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Risk Assessment of Ritual Use of Oral Dimethyltryptamine (DMT) and Harmala Alkaloids


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To extend previous reviews by assessing the acute systemic toxicity and psychological hazards of a dimethyltryptamine and beta-carboline brew (ayahuasca/hoasca) used in religious ceremonies. A systematic literature search, supplemented by interviews with ceremony participants. No laboratory animal models were located that tested the acute toxicity or the abuse potential of ayahuasca. Separate animal studies of the median lethal dose of dimethyltryptamine (DMT) and of several harmala alkaloids indicated that a lethal dose of these substances in humans is probably greater than 20 times the typical ceremonial dose. Adverse health effects may occur from casual use of ayahuasca, particularly when serotonergic substances are used in conjunction. DMT is capable of inducing aversive psychological reactions or transient psychotic episodes that resolve spontaneously in a few hours. There was no evidence that ayahuasca has substantial or persistent abuse potential. Long-term psychological benefits have been documented when ayahuasca is used in a well-established social context. A decoction of DMT and harmala alkaloids used in religious ceremonies has a safety margin comparable to codeine, mescaline or methadone. The dependence potential of oral DMT and the risk of sustained psychological disturbance are minimal.
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Risk assessment of ritual use of oral
dimethyltryptamine (DMT) and harmala alkaloids
Robert S. Gable
Claremont Graduate University, Claremont, CA, USA
Aim To extend previous reviews by assessing the acute systemic toxicity and psychological hazards of a dimethyl-
tryptamine and b-carboline brew (ayahuasca/hoasca) used in religious ceremonies. Method A systematic literature
search, supplemented by interviews with ceremony participants. Results No laboratory animal models were located
that tested the acute toxicity or the abuse potential of ayahuasca. Separate animal studies of the median lethal dose of
dimethyltryptamine (DMT) and of several harmala alkaloids indicated that a lethal dose of these substances in humans
is probably greater than 20 times the typical ceremonial dose. Adverse health effects may occur from casual use of
ayahuasca, particularly when serotonergic substances are used in conjunction. DMT is capable of inducing aversive
psychological reactions or transient psychotic episodes that resolve spontaneously in a few hours. There was no
evidence that ayahuasca has substantial or persistent abuse potential. Long-term psychological benefits have been
documented when ayahuasca is used in a well-established social context. Conclusion A decoction of DMT and
harmala alkaloids used in religious ceremonies has a safety margin comparable to codeine, mescaline or methadone.
The dependence potential of oral DMT and the risk of sustained psychological disturbance are minimal.
Keywords Abuse potential, ayahuasca, dimethyltryptamine, DMT, toxicity.
Correspondence to: Robert S. Gable, 2738 Fulton Street, Berkeley, CA 94705, USA. E-mail:
Submitted 19 February 2006; initial review completed 12 June 2006; final version accepted 11 July 2006
Among substances suspected of having abuse potential,
N,N-dimethyltryptamine (DMT) has received relatively
little attention. However, in 2006, a case was decided by
the US Supreme Court that involved the question as to
whether a DMT and b-carboline plant decoction
(ayahuasca/hoasca) is safe for ceremonial use by
members of a small spiritualist Christian church [1]. The
church prevailed in a unanimous decision in part
because the government, which opposed the use of DMT,
could not meet its burden of showing that hoasca posed a
serious health risk to church members. This paper is a
review of the known acute systemic risks of oral DMT
and concomitantly ingested harmala alkaloids.
Risk refers to the quantified probability of a future
harm. The concept of risk requires a causal relationship
between a hazard (such as a drug overdose) and a known
unfavorable outcome (such as illness or death). In order
to establish this causal relationship, a stimulus must
produce an effect more often than would normally occur
in the absence of that stimulus. Thus, the probabilistic
estimate of risk is often an intrinsic aspect of the research
process by which a causal relation is demonstrated. In the
case of oral DMT, probabilistic estimates can be made for
very few of the drug’s effects at the present time. Some
effects, both favorable and unfavorable, that have been
attributed to DMT may amount to little more than plau-
sible associations. Given the limited amount of published
scientific data regarding oral DMT, this paper takes a
broad view of potential hazards with the expectation that
future research will better establish the risks that might
actually exist.
Ayahuasca (EYE-ah-WAS-ka) or hoasca (WAS-ka) is a
mixture consisting essentially of two compounds. One is
an amine—the simplest and most common being the
tryptamine DMT. The second compound is a monoamine
oxidase inhibitor (MAOI) in the form of a b-carboline
such as harmine, harmaline or tetrahydroharmine. DMT
alone has predicable and significant psychological
REVIEW doi:10.1111/j.1360-0443.2006.01652.x
© 2007 The Author. Journal compilation © 2007 Society for the Study of Addiction Addiction,102, 24–34
activity when smoked, injected or insufflated; but when
used orally it only becomes, or remains, psychoactive in
combination with an MAOI [2–4].
Ayahuasca/hoasca is prepared customarily by com-
bining the leaves from the Psychotria viridis bush along
with bark scraped from the stem of the Banisteriopsis caapi
vine [4,5]. The ingredients are boiled for several hours
and then decanted. The resulting thick, brown, oily liquid
(referred to colloquially in some locales as ‘vine of the
souls’ or ‘vine of the dead’) has been used throughout the
Amazon Basin as a medicinal and ceremonial beverage
since antiquity [6].
Various sacramental brews containing DMT and
b-carbolines, used primarily in Amazonia, are generally
known as ayahuasca. The term ‘hoasca’, a Portuguese
transliteration of ayahuasca, is limited historically and
properly to a subclass of ayahuasca beverages associated
with a specific sacramental use ([5], chapter 16, ‘Hoasca
versus Ayahuasca’). The most commonly recognized sac-
ramental use of ayahuasca occurs among members of
two churches in Brazil: the O Centro Espirita Beneficiente
Uniao Do Vegetal (UDV), founded in 1961 with approxi-
mately 8000 current members, and the Santo Daime,
founded around 1940 with approximately 2500 current
members. Hoasca preparation occurs as part of a reli-
gious ritual known as preparo in the UDV. The Santo
Daime church also uses a decoction of P. viridis and B.
cappi called santo daime or simply daime, and its prepara-
tion ritual is known as feitio [7]. In the present paper,
‘hoasca’ will refer exclusively to UDV’s sacramental
decoction of plant DMT and harmala alkaloids.
The UDV cultivates the plants that are used in their
hoasca ‘tea’ on land that the church owns and maintains
for that purpose. The preparo ceremony can involve up to
200 people working together at a UDV temple over a
period of several days. Photographs of the process appear
in Metzner ([8], pp. 20, 21, 205). In 1992, the Brazilian
Federal Narcotics Council granted legal status for the use
of hoasca in religious contexts.
The present paper extends previous reviews [9,10] that
compared the acute lethal toxicity and the abuse poten-
tial of various psychoactive substances. A simple induc-
tive and iterative procedure was used to locate English-
language serial publications, from 1969 to 2005,
accessible through six databases: Biosis Previews, Digital
Dissertations, Google, PsychAbstracts, Pubmed and
Toxline. The Science Citation Index was occasionally used
to follow-up unusually salient reports. Six primary search
terms—‘ayahuasca’, ‘hoasca’, ‘dimethyltryptamine’,
‘harmine’, ‘harmaline’ and ‘tetrahydroharmine’—were
keyed into the search engines and scanned for the topics
‘overdose’, ‘lethal dose’, ‘lethality’, ‘toxicity’, ‘death’,
‘therapeutic index’, ‘abuse potential’ and ‘dependency’.
The most relevant books, reference works and special
journal issues (e.g. [5,8,11–12]) were also consulted,
thus expanding the information sources beyond those
located only by the search descriptors. In 2003, this
author met with 16 people 2 hours before and periodi-
cally for 12 hours after an ayahuasca ceremony led by a
Peruvian shaman. In 2005, the author had access to a
detailed legal document [13] consisting of more than
1000 pages that served as the evidentiary basis for health
information about hoasca for use in the US Supreme
Court case mentioned previously [1].
An item retrieved during the literature search was
considered potentially relevant if it met at least two of
four criteria: (1) DMT or one of the monoamine oxidase
inhibitors was quantified with respect to an effective or a
toxic dose; (2) the health status of the individual was
indicated; (3) the possible use of concomitant substances
was mentioned; and (4) the data source appeared to be
technical or scholarly in nature.
Fewer than 100 scholarly articles that focused specifically
on ayahuasca/hoasca were located in English-language
serial publications. The majority of these ar ticles involved
inapplicable topics such as neurological experiments, eth-
nographic descriptions or potential medical uses. The
descriptors ‘dimethyltryptamine’, ‘harmine’, ‘harmaline’
and ‘tetrahydroharmine’ resulted in approximately 200
citations retrieved from the databases, excluding Google
and the Science Citation Index. However, after cross-
indexing the keyword ‘toxicity’ with these four descrip-
tors, the number of non-redundant citations that met the
screening criteria was fewer than 25. When all relevant
citations from serial publications were supplemented
with excerpts from scholarly books, monographs and
published reports, the total number of documents printed
and filed was approximately 140.
Description of ayahuasca/hoasca brew
The DMT alkaloid has been reported as ranging from
0.1% to 0.66% dry weight in P. viridis leaves [14]. Sur-
prisingly, the DMT in leaf samples from a single P. viridis
plant has been shown to vary from approximately 3 mg/g
to 9.5 mg/g dry weight in the course of one day. The
concentrations of the b-carboline alkaloids in B. caapi
have been reported as ranging from 0.05% to 1.95% dry
weight [15,16].
Substantial variation in concentrations and propor-
tions of the constituents of ayahuasca brews can be
expected as a consequence of the varying chemical
Risk assessment of oral DMT 25
© 2007 The Author. Journal compilation © 2007 Society for the Study of Addiction Addiction,102, 24–34
composition of the source plants as well as different
methods of preparation. Average DMT doses in assayed
ayahuasca brews have ranged from 8.8 mg [17] to 42 mg
[18]. The content of other alkaloids also varied widely
(see Table 1). This fivefold variance of DMT quantities in
ayahuasca brews might be compared to the common
fivefold variance in caffeinated beverages which range
typically from 0.2 mg/ml of caffeine in green tea to
1.0 mg/ml of caffeine in filtered coffee [19].
The ritual structure in which hoasca is ingested
provides some control of dosage and subsequent psycho-
logical effects. Because the natural sources used in prepa-
ration of the tea does not allow UDV members to
standardize their hoasca brew with respect to DMT or
b-carbolines, the person conducting the ceremony drinks
the brew before administering it to UDV members as a
means of testing for potency. Different amounts of the
brew are initially offered to individual participants and,
depending upon reactions, a participant may be offered a
second cup at his or her request.
A clear distinction must be made between prepara-
tions consisting exclusively of DMT that are injected,
smoked or insufflated versus DMT preparations that are
oral mixtures of DMT and MAOI. Injected, smoked or
insufflated DMT is noted for its very rapid activity. Peak
cognitive effects last only 3–10 minutes, and normal con-
sciousness returns within 30 minutes. In contrast, initial
somatic effects (e.g. nausea, tingling, increased body tem-
perature) after ingesting oral DMT appear in approxi-
mately 20 minutes, followed by the onset of cognitive
effects that peak between 60 and 120 minutes [20]. The
cognitive effects diminish gradually to a normal state in
approximately 4 hours. At normally used doses, the psy-
chological effects of oral DMT are less intense than those
of injected, smoked or insufflated DMT.
Acute lethality
A traditional and standard criterion for assessing the
relative toxicity of various substances has been the lethal
dose of a substance. The median lethal dose (LD50)isthe
statistically derived quantity of a substance given in a
single dose that causes death in 50% of the experimental
animals. One early study by Trevan [21] used more than
900 mice to assess the toxicity of cocaine and of insulin.
More humane standards, such as the minimal lethal dose
or the maximal non-lethal dose, are being gradually
implemented by toxicologists, although many regulatory
agencies still rely on the traditional LD50. Some test pro-
cedures have been advocated that can reduce the number
of killed animals to as few as six [22].
The criterion of single-dose acute lethality is an
extremely limited estimate of human toxicity because it
does not take into account variables such as interspecies
differences, repeated dosing, environmental conditions,
prior health status and psychological factors. None the
less, the influence that such variables might have on
an established dose–response relationship should not
obscure the fact that the LD50 is a clearly defined, repli-
cable and important benchmark of toxicity.
The LD50 of DMT in mice is reported as 47 mg/kg
intraperitoneally and 32 mg/kg intravenously [23]. No
other LD50 data on DMT are believed to be available in
the English language at this time. Five compounds
with structural resemblance to DMT—serotonin,
psilocin, psilocybin, bufotenin and 5-methoxy-N,N-
dimethyltryptamine (5-MeO-DMT)—all have an intra-
venous LD50 among rodents that are similar to, or
substantially less toxic than, DMT. In two rare studies
reporting oral lethal doses of these related compounds,
the LD50 of serotonin in mice was 60 mg/kg [23]; the
LD50 of 5-MeO-DMT in mice was 278 mg/kg [24].
The principal b-carboline alkaloids added to DMT in
ayahuasca mixtures are harmine, harmaline and tet-
rahydroharmine. In addition to the B. caapi vine, these
alkaloids can be found in the Peganum harmala (Syrian
rue) shrub, a desert plant native to Central Asia. An
aqueous extract of P. harmala seeds administered orally to
rats resulted in a LD50 of 2 g/kg [25]. Because the
b-carboline admixtures in ayahuasca appear to be less
Table 1 Quantity (in milligrams) of alkaloids in ayahuasca/hoasca brews.1
Dose size 2DMT Harmine Harmaline THH Reference
140 ml 35.6 238 28 150 [2,14,18]
237 ml 33 17 26 Not stated [75]
60 ml 36 280 25 96 [15]
Gelatin capsule 30 120 None None [4]
100 ml 9.1 47.5 Trace 4.2 [17]
100 ml38.8 9.2 Not stated 26.5 [17]
Gelatin capsule 42 71 4.8 57 [30]
200 ml 25 30 trace 10 [16]
1Adapted, in part, from Riba [76]. 2Estimated average given to a 70 kg adult in the study referenced. 3Two samples of ayahuasca reported in the same
26 Robert S. Gable
© 2007 The Author. Journal compilation © 2007 Society for the Study of Addiction Addiction,102, 24–34
toxic than DMT, our attention should focus on the DMT
A simple extrapolation of DMT lethality data from
mice to humans is obviously untenable. We are therefore
forced to make some intrepid, but not original, assump-
tions. One traditional rule for scaling unknown differ-
ences between humans and non-human animal species is
simply to assume that humans are 10 times more sensi-
tive, based on body weight, than rodents [26]. To be even
more cautious in light of the absence of LD50 data regard-
ing oral DMT, let us assume that humans are 20 times
more sensitive than rodents. This would result in a
human LD50 of 1.6 mg/kg for DMT administered intrave-
nously, or a total intravenous dose of 112 mg for a typical
70 kg person. Because we are interested in the potential
toxicity of oral DMT in ayahuasca, it is necessary to
convert our estimated intravenous LD50 dose of
1.6 mg/kg DMT to an oral equivalent. Usually, an intra-
venously administered dose of a substance is assumed to
have bioavailability of 100%. The bioavailability of an
oral dose is significantly less. An oral DMT dose of
1.0 mg/kg has been reported to increase blood pressure
and heart rate comparable to a 0.1–0.2 mg/kg intrave-
nous dose [20]. With respect to psychological reactions,
an intravenous DMT bolus of 0.4 mg/kg has been docu-
mented carefully as ‘highly psychedelic’ ([12], p. 138),
while an oral dose of DMT ‘in excess of 2.0 mg/kg’ in
ayahuasca is known to produce maximal effects ([4],
p. 175). Let us assume an intravenous-to-oral conversion
factor of 1 : 5, based on the assumption that 0.4 mg
intravenously is equivalent to approximately 2.0 mg of
oral DMT. If 1.6 mg/kg is a median lethal dose of
intravenous DMT, then a median lethal dose of oral
DMT would be 8 mg/kg, or a total dose of 560 mg for a
70 kg individual. Note, however, that 560 mg is the esti-
mated median dose, and therefore one-half of potential
DMT fatalities would occur at an oral dose less than
560 mg.
A safety ratio or safety margin for ayahuasca can be
estimated by comparing the calculated LD50 to the cus-
tomary effective dose. The average ceremonial dose of
DMT, as listed in Table 1, is about 27 mg; therefore, the
safety margin for ayahuasca is approximately 20 (560/
27 =20.7).
Cardiac stress
Intravenous DMT is known to increase heart rate
rapidly, as well as systolic and diastolic blood pressure.
Strassman & Qualls [27] reported that a 0.4 mg/kg dose
of DMT at the postinjection interval of 2 minutes raised
the heart rate approximately 26 beats per minute (bpm),
and raised systolic pressure by 35 mmHg and diastolic
pressure by 30 mmHg. DMT plus b-carbolines in
ayahuasca ingested in doses ranging from 0.48 mg/kg
to 1.0 mg/kg were shown to induce peak increases in
heart rate and blood pressure at about one-third that of
intravenous DMT after 90 and 120 minutes [3,20].
Table 2 summarizes these data along with comparisons
of some commonly used psychoactive substances. The
reference cited for each of the substances in Table 2 is
the primary, but not exclusive, source of the information
On the basis of acute heart rate and blood pressure
data, the hemodynamic effects of a typical dose of
ayahuasca appear to be less potentially hazardous than
many commonly used psychoactive substances.This ten-
tative conclusion assumes that any substance listed in
Table 2 Heart rate and blood pressure increases after administration of DMT or other psychoactive substances.
Heart rate
(mmHg) Reference2
Intravenous 0.4 2 minutes 26 35 30 [27]2
Oral 0.48 20 minutes 7.4 9.0 9.3 [3]
Oral 0.5 45 minutes 6.4 8.8 10.4 [20]
Oral 0.75 45 minutes 8.0 13.4 9.8 [20]
Oral 1.0 45 minutes 9.2 13.8 8.6 [20]
Alcohol oral 1157 15 minutes 9 -2 1 [77]
Caffeine oral33.3 15 minutes 4.0 5.0 5.0 [29]
Cocaine insufflated41.37 55 minutes 17 14 14 [78]
Marijuana smoked (98.6 ng/ml)515 minutes 11.6 (See footnote 6) [79]
MDMA oral 1.5 60 min 28 25 7 [80]
1Assumes an individual who has not developed toleranceto the indicated substance. 2The reference listed is the primary, but not the exclusive, source for
the data summarized in the table. Some original data were averaged. 3Caffeine powder mixed with grapefruit juice; caffeine dose was equivalent to two
or three cups of instant coffee. 4Administered as 120 mg of white powder (cocaine and lactose) in four ‘lines’, snorted two lines per nostril. 5Plasma THC
from 10 puffs, at 1-minute intervals, from a marijuana cigarette containing 1.75% THC. 6Typically, a slight increase in blood pressure when in a supine
position, a decrease when in an upright position.
Risk assessment of oral DMT 27
© 2007 The Author. Journal compilation © 2007 Society for the Study of Addiction Addiction,102, 24–34
Table 2 is administered once by the route and in the
quantity indicated without any concomitant pharmaco-
logically active substances. Occasional stroke, myocardial
infarction and other adverse cardiovascular events can be
expected to be associated with, even if not directly caused
by, the use of ayahuasca or other drugs or foods that
induce acute hemodynamic changes. Individual differ-
ences in metabolism and health status often result in a
wide range of reactions to psychoactive substances. For
example, the heart rate of some of the participants in the
Strassman & Qualls intravenous DMT study [27] peaked
at 150 bpm, while the heart rate of other participants
was raised no higher than 95 bpm. Furthermore, the
hemodynamic reaction to ayahuasca may depend on the
relative concentrations of DMT to the b-carbolines. In
decoctions tested by Pomilio, Vitale & Ciprian-Ollivier
[17], an exceptionally low concentration of DMT com-
pared to b-carbolines significantly decreased heart rate.
An experiment with dogs found that harmala alkaloids
decreased heart rate but were inconsistent in their effect
on blood pressure [28].
Because heart rate increases with ayahuasca are so
minimal, the differences may be the result of unrelated
physical activity of the participants. Such changes might
be put into perspective by a study conducted by Hartley,
Lovallo & Whitselt [29]. A beverage containing a 230 mg
dose of caffeine (equivalent to two or three 150 ml cups of
instant coffee) resulted in only negligible increases in
heart rate (4 bpm) and blood pressure (5 mmHg). Later in
the same study, the researchers asked the 77 study par-
ticipants to deliver a 3-minute speech ‘to a video camera
in front of 2 experimenters wearing white coats’ ([29],
p. 1023). Under this anxiety-producing condition, the
average increase in heart rate was 30 bpm; the systolic
pressure increased an average of 28 mmHg and the dias-
tolic pressure increased an average of 21 mmHg. These
increases are more than twice those occurring with oral
It is generally held that the b-carbolines in ayahuasca
are reversible and highly selective inhibitors of MAO [30].
The ayahuasca-induced blockade of MAO presumably
allows a larger quantity of serotonin to accumulate in
nerve terminals. Excessive accumulation can produce a
range of adverse physiological symptoms, a ‘serotonin
syndrome’, that includes tremor, diarrhea, autonomic
instability, hyperthermia, sweating, muscle spasms and
possible death [31].
A few irreversible or non-selective MAO inhibitors
(e.g. phenelzine, tranylcypromine) are associated
strongly with instances of severe serotonin syndrome,
but a large number of opiates, analgesics, tricyclic anti-
depressants, selective serotonin reuptake inhibitors
(SSRIs) and anti-migraine agents have also been
implicated [31]. Individuals who have recently used
ginseng, St John’s wort, dextromethorphan or 3,4-
methylenedioxymethamphetamine (MDMA: ecstasy)
should be cautious about using ayahuasca. Physical dis-
comfort or chronic pain (e.g. backache) may be exacer-
bated by ayahuasca, so potential users should be warned
of this side effect.
Table 3 lists six reported instances in which there
were severe toxic reactions to a psychoactive tryptamine
and/or a b-carboline. The death of a 25-year-old male
caused by amine intoxication [32] involved 5-MeO-DMT
in addition to DMT and b-carboline. No laboratory
animal studies were located during the present review
that compared the toxicity of orally active 5-MeO-DMT
with orally active DMT. However, 5-MeO-DMT is
reported to be more potent than DMT when smoked [5]
or taken orally with harmaline [4]. Experienced
researchers have cautioned that these substances should
not be casually interchanged in ayahuasca-like prepara-
tions. The male decedent ingested an unknown quantity
of ‘herbal tonics’ that presumably contained MAOIs in
addition to the DMT and 5MeO-DMT because he was
found to have a blood concentration of tetrahydro-
harmine three times higher than that found among 14
volunteers in a UDV hoasca study [2]. The autopsy was
performed the day after the body was discovered, so
post-mortem drug redistribution makes it difficult to
determine what the peak cardiac or peripheral blood
concentration of tetrahydroharmine or 5-MeO-DMT
might have actually been.
The briefly described fatality of a 71-year-old diabetic
female, listed in Table 3, repor ted that only tobacco leaves
and B. caapi were the constituents of the so-called
‘ayahuasca’ brew [33]. The abstract did not document
the concentration of any b-carbolines, but did report
measurements (at unstated time intervals) of
1900 ng/ml and 710 ng/ml of blood nicotine. These con-
centrations exceed by at least 20 times the average post-
mortem nicotine concentration (34 ng/ml) reported by
Ekwald & Clemedson [34]. ‘The cause of death [of the
71-year-old] was attributed to acute nicotine intoxica-
tion’ ([33], p. 287). Administration of the unorthodox
nicotine/b-carboline brew by enema to this older person,
who was a non-smoker, precludes the relevance of this
case to typical ayahuasca/hoasca use.
The quantity of P. harma seeds consumed as a single
intoxicant by the two individuals cited in Table 3 [36,37]
should be distinguished from the lower quantity of B.
caapi or P. harmala that is used customarily in an ayahua-
sca brew. These individuals ingested 15–50 times more
b-carboline alkaloids than the 3 g needed to maintain the
oral activity of DMT in an ayahuasca preparation [5].
Herraiz [38] has noted that coffee may act as a MAOI, and
the caffeine used by one of the decedents probably inten-
sified the effect of the harmala seeds.
28 Robert S. Gable
© 2007 The Author. Journal compilation © 2007 Society for the Study of Addiction Addiction,102, 24–34
The last item listed in Table 3 involved more than 30
individuals between the ages of 20 and 50 years who
‘were participating in a meditation session named
“releasing autohypnosis of forest medicine men”’ ([39],
p. 50). The published report does not detail the number of
participants who were hospitalized, their gender or their
health status following the ingestion of 100–200 ml of
herbal tea, although all the patients recovered satisfacto-
rily. Fatalities from atropine or scopolamine are rare, and
from harmine are extremely rare. The reported dose of
atropine (4 mg) and of scopolamine (78 mg) received by
the meditation session participants is eight to 13 times
less than the estimated minimal lethal dose of these sub-
stances [40,41]. The severe reactions of at least a few of
the individuals who required mechanical ventilation
was attributed by the report authors to the combined
synergistic actions of harmine, atropine and scopola-
mine. This incident provides additional evidence of the
potential danger of combining pharmacologically active
substances in non-traditional ways.
To this author’s knowledge, there have been no deaths
caused by hoasca or any other traditional DMT/b-
carboline ayahuasca brews. The probability of a toxic
overdose of ayahuasca is seemingly minimized by seroto-
nin’s stimulation of the vagus nerve which, in turn,
induces emesis near the level of an effective ayahuasca
dose. The risk of overdose appears to be related primarily
to the concurrent or prior use of an additional serotoner-
gic substance. People who have an abnormal metabolism
or a compromised health status are obviously at a greater
risk than the normal population, and might prudently
avoid the use of ayahuasca preparations.
Table 3 Acute toxic reactions to ayahuasca-related compounds.
Age/sex Primary Estimated Effects Toxicological Factors Reference
25 m5-MeO-DMT Unknown quantity
of ‘herbal tonics’
Death caused by
5-Meo-DMT 1.88
mg/l, THH
0.38 mg/l,
0.17 mg/l
Camping in park,
71 F Ayahuasca
Not reported Death caused by
Nicotine 1900 mg/l
and 710 mg/l
Non-smoker, no
emesis, brew
administered by
36 mAyahuasca
100 ml of brew Gross motor tremors,
resolved without
treatment after 4
No blood chemistry
Daily use of 20 mg
of oral fluoxetine
35 mPeganum
150 g of P. harmala
Heart rate 100 bpm,
bp 80/40 mmHg,
convulsion, stable
in few hours after
b-carbolines not
Gastric ulcer, mild
anemia but other
27 F P. harmala 50 g of P. harmala
Hallucinations, GI
resolved in a few
b-carbolines, caffeine
level not reported
Seeds ingested with
A brew of harmine
27 mg, atropine
atropine 4 mg,
78 mg
Tachycardia, coma,
all patients
with supportive
Harmine 179 mg/l,
atropine 27 mg/l
515 mg/l
Ingested alkaloids
had ‘synergistic
1Coffee brews contain b-carboline alkaloids. 2‘More than 30 people aged 20–50 years’. No information provided regarding sex or health status of
Risk assessment of oral DMT 29
© 2007 The Author. Journal compilation © 2007 Society for the Study of Addiction Addiction,102, 24–34
Psychological dysfunction
The general sequence of psychological and cognitive
responses to ayahuasca is dose-dependent and predict-
able; however, the reactions of any particular individual
at any one session are not. With a medium dose of DMT,
objects in the environment appear to vibrate and increase
in brightness. Rapidly moving patterns and scenes
emerge that are visible with eyes either open or closed.
This experience is referred to as being a ‘visionary state’
([42], p. 109). It should be noted that these altered per-
ceptions and cognitions do not usually cause users to
become unaware of their surroundings or lose the ability
to speak coherently. Many users walk to the restroom as a
result of diarrhea.
Riba and colleagues [20] described the reactions of six
volunteers after they each received doses of 0.05, 0.75
and 01.0 mg/kg of ayahuasca. Results obtained on
Addiction Research Center Inventory (ARCI) scales
showed that as the doses increased, emotions of happi-
ness, sadness, awe and amazement also increased. At
medium and high doses, the volunteers agreed that the
experience seemed similar to a dream and that the sense
of self and the passing of time were deeply affected. For
example, the awareness between individuals can become
so interlinked that typical self-centered judgements about
the contents of another person’s statement are simply
absent. With respect to time perception, some people
report that during an ayahuasca session they are swept
into a conscious state where the usual orderly pro-
gression of time becomes obviously non-existent, and
they experience ‘eternity’ ([43], p. 45). This sensation/
perception was often associated with the emotion of well-
being, but it can also be accompanied by feelings of terror.
Virtually all data sources indicate that the DMT or
ayahuasca experience has a substantial degree of unpre-
dictability with respect to both aversive and positive
aspects, depending on variables such as dosage, partici-
pant’s intention and setting. Reactions during ayahuasca
ceremonies have ranged from profound calmness [44] to
anguished cries for forgiveness [45].
In interviews with 150 informants, Shannon [46]
reported that, even among individuals without academic
education or philosophical training, the ayahuasca expe-
rience prompted users to reflect seriously on the phenom-
ena of life, nature and human consciousness. A pilot
study by Grob and colleagues [47] comparing 15
members of the UDV with a control group of 15 non-
members revealed that the UDV members showed more
rigidity, regimentation, reflection and word-recall on
various tests than non-members. According to Grob
([47], p. 90), ‘all of the 15 UDV subjects claimed that
their experience with ritual use of hoasca as a psychoac-
tive ritual sacrament had had a profound [positive]
impact on the course of their lives’. Most of the UDV
members had a history of moderate to severe alcohol use
prior to joining the UDV. This variable was not reported
for the control group, so the generalization of this study’s
result to the general population is uncertain.
Certain perceptual characteristics of the ayahuasca
experience overlap those of schizophrenia, and a few
researchers have reported that urinary or blood levels of
DMT are above normal in schizophrenic individuals
[48,49]. This has led to the hypothesis that the non-
destruction of dimethylated indolealkyalamines such as
DMT could play a role in progressive deterioration of cog-
nitive processes [50]. Other studies have produced con-
flicting results and alternative conclusions [51,52]. Jacob
& Presti ([53], p. 935) proposed that increased DMT,
acting at the G-protein-coupled trace amine receptor,
might actually serve in schizophrenics as ‘a homeostatic
response to calm or suppress psychotic activity, rather
than exacerbate it’. At present, the proposition that
endogenous DMT in schizophrenia is related biochemi-
cally to ayahuasca-induced states of consciousness
remains a speculative hypothesis.
The hallucinogenic effect of ayahuasca and other
tryptamine derivatives can precipitate severe adverse psy-
chological reactions, and this is especially true when
administered outside established ceremonial practices
[54]. For example, two cases of unsupervised use of
5-methoxy-N,N-diisopropyltryptamine (5-MeO-DIPT,
‘foxy’) have been reported in which an unknown amount
of 5-MeO-DIPT caused sensory hallucinations requiring
several hours of hospitalization [55,56]. Transient psy-
chotic episodes are also known to occur with high doses
of psilocybin [57] and LSD [58]. LSD, psilocybin and
5-MeO-DIPT are, however, orally active and more potent
than DMT; thus the comparability of these three sub-
stances with DMT is somewhat problematic.
Over a period of 5 years, the medical studies section of
the UDV documented between 13 and 24 cases in which
ayahuasca might have been a contributing factor in a
psychotic incident ([13], p. 701). The incidents docu-
mented by the UDV occurred from an estimated total of
25 000 servings of the hoasca tea. Although the preva-
lence rate of psychosis or schizophrenia among adults in
the United States varies according to the way in which
diagnostic criteria are applied, the generally accepted
estimate is approximately 1.3% [59]. A reported UDV rate
of psychotic episodes under 1% suggests that the use of
hoasca is not a triggering event for sustained psychosis.
Many or most of the UDV psychotic episodes were tran-
sient in nature and resolved spontaneously ([13], p. 623).
Dependence and abuse potential
The extent to which ayahuasca might lead to physiologi-
cal dependence or compulsive drug-seeking is an
30 Robert S. Gable
© 2007 The Author. Journal compilation © 2007 Society for the Study of Addiction Addiction,102, 24–34
important public health concern. The physiological
dependence potential of DMT and ayahuasca remains to
be documented convincingly. Hallucinogenic substances
structurally similar to DMT are rarely used in a compul-
sive manner that would meet the dependence criteria of
the Diagnostic and Statistical Manual version IV (DSM-IV)
[60]. No studies were located during the present review
that reported that the termination of DMT resulted in an
abstinence syndrome.
With respect to drug tolerance, however, a few non-
human animal studies have been conducted that show
varying degrees of tolerance to behavioral and physi-
ological responses over a period of 3 or 4 weeks [61–63].
Little or no tolerance to emotional or autonomic effects
was reported in one study, where human volunteers were
administered DMT four times at 30-minute intervals
[64], and in another study where DMT was administered
twice daily for 5 days [52].
Despite the presumed absence of physiological depen-
dency and tolerance, ayahuasca might, nonetheless,
function as a positive reinforcer leading to significant
abuse potential. We would want to know, for example,
what proportion of individuals who try DMT or ayahua-
sca once or twice fall into a pattern of chronic use that
they then find difficult to quit. The UDV has reported that
15–20% of first-time participants in hoasca ceremonies
become UDV members ([13], p. 700). This subsequent
participation in the UDV church is within the reported
range of first-time visitors who become members of
Christian churches in the United States [65].
Future consumption patterns of ayahuasca are diffi-
cult of determine because, in part, the frequency of
present use in the general population is so low, but its
general psychopharmacological profile suggests that it
lacks the abuse potential of amphetamines, cocaine,
opiates or other widely abused substances. Indeed,
accounts of any strong and sustained reinforcing effects
of tryptamine compounds are rare in experimental litera-
ture. More typically, non-human animal studies conclude
that administration of tryptamine derivatives such as
mescaline, psilocybin or DMT result in erratic patterns of
self-administration indicating that ‘these compounds
have weak reinforcing effects, or alternatively, mixed rein-
forcing and aversive effects’ ([66], p. 156).
Any attempt to characterize the possible acute adverse
health effects of ayahuasca is hampered by the very
limited number of relevant scientific studies of DMT and
b-carboline decoctions. This situation invites an easy
commingling of facts, speculations, inferences, biases,
conjectures and hidden agendas. Arguments made in the
course of litigation are especially prone to linguistic
obfuscation of empirical weaknesses. None the less, legal
and policy decisions must be made in the light of what
almost always seems to be insufficient evidence. Data
available at this time indicate that the acute systemic tox-
icity of ayahuasca is, by comparison, substantially less
than alcohol. The average acute lethal dose of ethyl
alcohol is well-documented at approximately 330 g [67],
10 times the normal recreational dose. The acute lethal
dose of ayahuasca was calculated in this review as 20
times the effective dose. This safety margin is similar to
codeine, mescaline and methadone [9]. Previous esti-
mates of the LD50 of DMT have been as high as 40 or 50
times the customary dose [9,68]; the difference is prima-
rily a result of varying the safety factors that are used to
extrapolate data from non-human laboratory animal
studies to humans.
No acute health hazards, excluding potential seroton-
ergic reactions, have been documented as a routine,
serious threat from ayahuasca when ingested within the
range of customary dosages. Possible chronic health
effects of ayahuasca were not considered in the present
Most public attention is focused on hazards that we
want to avoid, such as accidents, heart attacks or bank-
ruptcy. However, there are hazards that people accept,
perhaps grudgingly, because they perceive a potential
benefit—for instance, crossing a street against the traffic
light, speeding to a hospital with a sick child, agreeing to
an adjustable mortgage. Andritzky [69] has described the
traditional use of ayahuasca in Amazonia during healing
rituals. A more contemporary North American illustra-
tion was provided by a university administrator who
reported that he previously considered Schedule I drugs
to be a taboo option until he was diagnosed with meta-
static liver cancer [70]. When potential benefits are con-
sidered, the option with the least risk is not necessarily
the best choice.
Indeed, some risks are not merely accepted, but
actively sought. Examples include hang-gliding, road
racing and alcohol drinking contests. Recently, the inter-
net has become a favored source of information for
individuals seeking drug-related experiences. Boyer,
Shannon & Hibberd [71] have profiled 12 adolescents in a
drug treatment program who reported being influenced
detrimentally by drug information, including a descrip-
tion of Syrian rue, that they found on the internet.
However, the internet also contains descriptions of
intoxicated misadventures that might serve as a caution-
ary tale (e.g. a self-reported ayahuasca overdose caused
by the user’s self-described ‘swaggering arrogance’ ([72],
p. 1). Virtually all poisoning reports with tryptamine/
MAOI mixtures involve individuals who prepared their
own brew and/or who ingested an additional psychoac-
tive substance [35,39,72,73].
Risk assessment of oral DMT 31
© 2007 The Author. Journal compilation © 2007 Society for the Study of Addiction Addiction,102, 24–34
The relative lack of abuse potential of ayahuasca in
social settings seems very plausible. The unpredictable
occurrence of frightening images and thoughts, plus pre-
dictable nausea and diarrhea, makes it a very unlikely
candidate for a ‘club drug’.
Finally, it might be noted that the discipline of toxicol-
ogy has its own queasiness—especially about spiritual
concepts such as ‘transcendence’, ‘ineffability’ and
‘grace’ that often appear in descriptions of ayahuasca
sessions by physically and psychologically healthy indi-
viduals [74]. Many reported experiences are similar to
descriptions of samadhi in advaitan Hinduism, satori in
Zen Buddhism or beatific vision in Christianity. Such
alleged beneficial experiences lie outside the pathology-
oriented realm of toxicology, but not necessarily or com-
pletely beyond the scientific requirement of falsifiability.
Variations in consciousness are, at least in theory, worthy
of serious scientific study because of their central place in
human endeavors.
This review was funded, in part, by the Life Science
Research Group, Inc., an independent non-profit research
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... Based on rodent studies, the average lethal dose (LD50) for humans for i.v. and oral DMT administration have been estimated to be approximately 1.6 and 8 mg/kg, respectively (Gable, 2007). Death caused by ayahuasca is quite rare (Dos Santos et al., 2017). ...
... When several studies were analyzed to compare changes in HR, SBP, and DBP brought on by various psychoactive substances, the hemodynamic effects of ayahuasca appeared less hazardous than i.v. DMT, oral alcohol, insufflated cocaine, smoked marijuana, and oral methylenedioxymethamphetamine (Gable, 2007). As with any substance triggering acute hemodynamic changes, some minor adverse cardiac events may occur with the use of ayahuasca, although an increase in values of hemodynamic parameters could be attributed to changes in physical activity or other causes, such as anxietyprovoking stimuli. ...
... The LD50 for DMT is 47 mg/kg i.p. and 32 mg/kg i.v. in mice, which is similar to the IV LD50 for other compounds resembling DMT structurally (psilocin, psilocybin, bufotenin, and 5-MeO-DMT), when administered to rodents (Dargan and Wood, 2013). When comparing the toxicity of various psychoactive drugs, ayahuasca has a safety margin similar to codeine, mescaline, and methadone, with ta lethal dose about 20 times the usual effective dose (Gable, 2004). There are no reports of deaths directly related to ayahuasca use. ...
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Classical psychedelics represent a family of psychoactive substances with structural similarities to serotonin and affinity for serotonin receptors. A growing number of studies have found that psychedelics can be effective in treating various psychiatric conditions, including post-traumatic stress disorder, major depressive disorder, anxiety, and substance use disorders. Mental health disorders are extremely prevalent in the general population constituting a major problem for the public health. There are a wide variety of interventions for mental health disorders, including pharmacological therapies and psychotherapies, however, treatment resistance still remains a particular challenge in this field, and relapse rates are also quite high. In recent years, psychedelics have become one of the promising new tools for the treatment of mental health disorders. In this review, we will discuss the three classic serotonergic naturally occurring psychedelics, psilocybin, ibogaine, and N, N-dimethyltryptamine, focusing on their pharmacological properties and clinical potential. The purpose of this article is to provide a focused review of the most relevant research into the therapeutic potential of these substances and their possible integration as alternative or adjuvant options to existing pharmacological and psychological therapies.
... The use of ayahuasca has expanded globally (Sánchez and Bouso 2015), and its increasing use by Westerners makes it a public health concern. The scientific information gathered to date suggests that ayahuasca has a good safety and tolerability profile following acute administration in controlled settings (Riba et al. 2001;Rocha et al. 2021) and after prolonged ritual use (Barbosa et al. , 2016Bouso et al. 2012;Gable 2007;Mello et al. 2019). Observational evidence also suggests a low risk for abuse (Barbosa et al. , 2016Bouso et al. 2012;Fábregas et al. 2010;Gable 2007) and beneficial effects for substance-related disorders, mood and anxiety disorders, and improvement of general well-being (Argento et al. 2019;Bouso et al. 2012;Cruz and Nappo 2018;Gable 2007;Gonzalez et al. 2021;Grob et al. 1996;Horák, Hasíková, and Verter 2018;Lawn et al. 2017;Ona et al. 2019;Perkins et al. 2021aPerkins et al. , 2021bRévész et al. 2021). ...
... The scientific information gathered to date suggests that ayahuasca has a good safety and tolerability profile following acute administration in controlled settings (Riba et al. 2001;Rocha et al. 2021) and after prolonged ritual use (Barbosa et al. , 2016Bouso et al. 2012;Gable 2007;Mello et al. 2019). Observational evidence also suggests a low risk for abuse (Barbosa et al. , 2016Bouso et al. 2012;Fábregas et al. 2010;Gable 2007) and beneficial effects for substance-related disorders, mood and anxiety disorders, and improvement of general well-being (Argento et al. 2019;Bouso et al. 2012;Cruz and Nappo 2018;Gable 2007;Gonzalez et al. 2021;Grob et al. 1996;Horák, Hasíková, and Verter 2018;Lawn et al. 2017;Ona et al. 2019;Perkins et al. 2021aPerkins et al. , 2021bRévész et al. 2021). ...
... The scientific information gathered to date suggests that ayahuasca has a good safety and tolerability profile following acute administration in controlled settings (Riba et al. 2001;Rocha et al. 2021) and after prolonged ritual use (Barbosa et al. , 2016Bouso et al. 2012;Gable 2007;Mello et al. 2019). Observational evidence also suggests a low risk for abuse (Barbosa et al. , 2016Bouso et al. 2012;Fábregas et al. 2010;Gable 2007) and beneficial effects for substance-related disorders, mood and anxiety disorders, and improvement of general well-being (Argento et al. 2019;Bouso et al. 2012;Cruz and Nappo 2018;Gable 2007;Gonzalez et al. 2021;Grob et al. 1996;Horák, Hasíková, and Verter 2018;Lawn et al. 2017;Ona et al. 2019;Perkins et al. 2021aPerkins et al. , 2021bRévész et al. 2021). ...
Ayahuasca is a plant decoction in traditional Amazonian medicine. Its ritual use has been internationalized, leading to policy challenges that countries should address. This study evaluates the impact of regular ayahuasca ceremony participation on health by assessing the health status of 377 participants in ayahuasca ceremonies in the Netherlands using validated health indicators. A questionnaire was developed and administered to study participants. The questionnaire included several health indicators with public health relevance (e.g., BMI, diet, physical activity) and psychometrically validated questionnaires (ELS and COPE-easy). The data retrieved through health indicators was compared to normative Dutch data. Participants (50.1% women) were mostly Dutch (84.6%) with a mean age of 48.8 years (SD = 11.6). Compared to normative Dutch data, regular participants in ayahuasca ceremonies showed better general well-being, fewer chronic or lifestyle-related diseases, more physical activity, and a more balanced diet. Participants also used less alcohol during the COVID-19 pandemic, and although they used more illegal drugs than the general population, they did not report associated harms. Our findings suggest that regular participation in ayahuasca ceremonies is not linked to relevant health harms. This data could help drug policymakers to develop and implement evidence-based public policies.
... Esses efeitos muitas vezes se assemelham aqueles induzidos pelos chamados 'psicodélicos clássicos' (que atuam principalmente sobre o receptor 5-HT2A), como o LSD, a psilocibina e a mescalina (Nichols, 2016). Entretanto, uma característica que chama a atenção na experiência com ayahuasca é a capacidade do indivíduo de interagir com o meio circundante, que em geral se mantém preservada, sendo inclusive possível realizarem-se testes de desempenho em atividades cognitivas complexas (Riba et al., 2001(Riba et al., , 2003Gable, 2007;Bouso et al., 2013). Porém, assim como ocorre com outras substâncias psicodélicas, experiências de ansiedade, confusão, medo, terror e pânico também são relatadas no caso da ayahuasca. ...
... Nesse sentido, os casos de reações psicóticas ocorridas em contextos rituais foram associados a múltiplos fatores -principalmente a diagnósticos psiquiátricos anteriores, a presença de sintomas psicóticos na época do ritual ou ao uso de outras drogas (p.ex., Cannabis ou outros psicodélicos) -e não apenas à ingestão de ayahuasca ou DMT . Contudo, a incidência geral de episódios psicóticos em contextos rituais parece ser rara e menor do que a prevalência de problemas psiquiátricos na população em geral, tendo sido estimada em menos que 0,1% (Gable, 2007;Bouso et al., 2017). De qualquer forma, esses dados sugerem que a ayahuasca é, a princípio, contraindicada para pessoas com transtornos psiquiátricos graves, particularmente aqueles propensos à psicose . ...
... Em relação ao potencial de abuso relacionado ao uso de ayahuasca, uma série de evidências demonstra que o risco é baixo (Gable, 2007;Fabregas et al., 2010;Lawn et al., 2017). A ayahuasca tipicamente não induz um desejo de utilizar a substância novamente logo após uma sessão, o que pode estar relacionado, ao menos parcialmente, com a natureza menos prazerosa da experiência, tendo em vista os efeitos de desconforto físico, náusea, vômitos e diarreia, e desconforto psicológico (enfrentar medos e traumas, visões ameaçadoras) que ocorrem com frequência e de maneira imprevisível. ...
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Introdução: Doenças graves levantam questões existenciais que podem ser fonte de sofrimento psicológico e prejudicar o tratamento. Estudos com substâncias psicodélicas demonstram efeitos terapêuticos para ansiedade e depressão associadas a doenças físicas graves, principalmente câncer. Evidências indicam que a ayahuasca – uma bebida psicoativa de origem indígena preparada a partir das plantas Banisteriopsis caapi e Psychotria viridis, utilizada na medicina tradicional amazônica e em contextos ritualísticos/religiosos em diversos países – pode atuar como agente terapêutico no tratamento de transtornos psiquiátricos, destacando-se a depressão e a dependência de substâncias. Estudos preliminares sugerem também que a ayahuasca pode promover efeitos terapêuticos para doenças físicas. Objetivo: O presente estudo busca explorar como o uso ritual da ayahuasca durante o tratamento de doenças físicas graves influenciou o modo como as pessoas que vivenciaram essa experiência compreendem e se relacionam com a doença, procurando identificar os processos psicológicos envolvidos nos efeitos terapêuticos relatados. Métodos: Empregaram- se métodos de pesquisa qualitativa, em abordagem retrospectiva, exploratória e descritiva. Uma amostra intencional foi construída empregando-se critérios de intensidade e heterogeneidade, sendo que o fechamento foi determinado por saturação teórica. Quatorze participantes com diagnóstico atual ou anterior de doenças físicas graves e que fizeram uso ritual da ayahuasca durante o período do tratamento médico foram incluídos, envolvendo casos de câncer, HIV+ e doenças de natureza neurológica, reumatológica, gastrointestinal ou dermatológica. Os dados foram coletados por meio de entrevistas semiestruturadas de questões abertas em profundidade e o conteúdo foi analisado por análise temática, com temas emergentes. Resultados: Os temas identificados cobrem aspectos psicológicos, físicos e espirituais. Os participantes relataram que a experiência ritual com ayahuasca promoveu um espaço de introspecção e análise de conteúdos autobiográficos, com a ocorrência de catarses emocionais e a emersão de sentimentos positivos, o que contribuiu para a redução da ansiedade e de sintomas depressivos, favorecendo o bem-estar psicoemocional. Descreve-se também que a experiência facilitou a identificação de significados sobre a origem e o propósito da doença, bem como a sua ressignificação e aceitação, com reflexos positivos sobre a relação com a doença. Reflexões existenciais amplificadas pela experiência com ayahuasca parecem ter influenciado as concepções dos participantes sobre a vida e a morte, favorecendo a diminuição do medo da morte, maior apreciação da vida, mudanças em relações interpessoais e no estilo de vida. Os participantes relataram também que a experiência com ayahuasca promoveu um fortalecimento da espiritualidade, o que teria beneficiado o tratamento médico. No âmbito da saúde física, relatou-se que os efeitos psicofisiológicos da ayahuasca poderiam ter contribuído para a boa tolerabilidade do tratamento farmacológico, a estabilidade imunológica e a redução de dores crônicas – embora não tenham sido levantadas evidências clínicas comprobatórias. Conclusão: Os resultados deste estudo sugerem que o uso ritual da ayahuasca pode atuar como facilitador no processo de aceitação da doença, por meio de efeitos psicológicos que atuam sobre os significados atribuídos à doença, à vida e à morte, podendo favorecer um relacionamento mais equilibrado com a doença.
... However, it also involves risks. The blockage of MAO implies the accumulation of serotonin at the nerve terminals, which in combination with other serotonergic drugs potentially leads to serotonin syndrome [4,18,38]. There is also a risk of developing psychosis or nonpsychotic mania in vulnerable users or those with a family history (Rafael G [13]). ...
... Alterations in serotonin metabolism (identified by decreased levels of 5HIAA and the ratios 5HIAA/tryptophan and 5HIAA/serotonin) after ayahuasca consumption are in agreement with the MAO inhibition produced by β-carbolines [43]. This blockage of MAO would imply the accumulation of serotonin at the nerve terminals leading to serotonin syndrome [4,18]. Our results showed that this inhibition is positively correlated with most of the subjective effects of ayahuasca. ...
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There has been a renewed interest in the potential use of psychedelics for the treatment of psychiatric conditions. Nevertheless, little is known about the mechanism of action and molecular pathways influenced by ayahuasca use in humans. Therefore, for the first time, our study aims to investigate the human metabolomics signature after consumption of a psychedelic, ayahuasca, and its connection with both the psychedelic-induced subjective effects and the plasma concentrations of ayahuasca alkaloids. Plasma samples of 23 individuals were collected both before and after ayahuasca consumption. Samples were analysed through targeted metabolomics and further integrated with subjective ratings of the ayahuasca experience (i.e., using the 5-Dimension Altered States of Consciousness Rating Scale [ASC]), and plasma ayahuasca- alkaloids using integrated network analysis. Metabolic pathways enrichment analysis using diffusion algorithms for specific KEGG modules was performed on the metabolic output. Compared to baseline, the consumption of ayahuasca increased N-acyl-ethanolamine endocannabinoids, decreased 2-acyl-glycerol endocannabinoids, and altered several large-neutral amino acids (LNAAs). Integrated network results indicated that most of the LNAAs were inversely associated with 9 out of the 11 subscales of the ASC, except for tryptophan which was positively associated. Several endocannabinoids and hexosylceramides were directly associated with the ayahuasca alkaloids. Enrichment analysis confirmed dysregulation in several pathways involved in neurotransmission such as serotonin and dopamine synthesis. In conclusion, a crosstalk between the circulating LNAAs and the subjective effects is suggested, which is independent of the alkaloid concentrations and provides insights into the specific metabolic fingerprint and mechanism of action underlying ayahuasca experiences.
... β-carbolines in ayahuasca decoctions are mostly derived from B. caapi. These compounds represent 0.05% to 1.95% of dry matter and are much more concentrated in seeds and roots than in stems and leaves [32]. Different procedures DMT in Ayahuasca comes mainly from P. viridis and its concentration ranges from 0.1% to 0.66% in dry matter [31]. ...
... β-carbolines in ayahuasca decoctions are mostly derived from B. caapi. These compounds represent 0.05% to 1.95% of dry matter and are much more concentrated in seeds and roots than in stems and leaves [32]. Different procedures used for the preparation of ayahuasca decoction, as well as the use of different parts of plants of the same or different species, can result in a high variability of concentrations of individual components. ...
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Ahyahuasca is a term commonly used to describe a decoction prepared by cooking the bark or crushed stems of the liana Banisteriopsis caapi (contains β-carbolines) alone or in combination with other plants, most commonly leaves of the shrub Psychotria viridis (contains N,N-dimethyltryptamine-DMT). More than 100 different plants can serve as sources of β-carbolines and DMT, which are the active alkaloids of this decoction, and therefore it is important to know the most accurate composition of the decoction, especially when studying the pharmacology of this plant. The aim was to summarize the latest sensitive methods used in the analysis of the composition of the beverage itself and the analysis of various biological matrices. We compared pharmacokinetic parameters in all of the studies where decoction of ayahuasca was administered and where its composition was known, whereby minimal adverse effects were observed. The therapeutic benefit of this plant is still unclear in the scientific literature, and side effects occur probably on the basis of pre-existing psychiatric disorder. We also described toxicological risks and clinical benefits of ayahuasca intake, which meant that the concentrations of active alkaloids in the decoction or in the organism, often not determined in publications, were required for sufficient evaluation of its effect on the organism. We did not find any post-mortem study, in which the toxicological examination of biological materials together with the autopsy findings would suggest potential lethality of this plant.
... This finding is of special relevance for the acute toxicity investigation since the oral route/administration is the closest to the popular consumption of ayahuasca. A previous report indicated there was no evidence of acute toxicity or abuse potential for ayahuasca in animal models upon oral administration and using comparable concentrations of the phytochemical components (Gable, 2007). On the other hand, the group which received intraperitoneal administration of a high dose (2600 mg/kg) in the present study showed severe toxicity symptoms, typical from what is known as serotonergic syndrome, in accordance to a previous study (dos Santos, 2013), and evolved to the deaths of all experimental animals within 24 h after administration, indicating an acute toxic effect. ...
... However, studies investigating ayahuasca use in religious/ritualistic and therapeutic approaches have demonstrated that patients presented decreased substance (e.g., alcohol and other drugs) use, along with no harmful effect Berlowitz et al., 2019;Thomas et al., 2013). In agreement with these results, a review focusing on several preclinical and clinical studies concluded that the dependence potential of ayahuasca and the risk of sustained mood alterations are relatively low (Gable, 2007). Research carried out with members of religions who have been using ayahuasca for many years did not find any increase in the prevalence of psychopathologies (Barbosa et al., 2012;dos Santos et al., 2016). ...
Ethnopharmacological relevance Ayahuasca, a psychoactive beverage prepared from Banisteriopsis caapi and Psychotria viridis, is originally used by Amazon-based indigenous and mestizo groups for medicinal and ritualistic purposes. Nowadays, ayahuasca is used in religious and shamanic contexts worldwide, and preliminary evidence from preclinical and observational studies suggests therapeutic effects of ayahuasca for the treatment of substance (including alcohol) use disorders. Aim of the study To investigate the initial pharmacological profile of ayahuasca and its effects on ethanol rewarding effect using the conditioned place preference (CPP) paradigm in mice. Materials and methods Ayahuasca beverage was prepared using extracts of B. caapi and P. viridis, and the concentration of active compounds was assessed through high performance liquid chromatography (HPLC). The following behavioral tests were performed after ayahuasca administration: general pharmacological screening (13, 130, or 1300 mg/kg – intraperitoneally – i.p., and 65, 130, 1300, or 2600 mg/kg – via oral – v.o.); acute toxicity test with elevated doses (2600 mg/kg – i.p., and 5000 mg/kg – v.o.); motor activity, motor coordination, and hexobarbital-induced sleeping time potentiation (250, 500, or 750 mg/kg ayahuasca or vehicle – v.o.). For the CPP test, the animals received ayahuasca (500 mg/kg – v.o.) prior to ethanol (1.8 g/kg – i.p.) or vehicle (control group – i.p.) during conditioning sessions. Results Ayahuasca treatment presented no significant effect on motor activity, motor coordination, hexobarbital-induced sleeping latency or total sleeping time, and did not evoke signs of severe acute toxicity at elevated oral doses. Ayahuasca pre-treatment successfully inhibited the ethanol-induced CPP and induced CPP when administered alone. Conclusions Our results indicate that ayahuasca presents a low-risk acute toxicological profile when administered orally, and presents potential pharmacological properties that could contribute to the treatment of alcohol use disorders.
... Psychedelics, in particular, generally have low physiological toxicity, safe psychological responses, low addictive/dependence potential, low chance of neurological deficits after use and no associated persisting adverse physiological or psychological effects during or after use [5][6][7][8][9][10][11]. In addition to these properties, psychedelics produce only relatively minor side effects in comparison to commonly prescribed antidepressants [3,12], produce therapeutic effects in patients more quickly than commonly prescribed antidepressants that may take several weeks to produce effects [4] and may produces positive, long-lasting effects after only a single dose/therapy session [12]. ...
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The word “psychedelic” (psyche (i.e., the mind or soul) and delos (i.e., to show)) has Greek origin and was first coined by psychiatrist Humphry Osmond in 1956, who had been conducting research on lysergic acid diethylamide (LSD) at the time. Psychedelic drugs such as N,N-DMT/DMT (N,N-dimethyltryptamine), 5-MeO-DMT (5-methoxy-N,N-dimethyltryptamine), LSD (lysergic acid diethylamide), MDMA (3,4-methylenedioxymethamphetamine) and psilocybin have had significant value as an entheogen in spiritual, religious (shamanic) and sociocultural rituals in Central and South American cultures for thousands of years. In the 1960s, the globalization of these drugs and their subsequent spread outside of their indigenous, old-world cultures, led to the subsequent implementation of strict drug control laws in many Western countries. Even today, psychedelics are still classified as Schedule I drugs, resulting in a still lingering negative stigmatization/perception, vilification, and ultimate criminalization of psychedelics. This controversy still lingers and still limits scientific research and full medical acceptance. For many years up until recently, the spiritual, religious and medicinal value of these drugs could not be explored in a scientific context. More recently, a second wave of psychedelic research is now focusing on psychedelics as neuropharmaceuticals to treat alcohol and tobacco addiction, general mood and anxiety disorders and cancer-related depression. There is now a vast array of promising evidence-based data to confirm the years of anecdotal evidence of the medicinal values of psychedelics. Natural therapeutic alternatives such as psychedelic drugs may provide a safe and efficacious alternate to conventional drugs used to treat mood and anxiety disorders. In a Western context in particular, psychedelic drugs as therapeutic agents for mood and anxiety disorders are becoming increasingly of interest amidst increasing rates of such disorders globally, changing social constructions, the implementation of government regulations and increasing investment opportunities, that ultimately allow for the scientific study to generate evidenced-based data. Alternative psychotherapeutic interventions are gaining interest also, because of their low physiological toxicity, relatively low abuse potential, safe psychological effects, and no associated persisting adverse physiological or psychological effects during and after use. On the other hand, conventional psychotic drugs and anti-depressants are becoming less favorable because of their adverse side effects. Psychedelic neuropharmaceutical interventions may with medical oversight be the solution to conventional psychiatric disorders such as depression and anxiety, and an alternative to conventional psychiatric treatment options. This paper will review the therapeutic potential of psychedelic drugs as alternative therapeutic options for mood and anxiety disorders in a controlled, clinical setting, where the chances of adverse psychological episodes occurring are mitigated.
... viridis) and scraps from the stem of Banisteriopsis caapi (B. caapi) [4,5]. However, over the years, the preparation of Ayahuasca has undergone variations [1,2,6]. ...
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Ayahuasca is a psychoactive beverage that contains the psychoactive compound N,N-dimethyltryptamine and β-carboline alkaloids. This study aims at determining in vitro the bioavailability and bioaccessibility of the main compounds present in decoctions of four individual plants, in a commercial mixture and in four mixtures of two individual plants used in the preparation of Ayahuasca. The samples were subjected to an in vitro digestion process, and the Caco-2 cell line was used as an absorption model. The integrity and permeability of the cell monolayer were evaluated, as well as the cytotoxicity of the extracts. After digestion and cell incubation, the compounds absorbed by the cell monolayer were quantified by high-performance liquid chromatography coupled to a diode array detector. The results showed that compounds such as N,N-dimethyltryptamine, Harmine, Harmaline, Harmol, Harmalol and Tetrahydroharmine were released from the matrix during the in vitro digestion process, becoming bioaccessible. Similarly, some of these compounds, after being incubated with the cell monolayer, were absorbed, becoming bioavailable. The extracts did not show cytotoxicity after cell incubation, and the integrity and permeability of the cell monolayer were not compromised.
... With ayahuasca, little information is available on circumstances of severe toxicities, although presence of MAOIs in the brew may plausibly explain the increased risk for severe drug-drug interactions with prescription, over the counter or herbal supplements, as well as other psychedelics and recreational drugs (Malcolm and Lee 2017;Heise and Brooks 2005;Callaway and Grob 1998). Ayahuasca by itself is unlikely to pose a high risk of ST and its propensity to induce vomiting may also limit the ability to consume large quantities (Gable 2007). ...
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RationaleIn recent years, psychedelic substances with serotonergic mechanisms have accumulated substantial evidence that they may provide therapeutic benefits for people suffering with psychiatric symptoms. Psychiatric disorders targeted by these psychedelic-assisted therapies are managed with serotonergic drugs like selective serotonin reuptake inhibitors (SSRIs) as the current standard of care, so it is important to evaluate the potential risks of drug-drug interactions and serotonin toxicity (ST) between these agents.ObjectivesA critical evaluation of the scientific literature is necessary to delineate the risks of ST when combining psychedelics with available serotonergic pharmacotherapy options. This review article describes signs and symptoms of ST, characterizes mechanisms of ST risk, summarizes what is known about serotonergic psychedelic drug interactions, and outlines potential management strategies.ResultsTrue ST typically occurs with a serotonergic drug overdose or in combinations in which a drug that can increase intrasynaptic serotonin is combined with a monoamine oxidase inhibitor (MAOI). Serotonergic psychotropics that do not contain MAOIs are low risk in combination with psychedelics that also do not contain MAOIs. Signs and symptoms warranting immediate medical attention include myoclonus, extreme and fluctuating vital signs, agitation or comatose mental state, muscle rigidity, pronounced hyperthermia (fever), and/or seizure activity.Conclusions Serotonin-related adverse reactions exist along a spectrum with serotonin syndrome being the most severe manifestations of ST. Due to varying serotonergic mechanisms of psychedelics and psychotropics, with varying propensities to increase intrasynaptic serotonin, some combinations may present a significant risk for serotonin toxicity (ST) while others are likely benign.
This chapter describes the pharmacology, clinical effects and toxicology of naturally occurring tryptamines (including dimethyltryptamine and mitragynine), and synthetic tryptamines (unsubstituted, 4-substituted and 5-substituted). A description of the diverse pharmacokinetic properties of tryptamines is followed by a review of receptor interactions, particularly serotonin receptor agonism responsible for hallucinogenic psychoactive effects. User reports detailing desired effects of tryptamines are reviewed. The chapter describes prevalence data demonstrating increasing use of synthetic tryptamines in the developed world, and the use of naturally occurring tryptamines including mitragynine outside of traditional settings. Animal and human experimental data demonstrating tryptamine toxicity is reviewed, followed by a summary of user reports describing unwanted effects. The chapter concludes by reviewing deaths associated with tryptamine exposure including deaths associated with the increasing use of mitragynine.
Background: The psychoactive stimulant 3,4-methylenedioxymethamphetamine (MDMA), also known as ecstasy, is widely used in nonmedical settings. Little is known about its cardiovascular effects. Objective: To evaluate the acute cardiovascular effects of MDMA by using transthoracic two-dimensional and Doppler echocardiography. Design: Four-session, ascending-dose, double-blind, placebo-controlled trial. Setting: Urban hospital. Patients: Eight healthy adults who self-reported MDMA use. Intervention: Echocardiographic effects of dobutamine (5, 20, and 40 μg/kg of body weight per minute) were measured in a preliminary session. Oral MDMA (0.5 and 1.5 mg/kg of body weight) or placebo was administered 1 hour before echocardiographic measurements in three weekly sessions. Measurements: Heart rate and blood pressure were measured at regular intervals before and after MDMA administration. Echocardiographic measures of stroke volume, ejection fraction, cardiac output, and meridional wall stress were obtained 1 hour after MDMA administration and during dobutamine infusions. Results: At a dose of 1.5 mg/kg, MDMA increased mean heart rate (by 28 beats/min), systolic blood pressure (by 25 mm Hg), diastolic blood pressure (by 7 mm Hg), and cardiac output (by 2 L/min). The effects of MDMA were similar to those of dobutamine, 20 and 40 μg/kg per minute. Inotropism, measured by using meridional wall stress corrected for ejection fraction, decreased after administration of dobutamine, 40 μg/kg per minute, but did not change after either dose of MDMA. Conclusions: Modest oral doses of MDMA increase heart rate, blood pressure, and myocardial oxygen consumption in a magnitude similar to dobutamine, 20 to 40 μg/kg per minute. In contrast to dobutamine, MDMA has no measurable inotropic effects.
This chapter focuses on medical toxicology, and discusses the predominantly substance-induced effects. However, the general principles of toxicology are also valid in the field of veterinary medicine, and they also apply to physical agents, such as ionizing radiation. Risk assessments for certain ecosystems are discussed with respect to human exposure because otherwise this field requires special expertise, and different priorities must be considered. The assessment of toxicological risk is a difficult process. Evaluation of the necessary clinical and experimental data requires a high degree of toxicological and medical expertise, including a solid medical education and toxicological experience acquired over many years.
A new method for the determination of N,N-dimethyl-5-hydroxytryptamine (bufotenine), N,N-dimethyltryptamine (DMT)*, 5-methoxy-N,N-dimethyltryptamine (5-MeODMT), and N-methyltryptamine (NMT) was developed using highperformance liquid chromatography-mass spectrometry (HPLC-MS). Identification of the analytes is based on liquid chromatographic retention times of analytes and two fragment ions produced by a triple quadrupole mass spectrometer. Quantification is based on electrospray ionization (ESI), and multiple reaction monitoring (MRM) was also utilized for getting better selectivity. The analytes and internal standard were separated from the urine matrix by solid-phase extraction (SPE). The method was applied for the determination of these compounds in urine samples of patients from surgical, medical and psychiatric wards. Of the dimethylated amines, only bufotenine was found in significant amounts (up to 34 w g/L). In keeping with our earlier results, the bufotenine excretion of psychiatric patients ...
Abstract The experimental psychosis observed after drinking Hoascareproduces,the pathologic transmethylationtheory of schizophrenia. The occurrence of N,N-dimethyltryptamine (DMT) in the Hoascadrink and in the urine samples of subjects supports now that the biological and neuropsychological effects are produced by this methylated indolealkylamineassisted by the β- carboline derivatives. These results further confirm that the urinary hallucinogenic compounds detected in healthy subjects (post-Hoasca, but not before) are the same as those found in the urine samples of acute psychotic unmedicated,patients. The ability of Hoascato modulate serotonergic receptors was evaluated, and thereby to which extent cortisol, prolactin and serotonin levels as well as perceptual and cognitive processes were affected. The degree of Hoascamonoamine,oxidase (MAO) inhibition was directly correlated with the concentration of MAO- inhibiting β−carbolines. The additive combination,of harmine and tetrahydroharmine (THH) accounts for the MAO inhibition exhibited by Hoasca. Molecular Medicinal Chemistry,IDECEFYN vol 1 July-October 2003, 1- 7 http// ISSN 1666-888X