloch,
2021).
Despite obstacles, continued investigation is imperative to unravel entheogens’ therapeutic potential. Key
research avenues include elucidating their mechanisms of action, devising standardized administration
protocols, and determining optimal therapeutic dosages (Madrid-Gambin et al., 2023). Long-term effects
and associated risks also warrant investigation.
Adherence to rigorous clinical trial standards and transparent methodologies is crucial. Enthusiasm for
entheogenic applications in psychiatry underscores the need for rigorous research to develop safe,
effective mental health treatments (Aday et al., 2022).
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Conclusion
Entheogens, encompassing substances such as psilocybin, N,N-dimethyltryptamine (DMT), mescaline,
lysergic acid diethylamide (LSD), ayahuasca, ibogaine, and Salvia divinorum, represent a burgeoning area
of interest in medical research due to their potential therapeutic applications in various psychiatric
disorders and pain management. These substances exert their effects primarily through interactions with
serotonin receptors and other neurotransmitter systems in the brain, leading to profound alterations in
perception, mood, and cognition.
Clinical studies have demonstrated promising results in the treatment of addiction, anxiety, depression,
post-traumatic stress disorder (PTSD), and cluster headaches. However, safety considerations are
paramount, with adverse effects including nausea, vomiting, anxiety, panic attacks, and potential long-
term mood and behavioral changes. Proper medical supervision, dosage regulation, and consideration of
individual health factors are essential to mitigate these risks.
Challenges in entheogenic research include regulatory obstacles, funding constraints, ethical complexities,
and methodological limitations. Despite these challenges, continued investigation is imperative to unlock
the therapeutic potential of entheogens. Future research should focus on elucidating mechanisms of
action, standardizing administration protocols, determining optimal dosages, and assessing long-term
effects and associated risks.
Conflict of Interest Statement
The authors declare that this paper was written without any commercial or financial relationship that
could be construed as a potential conflict of interest.
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