Ayahuasca

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Ayahuasca

Ayahuasca also known by the names of hoasca, oasca, caapi, kahpi, daime (which means “give me” in Portuguese), yajé or yage, cipó, natema or natem, dapa, mihi, or vegetal is a plant-based psychedelic or hallucinogen. Psychedelics also known as “classic hallucinogens” or more specifically “serotonergic hallucinogens”, are a class of psychoactive substances that produce changes in all your senses, mood, thinking, sense of time and emotions ¹, ², ³. Psychedelics can cause a person to hallucinate, seeing or hearing things that do not exist or are distorted. Psychedelics are substances that exert their effects primarily by an agonist (or partial agonist) action on brain serotonin 5-hydroxytryptamine (5-HT_2A) receptors ¹. Ayahuasca is a concentrated liquid (decoction) made by prolonged heating or boiling of leaves of the Psychotria viridis bush commonly known as chacruna supplying the hallucinogen DMT (N,N-dimethyltryptamine) (Figure 2) and the stem and/or bark of the Banisteriopsis caapi vine commonly called ayahuasca rich in beta-carboline harmala alkaloids (Figure 3), although there can be a variety of other plants from 90 different plants inhabiting the Amazon rainforest included in the decoction for different traditional purposes ⁴, ⁵, ⁶, ⁷. For example, in Colombian Putumayo and Ecuador, the leaves of Diplopterys cabrerana also known as chaliponga are used instead of Psychotria viridis ⁸; in Peru, several plants are frequently added to the aqueous concoction of Banisteriopsis caapi and Psychotria species, most commonly Nicotiana tabacum (tobacco), Brugmansia spp., and Brunfelsia spp. ⁸, ⁹.

The main active alkaloids underlying the psychoactive effects of Ayahuasca were first characterised by Rivier and Lindgren ¹⁰. DMT (dimethyltryptamine) occurs in the leaves of Psychotria viridis bush ¹⁰, ¹¹, while Banisteriopsis caapi vine stem and/or bark accumulates the harmala alkaloids also known as Beta-carbolines: harmine, harmaline, and tetrahydroharmine (see Figure 3) ¹², ¹¹, ¹³, ¹⁴.

The harmala alkaloids, harmine and harmaline, are monoamine oxidase inhibitors (MAOIs), without which the DMT (dimethyltryptamine) would be inactivated by your gut and liver monoamine oxidases (MAOs), allowing DMT (dimethyltryptamine) to reach your systemic circulation and your brain, where it activates serotonin 5-hydroxytryptamine 5-HT1A/2A/2C receptors in frontal and paralimbic areas ¹⁵, ¹⁶, ¹⁷. While tetrahydroharmine acts as a weak serotonin reuptake inhibitor without any MAOI action ¹⁸, ⁶. Ayahuasca is drunk as a liquid.

Ayahuasca means “vine of the soul” or “vine of the dead” in the Quecha language, is a traditional Amazonian decoction ¹⁹, ²⁰, ²¹.

Ayahuasca can have varied effects depending on a person’s mood (often called the ‘set’) or the environment they are in (the ‘setting’) and can encompass a considerable degree of unpredictability ²²:

A person’s mood (the Set): a person’s state of mind, previous encounters with psychoactive drugs, and expectations of what’s going to happen ²³. For example, feelings of anxiety or fear before using ayahuasca can be magnified and result in an unpleasant experience.
The environment (the Setting): the environment in which someone consumes ayahuasca – whether it’s known and familiar, who they’re with, if they’re indoors or outdoors, the type of music and light ²³. For example, using ayahuasca in a calm, quiet and relaxed environment can lead to a please experience, but being in a noisy, crowded place may result in a negative experience.

If you do decide to take ayahuasca, it’s important to consider the following.

It is difficult to predict the strength and effects of ayahuasca. People can have very different experiences taking the same drug on different occasions.
People with mental health conditions or a family history of these conditions should avoid using ayahuasca.
Sometimes other drugs may be sold claiming to be ayahuasca that aren’t.
Taking ayahuasca in an environment and with people where you feel safe may alleviate unpleasant emotional effects.

Use of ayahuasca is likely to be more dangerous when ²⁴:

taken in combination with alcohol or other drugs
driving or operating heavy machinery
judgement or motor coordination is required
alone (in case medical assistance is required)
the person has mental health issues.

Ayahuasca was originally used by Amazonian shamans in ritual ceremonies and by folk healers for a variety of psychosomatic complaints ²⁵. The use of ayahuasca dates back to the earliest aboriginal inhabitants of the Amazonian basin, where it was used by indigenous shamans for communication with spirits, magical experiences, rites of initiation, and healing rituals ²⁶. Ayahuasca was held in high regard among inhabitants of the Amazonian basin, particularly for religious and healing purposes ⁵. These were small private ceremonies where the patient and the shaman, and perhaps one or two others, would consume ayahuasca. Shortly after consumption, vomiting and often intense diarrhea occur ⁵. Vomiting results from increased serotonin (5-HT) stimulating the vagus nerve centrally, and diarrhea may be a result of excessive intestinal stimulation by serotonin (5-HT) peripherally ¹⁸. But after this, visions begin to appear, and the nature of the disease and curative plants are revealed to the shaman and the patient ²⁷. Over the past several hundred years, the use of ayahuasca spread into Peru, Colombia, and Ecuador among indigenous Mestizo populations where it was integrated into folk medicine ²⁶. These practices evolved during the early 1930s ²⁸ for use as a religious ceremony or ritual in three Brazilian syncretic churches which combine indigenous and Christian traditions, the União do Vegetal (the largest, more meditative), the Santo Daime (the oldest, livelier, with music), and Barquinha (an Afro-Brazilian church), during twice monthly ceremonies lasting approximately four hours ²⁰, ¹⁸, ²⁹, ³⁰, ¹⁵. Such religious groups use Ayahuasca both as a healing tool and as a way to “get in touch with the divine realm” ³¹. Ayahuasca therapy has also been used by witch doctors in treating addictions. For example, Lemlij ³² describes a group therapy model where participants come as many weeks as they need and may make a voluntary monetary contribution at the end.

In the last two decades the growing number of religious institutions as well as centers of alternative therapies that are allowed to use ayahuasca have led to a worldwide spread throughout the urban centers of South and North America, Europe, Asia, and Africa where Ayahuasca consumption have been used by users seeking a spiritual experience or a direct psychedelic effect ³³, ³⁴, ³⁵, ³⁶, ³⁷, ³⁸, ³⁹. As such, Ayahuasca recreational use is sharply rising, with a global scale online survey showing an increased popularity on DMT consumption ⁴⁰. In fact, a lot of foreigners travel to the Amazon also known as “ayahuasca tourism” to participate in ceremonial rituals organised by indigenous people ³⁶. There is also an increased search of online “headshops” that legally trade-in ayahuasca ingredients ⁴¹, such as plants rich in DMT and harmala alkaloids, making them widely available to users.

However, DMT is illegal in most countries being classified as a Schedule 1 drug by the United Nations (UN) 1971 Convention on Psychotropic Substances ⁴². DMT is categorised as a Class A substance in the UK, as a Schedule 1 hallucinogenic substance by the Drug Enforcement Agency in the US and it is illegal to import, possess, sell, distribute, or consume ayahuasca ⁴³, ⁴⁰, ⁴⁴, ⁴⁵, as a Schedule 3 drug in Canada, a controlled substance in France and Portugal (the drug is included in the Table 2-A of the Decree Law no 15/93), and as a Schedule 1 drug under the German Narcotics Act; it is also banned in Japan ⁴⁶, ⁴⁷.

The harmala alkaloids are also regulated in a few countries, although not being subject to international control. In 2005, France added harmine, harmaline, tetrahydroharmine (THH), harmol, and harmalol to the list of controlled substances (Journal Officiel de la République Française no 102 du 3 mai 2005; NOR: SANP0521544A), being the only country in Europe where these substances are illegal. In Canada, harmalol and harmaline are also classified as Schedule III drugs under the 1996 Controlled Drugs and Substances Act ⁴⁸.

On the other hand, the herbal products used for ayahuasca preparation, and known to contain Schedule 1 international controlled substances like DMT, are not subject to international control and have a lack of legal control in most countries ³⁵, ⁴². An exception to this includes France, where non-licensed possession of P. viridis, B. caapi, P. harmala, and other plants containing DMT/harmala alkaloids have been banned since 2005 (Journal Officiel de la République Française no 102 du 3 mai 2005; NOR: SANP0521544A); and countries where all psychoactive compounds-containing plants are illegal, like Russia ⁴⁹.

Lastly, Ayahuasca is potentially dangerous if taken by people with certain health conditions or taking certain medications, particularly ones that also release serotonin. Deaths have occurred ⁵⁰, ⁵¹. People who should not take ayahuasca include those with ⁴³, ⁵², ⁵³:

A family history of mental health issues
Bipolar disorder
Depression taking antidepressants
Difficulty vomiting
Epilepsy
Fractures
Gastrointestinal disorders
Glaucoma
Infection
Recent surgery
Retinal detachment
Schizophrenia
Seizures
Serious liver, kidney, or gallbladder disease
Severe cardiovascular disease
Stroke
Tuberculosis
Parkinson’s disease
Psychosis
Uncontrolled or very high blood pressure
Ayahuasca is not recommended for pregnant or lactating women

There is no safe level for ayahuasca and the use of this plant medicine always carries some risk. How ayahuasca affects you depends on:

If you have taken it before
Other medications you are taking
The amount taken
The strength of the decoction (varies from batch to batch)
Your current state of health
Weight
Where you take it and the vibe.

Ayahuasca when consumed in unsupervised settings, the judgement of individuals can be compromised ⁴³, leading to the belief of having superpowers or flying ability ⁵⁴, having actions out of the ordinary like jump out of buildings ⁵⁵ or staring at the sun during long periods of time resulting in eye damage ⁵⁶, ⁵⁷.

The recreational use of psychedelics often results in what is called “bad trips” ², characterized by symptoms like anxiety, heart palpitations, and visual distortions ⁵⁸. “Too little” DMT was also associated with unpleasant feelings, not allowing the consumer to achieve the desired development of the characteristic perceptual effects, only giving them a tensely dysphoric state ⁵⁹. However, it is sometimes difficult to assess the potential hazardous effects caused by the recreational consumption of DMT, since the drug is commonly used in combination with other illicit substances, such as psychostimulants, depressants, narcotics, cannabis, and alcohol ⁶⁰. By virtue of MAO inhibition, severe adverse effects can occur when ayahuasca or the beta-carbolines alone are used concomitantly with selective serotonin reuptake inhibitors (SSRIs) such as antidepressants ⁶¹, as this combination leads to accumulation of serotonin (5-HT) at neuron synapses, resulting in a potentially fatal condition known as serotonin syndrome. Serotonin syndrome is a potentially life-threatening drug reaction ⁶², ⁶³. Serotonin syndrome is caused by medications that build up high levels of serotonin in your body. Too much serotonin causes signs and symptoms that can range from mild shivering and diarrhea to severe muscle rigidity, fever and seizures ⁶², ⁶³. Milder forms of serotonin syndrome may go away within a day or two of stopping the medications that cause symptoms and, sometimes, after taking drugs that block serotonin ⁶². Severe serotonin syndrome can cause death if not treated ⁶². Other compounds that may have serotonergic effects (e.g., lithium and triptans through the activation of serotonin receptors, levodopa through the increase in serotonin release) can also precipitate this fatal condition and should be avoided with ayahuasca ⁶⁴, ⁶⁵.

Vomiting and diarrhea are often reported as adverse effects resulting from ayahuasca consumption ⁶⁶, which may be due to increased central serotonin (5-HT) stimulation of the vagus nerve and peripheral stimulation of the intestine ⁶⁷. However, in a study conducted by Sanches et al. ⁶⁸ in patients with depression, the vomiting effect was not considered as a cause of severe discomfort. Nausea and exhaustion are also commonly mentioned as side-effects. All of these effects are, however, considered to be transient, only persisting for one or two days, and easily manageable ⁶⁹.

Traditional ayahuasca experiences are hosted by a shaman or curandero who prepares and concentrates the brew according to traditional methods and his experience. But there is no regulation of the industry and commercialization has taken over with money-grabbing imposters prevalent and hard to distinguish among legitimate ayahuasca centers. These may not have the same sense of ethics as some of the more genuine retreat centers or deliver the same experience, and at least 11 tourist deaths over the past decade have been associated with being part of an ayahuasca experience.

Ayahuasca should only be taken under the supervision of an experienced shaman or curandero because a trip can change your state of consciousness for several hours and you need to be kept safe.

Figure 1. Ayahuasca plant sources

Footnote: (A) Psychotria viridis bush commonly known as chacruna supplying the hallucinogen DMT (N,N-dimethyltryptamine) and (B & C) Banisteriopsis caapi bark and stem rich in beta-carboline harmala alkaloids, are the most common plant species used in ayahuasca preparations (decoction).

[Source ⁴⁸ ]

Figure 2. Dimethyltryptamine (DMT) and serotonin (5-HT)

[Source ⁵ ]

Figure 3. Beta-carbolines (harmine, harmaline and tetrahydroharmine)

[Source ⁵ ]

What does ayahuasca contain?

Ayahuasca is traditionally made using stem and/or bark of the Banisteriopsis caapi vine and leaves of the Psychotria viridis bush, both of which have hallucinogenic properties.

The main active ingredient, DMT (N, N-dimethyltryptamine) is a hallucinogen (psychedelic substance) that occurs naturally in Psychotria viridis. But DMT is easily broken down by monoamine oxidase (MAO) enzymes in the stomach, small intestine, and liver. This is why ayahuasca also contains Banisteriopsis caapi. Banisteriopsis caapi contains monoamine oxidase inhibitors (MAOIs) which in addition to having their own psychoactive effects, also stop DMT from being broken down by monoamine oxidase enzymes in the liver and gastrointestinal tract. This combination allows DMT to be absorbed and makes a powerful psychedelic drink.

What happens during an Ayahuasca experience?

If you are considering trying ayahuasca, always choose an experienced center with a guide you trust. Ayahuasca is not recommended for some people, and your guide should ask you to complete a questionnaire that should determine if it is safe for you to proceed with the experience.

Participants are asked to purify their bodies by abstaining from alcohol, caffeine, cigarettes, drugs, and sex for several weeks before a traditional ayahuasca experience. A healthy diet, preferably vegetarian should be followed for several days before the experience and the participant should be well-hydrated and in good physical health. The last meal should be eaten about 6 hours before ingesting ayahuasca.

What does an ayahuasca experience feel like?

Ayahuasca experiences tend to be a combination of both positive and negative effects, and some of the negative effects can be distressing. They are usually held at night and last until the effects of ayahuasca have worn off.

The effects usually come on within 20 to 60 minutes and can last 2 to 6 hours. Positive effects may include:

An awareness of yourself and the way you look at yourself (introspection)
Altered state of consciousness
Connection with mythological, religious, or spiritual dimensions beyond what is usually experienced
The emergence of memories and images from the past
Feelings of euphoria
Intense visual and auditory hallucinations
Out-of-body experiences.

The emotional intensity related to these experiences is usually much greater than normal. Some describe the experience as a mirror of their own interior which can make you question your most fundamental assumptions about who you are and what the world is.

Most people also experience negative effects, such as diarrhea and vomiting, although you may have been told this is considered a normal part of the ayahuasca experience. Other negative effects that may alternate with the positive effects or become the main experience can include:

Anxiety
Confusion
Dizziness
Fainting
Fear
Panic
Paranoia
Psychosis.

Ayahuasca can also cause a moderate increase in blood pressure and heart rate and increased body temperature.

How does Ayahuasca work?

Ayahuasca is a concentrated liquid (decoction) made by prolonged heating or boiling of the stem and/or bark of the Banisteriopsis caapi vine rich in beta-carboline harmala alkaloids and leaves of the Psychotria viridis bush supplying the hallucinogen DMT (N,N-dimethyltryptamine), although there can be a variety of other plants from 90 different plants inhabiting the Amazon rainforest included in the decoction for different traditional purposes ⁴, ⁵, ⁶, ⁷. For example, in Colombian Putumayo and Ecuador, the leaves of Diplopterys cabrerana also known as chaliponga are used instead of Psychotria viridis ⁸; in Peru, several plants are frequently added to the aqueous concoction of Banisteriopsis caapi and Psychotria species, most commonly Nicotiana tabacum (tobacco), Brugmansia spp., and Brunfelsia spp. ⁸, ⁹.

DMT (N,N-dimethyltryptamine) is a serotonin-like hallucinogen structurally resembling other indolealkylamines, including melatonin and psychedelic tryptamines such as psilocybin, and is known mostly for its activity as a serotonin 5-hydroxytryptamine (5-HT_2A) receptor agonist ⁷⁰, ⁷¹. DMT is found in fungi, marine sponges, tunicates, frogs, legumes, and grasses ⁷² and has been reported to be formed endogenously in human and rat brains ⁷³ as well as to be found in human urine, blood, and CSF. DMT has affinity for 5-HT1A/1B/1D/2A/2B/2C/6/7 receptors, with proven partial agonist activity at the 5-HT1A/2A/2C receptors ⁷⁴, ⁷⁵, ⁷⁶, ⁷⁷. Carbonaro et al. ⁷⁸ proposed that the mGluR2 glutamate receptors may have some involvement in DMT’s hallucinogenic effect. Current understanding is that psychedelic effects are mediated mainly by 5-HT2A/2C receptors. 5-HT2A receptor activation has also been associated with sympathetic activation which may explain some of the physiologic effects of ayahuasca administration ⁷⁹, ⁸⁰.

DMT activity was demonstrated at the rat trace amine-associated receptor 1 (TAAR1) by Bunzow et al. ⁸¹, where tryptamine is also thought to act as a neurotransmitter ⁷². Premont et al. ⁸² suggested that DMT may function endogenously as part of this system, and proposed that trace levels of endogenous DMT act to produce a calmer, more relaxed mental state and suppress psychosis.

DMT binds to sigma-1 receptors with a moderate affinity, and Fontanilla et al. ⁷⁶ proposed that DMT is likely to serve as an endogenous sigma-1 receptor ligand. The function of this receptor is not well understood, although it is found in lung, prostate, colon, ovaries, breasts, and liver, and is most concentrated in the brain. This receptor may play a role in depression, anxiety, and cancer ⁸³. Sigma-1 receptors are molecular chaperones situated on the mitonchondria-associated endoplasmic reticulum membrane, although when stimulated with high concentrations of ligands, may translocate to the cell’s plasma membrane, where they inhibit several ion channels. DMT has also shown affinity for α1- and α2-adrenergic receptors as well as the dopamine D1 receptor ⁸⁴.

DMT is thought to have dose-dependent effects in humans, visual hallucinations predominating at high doses, while stimulant effects are mostly noted at low doses ⁵⁹. After acute ayahuasca ingestion, psychoactive effects such as intense perceptual and cognitive changes, somatic effects, increased emotional liability, and positive mood are rapidly felt, being resolved within a maximum of 4 to 6 hours ⁸⁵, ⁸⁶, ⁸⁷. Such consumption also results in moderate and transitory cardiovascular, autonomic, neuroendocrine, and immunological effects, being well tolerated when consumed by healthy individuals.

A cycle of experiences designated as the “transcendental circle” by Kjellgren et al. ⁸⁸ are consistent among different individuals, following ayahuasca consumption. Changes in perceptions, visual field vibrating, and users feeling vulnerable are noted 30 min after ingestion, an experience known as the visionary state. Following this, terrifying feelings of confusion, paranoia, and fear can be experienced, which might be accompanied by nausea or vomiting. Then, participants usually mention contact with a spiritual world, characterised by feelings of oneness with the universe, profound peace, and ecstasy, and they are given lessons by spirit entities. The last phase involves fatigue and fading visuals ³⁵. While participants are still able to speak and are aware of their environment during these experiences ²², the perception of time can be altered ⁸⁷.

An ayahuasca experience resembles schizophrenic episodes; however, whether or not this herbal preparation or DMT are involved in a psychotic crisis is still a matter of debate. While some authors report that high levels of endogenous DMT are found in the urine and blood of individuals during a schizophrenic episode ⁸⁹, ⁹⁰, others found no significant difference in DMT levels between schizophrenic patients and normal individuals ⁹¹. It has been hypothesized that DMT is a homeostatic agent with psychotic suppression activity ⁹². Although having a resemblance, ayahuasca-DMT mainly produces visual hallucinations in healthy individuals, while auditory hallucinations are predominant in schizophrenia patients ⁶⁶. The few cases where psychotic episodes occurred were found to be transient in nature and resolved spontaneously ²², ⁹³. Case-control and cross-sectional studies with experienced Ayahuasca consumers revealed that this hallucinogenic herbal concoction is safe, with rare adverse effects, and not associated with psychopathological nor neuropsychological deficits ²², ³⁹, ⁹⁴.

Short-term emotional distress can be a psychological consequence of DMT or ayahuasca use. Development of long-lasting psychosis is infrequent, mostly occurring in individuals after the concomitant use of other drugs, personal or family history of psychosis/non-psychotic bipolar disorders, as well as ongoing psychotic or maniac symptomatology ⁹⁵. In controlled clinical settings, factors that could predispose long-term psychological adverse effects are screened prior to administration of ayahuasca or DMT, their consumption being exceptionally safe in this scenario ⁹⁵. However, when ayahuasca is administered outside clinical settings or established ceremonial rituals, severe and unpredictable adverse psychological reactions that remain to be elucidated can be triggered ⁹⁶.

Beta-carbolines (Figure 3) are tricyclic indole alkaloids resembling tryptamines ²⁸. 6-Methoxytetrahydro-beta-carboline has been found in the human pineal gland ⁹⁷. Several beta-carbolines are found in the Banisteriopsis caapi vine, including harmine, harmaline, and tetrahydroharmine. The first two act as selective and reversible monoamine oxidase A inhibitors (MAO-AIs), while tetrahydroharmine acts as a weak serotonin reuptake inhibitor without any monoamine oxidase A inhibitor action ¹⁸. Beta-carbolines are found naturally in wheat, rice, corn, barley and throughout different body tissues ⁹⁸. They elicit their effects through several mechanisms.

Beta-carbolines without DMT have been shown to produce psychological and physiologic effects, as in a case of intoxication following Paganum harmala seed extract ⁹⁹. The effects, including nausea, vomiting ⁷⁸, hallucinations, ataxia, confusion, and agitation were attributed to CNS stimulation by MAOI activity as well as the serotonin reuptake inhibition by tetrahydroharmine. Frison et al. ⁹⁹ suggested that the hallucinogenic effects could be a result of the affinity of harmine and harmaline for 5-HT receptors. Beta-carbolines from the B. caapi vine taken without DMT are used by the Piaroa of Southern Venezuala. Piaroa shamans and people who use B. caapi describe enhanced empathy, stimulant-like effects, and increased visual acuity, and they also use it as a hunting aid ¹⁰⁰, ¹⁰¹.

The main mechanisms of action proposed for beta-carbolines include the MAO-A inhibitory activity, dopamine efflux, and affinity for the serotonin 5-hydroxytryptamine (5-HT_2A) binding site ¹⁰². Other less studied mechanisms include dopamine transporter (DAT) inhibition at high concentrations in particular of beta-carboline compounds ¹⁰³, harmine as a specific tyrosine-phosphorylation-regulated kinase 1A (DYRK1A) inhibitor ¹⁰⁴ and affinity for the imidazoline (I2) binding site ¹⁰⁵. Harmine has also been found to regulate expression of the peroxisome proliferator-activated receptor gamma (PPAR-ɣ, also known as the glitazone receptor) and shows some antitrypanosomal activity ¹⁰⁶. Harmine upregulates the glutamate transporter (GLT-1, also called excitatory amino acid transporter 2, or EAAT2), the primary mechanism for inactivating synaptic glutamate ¹⁰⁷. Harmane, harmine, and norharmane have also been found to act as inverse agonists at the benzodiazepine binding site (between the α and ɣ subunits) of the GABA-A receptor ¹⁰⁸, dopamine (D(2)) and benzodiazepine receptors. Drug Alcohol Depend. 2000 Aug 1;60(2):121-32. doi: 10.1016/s0376-8716(99)00148-9)). Another study showed that 4 beta-carbolines (1,2,3,4-tetrahydronorharmane, norharmane, harmane, and 6-methoxyharmalan) act as competitive antagonists at the glycine receptor ligand binding site, leading to inhibition at the glycine receptor ¹⁰⁹.

A recent study on neurotransmitter concentrations in the amygdala and hippocampus of rats killed 40 minutes after administration of an ayahuasca infusion reported that ayahuasca reduced levels of glycine and GABA in rat amygdala ¹¹⁰. This is suggestive of an increased release of these neurotransmitters in the amygdala, leading to greater inhibition, while in the hippocampus, it increased GABA levels, suggestive of a decrease in GABA release and excitation at this structure ¹¹⁰. These opposite effects on the level of inhibitory neurotransmission in these two limbic structures may provide some explanation into the behavioural effects of ayahuasca, due to the importance of these structures in neural pathways involved in memory, learning, and emotion.

Harmine and harmaline affect dopamine pathways both by causing a significant increase in dopamine release from striatal cells and by acting as reversible MAO-A inhibitors. A study on the nucleus accumbens of rats ¹¹¹ found that harmine increases electrically evoked dopamine efflux in the nucleus accumbens shell. Brierley & Davidson ¹⁰² proposed that, given harmine has some affinity for the 5-HT2A/2C receptors but not for the dopamine receptor ¹¹², this effect has a 5-HT2A-mediated mechanism. Grella et al. ¹¹³ also found that certain beta-carbolines bind at the 5-HT2 receptor. In another experiment in rat striatum, dose dependent decreases in the levels of dopamine metabolites 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) were also seen, as well as decreases in levels of the serotonin breakdown product 5-hydroxyindoleacetic acid (5-HIAA), though not to the same extent as with the dopamine metabolites ¹¹⁴. These effects are additive when mixtures of various beta-carbolines are used ¹¹⁵. The dopamine transporter serves to actively shift dopamine from the synapse into the presynaptic neuron, acting as the primary mechanism for regulating dopaminergic activity ¹¹⁶. Harmine was found to inhibit dopamine uptake through the dopamine transporter (DAT) in rats. Dopaminergic neurotransmission is primarily modulated through regulation of the dopamine transporters, which act to shuttle extracellular dopamine back into the neurons. Harmine acts a potent ATP-competitive inhibitor of the DYRK1A enzyme, which inhibits synaptic vesicle endocytosis and dopamine transporter (DAT) membrane trafficking, possibly by phosphorylating vesicle proteins taking part in clathrin-mediated endocytosis that serves to regulate dopamine transporter trafficking ¹¹⁷, ¹¹⁸. DYRK1A overexpression has been implicated in defective neural development in Down Syndrome, and the protein has also been implicated in amyloid pathology as well as in tau protein phosphorylation (at serine 262/356/396) in both Down Syndrome and Alzheimer’s disease ¹¹⁹.

Ayahuasca was found to upregulate platelet serotonin transporters ¹²⁰. The glutamate transporter GLT-1/EAAT2 is the main mechanism for extracellular glutamate uptake in the brain, and dysfunction may lead to excessive synaptic glutamate and excitotoxicity. Harmine has been found to activate the GLT-1 gene promoter, leading to increased gene expression and greater extracellular glutamate uptake ¹⁰⁷. Certain beta-carbolines have been found to bind at imidazoline binding sites, including harmine and harmaline found in ayahuasca ¹⁰⁵. Husbands et al. ¹⁰⁵ suggested that the imidazoline type 2 (I2) receptors may play a role in the hallucinogenic nature of ayahuasca given that harmine and harmaline have much higher affinities for the I2 receptor than the 5-HT2A receptor. Harmine also increases superoxide dismutase and catalase activity, and these antioxidant effects may have relevance in depression and several neurodegenerative disorders ¹²¹.

In a study of brain blood flow using single photon emission computed tomography (SPECT) with 15 male volunteers, Riba et al. ¹⁶ reported that ayahuasca produced an activation of frontal and paralimbic brain regions and increased blood perfusion in both the anterior insula; greater intensity was observed in the right hemisphere and in the anterior cingulate and frontomedial cortex of the right hemisphere (areas involved in somatic awareness, subjective feelings, and arousal of emotion). Additional increases were observed in the left amygdala and parahippocampal gyrus, a structure also involved in emotional arousal. Sanches et al. ¹²² reported increased blood perfusion in the left nucleus accumbens, right insula, and left subgenual area 8 hours after ayahuasca ingestion and that ayahuasca was well tolerated. Riba et al. ¹⁶ indicated that these findings suggest an interaction of Ayahuasca with neural systems is important in introspection and processing of emotion and imply a modulatory role of serotonergic neurotransmission in these processes.

Ayahuasca causes a statistically significant increase in activation of many occipital, temporal, and frontal areas, including the primary visual area on magnetic resonance imaging (MRI) during closed eye imagery ¹⁷. Even with eyes closed, on Ayahuasca the levels of activation in the visual area were consistent with seeing a natural image. This action was seen in both the occipital cortex, which includes Brodmann areas 17, 18, 19, all involved in vision ¹⁷. Brodmann area 17 has also been correlated with perceptual changes and psychotic effects such as hallucinations. Areas involved in episodic memory were also activated, including the parahippocampal gyrus (Brodmann area 30) and the middle temporal cortex (Brodmann area 37) ¹⁷. The frontal cortex (Brodmann area 10) is also activated. Emotions and memories were intensified and past experiences were seen through vivid imagery, which gave the whole experience a “status of reality” ¹⁷. The posterior cingulate cortex is key component of the default mode network, a group of neural pathways involved in inwardly focussed thought, conception and awareness of self, remembering the past and envisioning the future. Bousa et al. ¹²³ found an inverse correlation between cortical thickness in the posterior cingulate cortex and intensity and duration of previous ayahuasca use, as well as scores on a personality trait called self-transcendence, a leaning toward spirituality and religiosity and suggested that regular use of psychedelic drugs could result in structural changes in brain areas involved in attentional processes, self-referential thought, and internal mentation. Ayahuasca caused decreased activity in the default mode network, and also decreased connectivity between various components of the default mode network on functional magnetic resonance imaging (fMRI) ¹²⁴.

Endocrine System effects

Callaway et al. ¹⁸ reported both growth hormone (GH) and prolactin increasing but returning to baseline by 360 minutes, and cortisol increasing to a maximum at 60 minutes, and dipping below basal levels at 360 minutes. Growth hormone (GH) and prolactin are also influenced by the serotonergic system, so their findings fit with other studies showing an increase in prolactin levels with DMT and other serotonergic drugs such as MDMA, fenfluramine, and citalopram ¹²⁵, ¹²⁶.

Immune System effects

Dos Santos et al. ¹²⁷ found that relative to placebo, ayahuasca increased total lymphocytes at 1.5 hours, and decreased them at 4.5 hours compared to placebo and to amphetamine, although there was no difference at 24 hours. There were significant decreases in both CD3 and CD4 lymphocytes at 1.5 and 2 hours, no significant changes in CD8 and CD19 lymphocytes, and significant increases in natural killer (NK) cells at 1.5 and 2 hours compared to placebo. No tolerance or sensitization was found with repeat doses ¹²⁸. Davydova et al. ¹²⁹ and dos Santos ¹³⁰ highlighted previous findings and postulated that DMT may activate peripheral 5-HT2A receptors on leukocytes with impacts on cytokine secretion and cell differentiation, and that increased glucocorticoid levels may have modulatory or inhibitory effects on immunity. Amphetamine and MDMA both induce changes similar to ayahuasca, with decreases in CD3 and CD4 lymphocyte levels and increases in NK cell levels ¹²⁷. Frecska et al. ¹³¹ found that DMT caused significantly increased levels of secreted interferon-β and interferon-γ in cultured human NK cells, and suggested that DMT’s action at the sigma-1 receptor could be the mechanism for this effect. In an in vitro study on human primary monocyte-derived dendritic cells, DMT and 5-MeO-DMT reduced production of several pro-inflammatory cytokines (IL-1β, IL-6, TNF-α) and chemokine IL-8, while they increased the secretion of the antiinflammatory cytokine IL-10 ¹³², ¹³³. The authors found that these effects were mediated through the sigma-1 receptor, and also noted that both DMT and 5-MeO-DMT impaired the ability of T helper 1 and T helper 17 cells to activate immune responses. House et al. ¹³⁴ noted that harmaline caused a dose-related suppression of CD8 activity, IL-2 and IL-4 production, B cell proliferation, and NK cell function.

Pupil Size and Body Temperature effects

DMT causes dose-dependent elevations in pupil size ¹²⁸, ¹³⁵. Callaway et al. ¹⁸ reported that pupillary diameter increased to a maximum of 4.9 ± 0.2 mm at 180 minutes, and returned to normal by 360 minutes. Mydriasis has been demonstrated in several intravenous DMT studies ¹³⁵, ¹³⁶. Mean pupillary light reflex (PLR) amplitude was reduced and PLR latency was increased significantly compared to placebo ¹²⁷. A reduced PLR amplitude and increased PLR latency is typically associated with anticholinergics. Two studies found that the serotonin-noradrenaline reuptake inhibitor (SNRI) venlafaxine has the same effect, and they interpreted this as noradrenergic inhibition of parasympathetic transmission on the Edinger-Westphal nucleus, responsible for iris constriction ¹³⁷, ¹³⁸.

With respect to body temperature, dos Santos et al. ¹²⁷ compared DMT (at a dose of 1 mg DMT/kg body weight), amphetamine, and placebo, and found that with placebo, body temperature steadily increased over the day, whereas both DMT and amphetamine caused a statistically significant decrease in body temperature during the first hour, followed by a gradual increase, which was larger for amphetamine. Studies involving IV DMT have shown inconsistent results, with one study showing increases and three others showing no change or ambiguous results ⁷⁹, ¹³⁶, ¹³⁸.

Cardiovascular effects

In a study of 18 volunteers, Riba et al. ¹⁵ showed maximum increases in diastolic blood pressure (DBP) of approximately 10 mmHg at 15 minutes, and a maximal systolic BP (SBP) rise of approximately 8 mmHg at 75 minutes following ingestion of ayahuasca containing a 0.85 mg/kg dose of DMT. With respect to heart rate, the maximum increase was approximately 5 beats per minute (BPM) at 60 minutes. Only two of the 18 volunteers had a systolic BP over 140 (maximum 146) at any point in time, and two volunteers had a diastolic blood pressure over 90 ¹²⁵. The same volunteer with the high systolic BP and diastolic blood pressure had a heart rate of 101 at 60 minutes. Callaway et al. ¹⁸ found maximal increases in blood pressure (BP) at 40 minutes, 11 mmHg for systolic BP and 9 mmHg for diastolic blood pressure. Heart rate, at its maximal increase, was 7 beats per minute (BPM) above baseline at 20 minutes (79 BPM), decreased to a low of 7 BPM below baseline by 120 minutes (65 BPM), then returned toward baseline by 240 minutes. The return to baseline may be due to increasing levels of central serotonin (5-HT), mediating cardiac response through the vagus nerve ¹⁸. Another study demonstrated significant increases in heart rate (HR), systolic BP, and diastolic blood pressure relative to placebo, with a maximum HR of 150 and systolic BP of 147 mmHg, while no diastolic blood pressure values went above 90 mmHg ¹²⁸.

Strassman and Qualls ⁷⁹ found dose-dependent elevations in HR and BP with IV DMT. They found a larger and more rapid increase than with oral ingestion, reporting that a 0.4 mg/kg IV dose raised HR by approximately 26 BPM at 2 minutes, as well as systolic BP by 35 mmHg and diastolic blood pressure by 30 mmHg. In the same study, peak heart rates were approximately 150 BPM while some were no higher than 95 BPM. Gable ⁷ analyzed several studies to compare changes in HR, systolic BP, and diastolic blood pressure brought on by various psychoactive substances, and concluded that the hemodynamic effects of ayahuasca appear less hazardous than IV DMT, oral alcohol, insufflated cocaine, smoked marijuana, and oral MDMA.

As with any substance that causes acute hemodynamic changes, some adverse cardiac events are possible with the use of ayahuasca ⁷, although such minimal increases could be attributed to changes in physical activity or other reasons, along the same lines as suggested by Hartley et al. ¹³⁹, who concluded that even just an anxiety-provoking stimulus increases these values more than caffeine; after 14 days of chronic administration, Pitol et al. ¹⁴⁰ found flattening and stretching of vascular smooth muscle cells, and significant increases in media thickness as well as the ratio of the media thickness to the lumen diameter.

Psychiatric Symptoms

There is conflicting information on whether endogenous DMT levels are higher in psychotic disorders, and research thus far has been inconclusive ⁷². Checkley et al. ¹³⁵ suggested that levels are higher during psychosis but normal after recovery, while Gillin et al. ¹⁴¹ argued that DMT levels do not differ significantly between schizophrenics and normal controls, and that DMT does not mimic symptoms of schizophrenia. Another theory proposed that DMT may even serve to suppress psychotic activity, acting as a homeostatic agent ⁷². Based on rates of psychotic episodes in the UDV, Gable ⁷ also concludes that ayahuasca is not a trigger for sustained psychosis. While ayahuasca and other psychedelics could precipate psychosis in predisposed individuals, rates of psychosis in the UDV are comparable to the general population in Brazil ¹⁴². Paterson et al. ¹⁴³ provided a case report of a 42-year-old male without significant psychiatric history who presented with substance-induced psychosis in the context of recent and repeated DMT use as well as long term cannabis use. He improved with quetiapine, divalproex, and hydroxyzine. Warren et al. ¹⁴⁴ also suggested that recreational DMT use could be a contributor to psychosis. Another case report discussed a man with preexisting bipolar disorder who had a manic episode following ayahuasca consumption ¹⁴⁵.

Short Term Psychological Effects

The ayahuasca experience begins approximately 40 minutes following ingestion, peaking between 60 and 120 minutes, with subjective effects fading by approximately 4 hours. Mabit ²¹ reports that ayahuasca users do not lose consciousness but experience alterations in it, while Strassman ¹⁴⁶) reported that with intravenous DMT injection, users experience a transient loss of their normal awareness lasting only a few minutes, with effects subsiding almost completely in half an hour. Some of the psychological effects during Ayahuasca ingestion are reported by Mabit ²¹ and include a powerful sense of self-confidence, a new perspective and reinterpretation of intrapsychic conflicts; users may reveal intimate truths, and ayahuasca may be powerful in facilitating psychotherapy.

Kjellgren et al. ²⁰ described the “transcendental circle”, a cycle of experiences consistent among different users following ayahuasca ingestion. Approximately 30 minutes after ayahuasca ingestion, subjects noted changing perceptions and shaking, and felt vulnerable and easily influenced. Shortly after, participants developed feelings of confusion, paranoia and fear; psychological defenses were diminished and participants experienced traumatic memories and gained new insight into personal matters ¹⁴⁷. This terrifying state peaks with intense vomiting, after which most participants noted an abrupt shift into an expansive state. Participants describe a transcendental experience in a spiritual world, encountering plant and animal spirits and even contact with a higher power, feelings of oneness with the universe, profound peace and ecstasy, and newly gained understandings of death and what comes after. Sense of time is altered, and users experience feelings of timelessness, time speeding up or slowing down, or traveling in time ¹⁴⁸, ¹⁴⁹. Users remain aware of their surroundings and are able to speak ⁷. Beyer ¹⁵⁰ refers to a similar pattern and describes three phases, the first with visual imagery and sometimes nausea or vomiting; the second phase is contact with a spiritual world in which users report useful lessons from spirit teachers, and the third phase involves fading visuals and feeling physically drained.

Several studies used the Hallucinogen Rating Scale, which measures subjective effects of psychedelic ingestion on six scales, including Somaesthesia (somatic effects), Affect (emotion and affect), Volition (willful desire to interact), Cognition (thought process and content), Perception (sensory experiences), and Intensity (the strength of the experience). The Hallucinogen Rating Scale was developed by Dr. Rick Strassman ¹⁴⁶) and is loosely based on the components of the mental status exam. Riba et al. ¹⁵ found that at least 75% of 18 healthy volunteers with experience in psychedelic use responded positively to 14 selected items in the Hallucinogen Rating Scale with a dose of 0.85 mg of DMT/kg of body weight, and described the effects of increased activation, euphoria, and wellbeing. They also reported perceptual changes and increased emotional lability. They also found a correlation between subjective effects of DMT and plasma concentration, and both peaked between 1.5 and 2 hours. Significant dose-dependent increases in all scores on subscales of the Hallucinogen Rating Scale have been found ¹²⁷, ¹²⁸, ¹⁵¹. When compared to intravenous DMT, ayahuasca produced a relatively mild high as measured by the Hallucinogen Rating Scale ²⁶.

With regard to visual effects, objects appear to vibrate or increase in brightness, colours intensify, moving geometric patterns and intricate images occur with eyes closed or open ⁷; kaleidoscopic imagery or visions of people, beautiful scenery, or snakes or jungle animals are common ¹⁴⁷, ¹⁵², ⁷⁹. Effects peak between 60 and 120 minutes ¹⁸. Visual creativity may be heightened for some time even after acute effects wear off ¹⁵³. Visual phenomena tend to linger even after acute effects subside, and this may be related to neurochemical changes in the visual cortex and the claustrum. The claustrum, a serotonergic nucleus in the brain, connects nearly all parts of the cerebral cortex. It is theorized that cortical areas with related functions tend to have overlapping claustral projections. Layer 6 (innermost) of the visual cortex and the claustrum have parallel circuits, both of which generate end-inhibition of layers 1 to 4 of the visual cortex through inhibitory interneurons. Lysergic acid diethylamide (LSD) and other hallucinogens are thought to also excite these inhibitory interneurons. Layers 1 to 4, important in interpreting shorter lines, have a property called end-stopping, in which they respond to lines up to a certain length; beyond these lengths, they are inhibited. Uncoupling of claustral and visual cortex sources of edge information, along with abnormal end-stopping properties and erroneous signalling, may explain some of the well known effects like trails, halos, wavy edges, and misinterpretation of contours ¹⁵³. Synesthesia is common, particularly auditory to visual synesthetic effects, and usually they are associated with music. The tempo and feel of the music are often reflected in the movements of the visions and how often the images change ¹⁵⁴. Shanon ¹⁵⁴ also noted enhanced improvisation and improvements in their ability to play their instruments by the musicians during Santo Daime rituals, as well as in himself at the piano.

Long-term Psychological Effects

Grob et al. ²⁶ performed a small study comparing 15 syncretic church (União do Vegetal church) ayahuasca users versus 15 matched controls as a part of their Hoasca Project. They found that among the ayahuasca users, all alcohol, depressive, and anxiety disorders remitted after joining the União do Vegetal church. As with the adolescent studies, it is hard to separate the effects of a strong supportive community and religious belonging from the actual effects of the substance, and to determine whether people with particular traits are drawn toward ayahuasca use or church involvement. In the same study, the Tridimensional Personality Questionnaire revealed that users scored significantly lower in the areas of novelty seeking and harm avoidance, but similarly on reward dependence compared to controls ¹⁵⁵. On neuropsychological testing with the World Health Organization, University of California, Los Angeles Auditory Verbal Learning Test (WHO-UCLA AVLT), users scored significantly higher in the area of word recall on the fifth trial. They also scored better in number of words recalled, delayed recall, and words recalled after interference, though these were not statistically significant. Grob et al. ²⁶ reported that long term ceremonial use does not appear to negatively affect neuropsychological function. Regular users of ayahuasca scored lower on two of the Addiction Severity Index subscales, Alcohol Use and Psychiatric Status, and ritual use does not seem to be associated with the negative psychosocial impacts of many other drugs of abuse ¹⁵⁶. Of 32 members belonging to the American Santo Daime church, 19 reported previous psychiatric histories, but all reported good mental health and only two currently had an active psychiatric disorder ¹⁹. Harris and Gurel ¹⁵⁷ reported that ayahuasca users scored higher in the areas of Joy in Life and Relationship to the Sacred, and had an experience just as spiritual as the Catholic retreat participants, and also had reduced alcohol consumption, healthier eating, better mood, and self-acceptance.

Barbosa et al. ¹⁵⁸ reported on 23 subjects just prior to their first ayahuasca experience in a religious setting and six months following, using three surveys, the Clinical Interview Schedule-Revised Edition (CIS-R), Short Form-36 Health Survey (SF-36), and the Temperament and Character Inventory-125 items (TCI-125). They found no adverse effects on quality of life, measured by the Clinical Interview Schedule-Revised Edition (CIS-R), and some participants showed significant improvements in mental health on the Short Form-36 Health Survey (SF-36) as well as in minor psychiatric symptoms on the Clinical Interview Schedule-Revised Edition (CIS-R). They also found that regular users (>9 sessions in six months) scored significantly higher on social and emotional functioning domains of the Short Form-36 Health Survey (SF-36) questionnaire than less frequent users. In a previous study, Barbosa et al. ²⁹ reported on 28 first time ritual users and also found the same reduction of minor psychiatric symptoms in a shorter time frame of 1 to 2 weeks following use. In another more recent study, Barbosa et al. ¹⁵⁹ looked at regular ayahuasca users within a religious setting. Using assessments including the Profile of Mood States (POMS), Big Five Inventory (BFI), Medical Outcomes Study Short Form-36 (SF-36), Addiction Severity Index (ASI), and the California Verbal Learning Test (CVLT), the authors showed that the regular ayahuasca users scored better in terms of mood, having more positive personality traits, better health, improved addiction problems, and better scores on the California Verbal Learning Test (CVLT). Barbosa et al. ¹⁵⁹ concluded that religious use of ayahuasca “does not adversely affect neuropsychological functioning and may have positive effects on substance abuse and mood”. One study assessed the effects of ayahuasca on creativity using the Torrance Tests of Creative thinking, and found that ingestion had no effect on the areas of “fluency,” “relative flexibility,” or “relative originality”; however, it increased participants’ ability to come up with “highly original solutions” to tasks ¹⁶⁰. In addressing the possibility that more creative individuals may seek out a consciousness-altering experience, they found that baseline creativity scores did not differ when compared to controls. Soler et al. ¹⁶¹ found that ayahuasca intake resulted in increased decentering ability (measured by the Experiences Questionnaire), as well as reduced inner reactivity and reduced judgmental processing of experiences on the Five Facets Mindfulness Questionnaire.

In a 2012 study, Bouso et al. ¹⁶² compared a variety of psychological measures in ayahuasca users against matched controls. They found that ayahuasca users scored lower on psychopathology measures (on The Symptom Check-List-90-Revised/SCL-90-R psychopathology questionnaire), performed better on cognitive tests (such as the Stroop Colour and Word Test and the Wisconsin Card Sorting Test), and scored higher on the Purpose in Life Test, Spiritual Orientation Inventory, and Psychosocial Well-Being Test. These differences remained the same at one year followup, and there was no evidence of any deleterious effect on mental health and no signs of cognitive impairment among ritual ayahuasca users. Kuypers et al. ¹⁶³ looked at ayahuasca’s effect on creative divergent thinking, a way of thinking believed to enhance psychological flexibility and allow for new cognitive, emotional, and behavioural strategies. Assessing participants before and during the acute effects of ayahuasca, the authors found significantly increased divergent thinking while the subjects were on ayahuasca, and suggested this may facilitate psychotherapeutic interventions. In a research study based on results from the Ayahuasca Researcher’s Behavioral Observation Scale (ARBOS), Shamanic Experience and Net Benefit scales, and the Temperament and Character Inventory Predictor scale, Burton ¹⁶⁴ suggests we can predict which patients would benefit from or be harmed by participating in an ayahuasca ceremony.

In a questionnaire, 25 Northern European ayahuasca users reported increased self-awareness, being more loving, more empathetic, having greater creativity and new interests especially with nature, and having a more meaningful inner world ²⁰. Winkelman ¹⁶⁵ reported similar effects including new insights and access to deeper levels of the self. Serious reflection on life, nature, and consciousness were consistent themes ⁷. Cakic et al. ⁷⁰ reported that increased “psychospiritual insight” was the most commonly reported positive effect among 12 Australian recreational DMT users, a finding in keeping with studies of religious and ceremonial ayahuasca use. Many users reported that prior to entering the church, they had alcohol problems and violent behaviour, and described themselves as impulsive, disrespectful, oppositional, and irresponsible. All 15 members involved in the Hoasca Project reported that ayahuasca had a profound influence on their lives, allowing them new insight into their self-destructive ways and motivating them to take control of their lives. They also reported better memory and concentration, and a consistently positive mood; however they all recognized the importance of the sense of community and guidance provided by ritual use within the church ²⁶.

Dr. Jacques Mabit ²¹ runs an addiction clinic in Peru and uses ayahuasca as a part of the treatment. He reports many positive effects: that ayahuasca increases intellectual capacity and concentration, reduces anxiety, increases tolerance of frustration, improves self-esteem, facilitates individuation processes, allows users to see beyond their own worldview and increases openness to new perspectives. Reports from his patients indicate that ayahuasca facilitates introspection and self-discovery, forgiveness without blame, recognition of mistakes, improved decision making ability, motivation to change, increased quality and quantity of dreams, reflections on life as a part of nature and discovery of previously unknown dimensions of life. As well, users seem to benefit from a structured, spiritual, religious, ritual manner of use ²¹. Loizaga-Velder and Verres ¹⁶⁶ interviewed 14 ritual participants who had long histories of severe substance dependence, and many had several unsuccessful treatments prior to ayahuasca assisted therapy. All participants reported ayahuasca rituals were pivotal to attaining abstinence or achieving less harmful patterns of drug use; they also reported ayahuasca was instrumental in understanding the causes of their addictions. Over half reported reduced cravings. In a study by Cavnar ¹⁶⁷, self-identified gay and lesbian ayahuasca users reported feeling affirmation of their sexual orientation.

Ayahuasca uses

Ayahuasca is drunk as a liquid and it has been used for centuries by First Nations peoples from contemporary Peru, Brazil, Colombia and Ecuador for religious ritual and therapeutic purposes ⁶. Ayahuasca is now being used by tourists seeking a spiritual experience, and by recreational users all over the world ²⁰. Research into medical use of ayahuasca indicates potential as a treatment in addictions, depression and anxiety, with a variety of other possible medical uses, though these require more research ¹⁶⁸. Ayahuasca use for depression may be associated with a reduction in short-term depression symptoms and suicidality ¹⁶⁹. However, confidence in these findings is also low due to a smaller number of trials overall with small sample sizes and some inconsistency ¹⁶⁹. Cakic et al. ¹⁷⁰ found that a group of Australian ayahuasca users (n=121) gained psychospiritual insigh from use. Cardenas and Gomez ¹⁷¹ examined motives for modern urban use by 40 residents of Bogota, Colombia. They found that subjects used ayahuasca to achieve mental wellbeing and also to enhance their ability to solve personal problems; in another study ¹⁵⁸, the participants cited “healing” and “equilibrium” as reasons for Ayahuasca use. Kjellgren et al. ²⁰ found similar motives among northern European users, including exploring their inner world, personal development, increasing self-awareness, examining psychological patterns, and enhancing creativity. Fiedler et al. ¹⁷² studied motives for use among Santo Daime members, and found that reasons were consistently religious or spiritual, as well as self-treatment.

Anecdotal evidence from studies conducted among ayahuasca consumers, and preliminary studies in patients suggest that Ayahuasca has broad therapeutic potential, especially for the treatment of substance dependence and anxiety and mood disorders ²⁶, ¹⁷³, ¹⁹, ¹⁵⁶, ¹⁷⁴, ¹⁶², ¹⁷⁵, ¹⁷⁶, ¹⁷⁷.

Ayahuasca Potential Benefits

Ayahuasca is a mixture of several active ingredients, the ratio of which in the final drink is very variable ¹⁷⁸ and therefore its effects depend on both the specific plants used and the method of preparation. The effects are remarkable on a physiological and mental level. However, the dosage of ayahuasca is extremely individual. It depends on the tolerance of the individual and his personal sensitivity, on the intention with which it is to be used, and above all on the intuition of the presiding mestre who works with the substance.

Ayahuasca was and is considered by Native Americans to be the most powerful medicinal plant on Earth ¹⁷⁹. They attribute the ability to teach and heal people to the decoction made out of this “magical” liana, and some even believe that it mediates the connection with the universe and spiritual beings ¹⁷⁹. Because of these reasons, the use of ayahuasca has spread from South America not only to Europe and to the United States, but throughout the whole world.

Studies and research have raised hopes for Ayahuasca therapeutic potential, but also concerns about its possible toxicity ¹⁸⁰, ¹⁸¹, ¹⁸². Authors Galvão Ana et al. ¹⁸³ emphasized in their work the importance of the effect of ayahuasca on the production of salivary cortisol, which acts in the regulation of various physiological, cognitive and emotional pathways. Their opinion was based on studies that suggested that regulating salivary cortisol levels to normal values was considered an important part of the treatment of depression ¹⁸³.

Some studies suggest that the main active ingredients of ayahuasca (DMT and beta-carbolines) have anti-inflammatory, neuroprotective and memory-improving effects ¹⁸⁴. Galvão-Coelho et al. ¹⁸⁵ observed a reduction in C-reactive protein (CRP) levels 48 h after the intake in ayahuasca-treated patients but not in placebo-treated subjects. However, the exact mechanism is unknown. The use of ayahuasca during the day subsequently affects the sleep cycle; however, does not worsen the quality of sleep ¹⁸⁶. A prolongation of the second sleep stage, shortening of the duration of rapid eye movement (REM) sleep phases and prolongation of non-REM phases was described ¹⁸⁶.

Multiple studies suggest that the use of ayahuasca may be beneficial for people with mood disorders, depression, anxiety or post-traumatic stress disorder ¹⁸⁷, ¹⁸⁸. At the same time, the studies focused on the possibilities of ayahuasca use in the fight against various addictions (alcoholism, nicotinism, cocainism etc.) ⁸, ¹⁸⁹, ¹⁹⁰, ¹⁹¹. Some authors assume that the use of ayahuasca could be implemented into the controlled treatment with health benefits ¹⁹², ¹⁹³, ¹⁹⁴, ¹⁹⁵. Recent studies suggest that regular intake of psychedelic microdoses leads to positive effects on health, mood, cognitive function, and reduced depression and anxiety ¹⁹², ¹⁹³, ¹⁹⁴, ¹⁹⁵, ¹⁹⁶. Yet the outcome of which is ambiguous and still debatable at this time ¹⁷⁹. Furthermore, the number of publications focused on the investigation of toxicological risks of ayahuasca is not small. In particular, the limits of the relevant evaluation of its benefits and risks lie in an insufficient number of studies dealing with the analysis of the concentrations of individual components in the organism after the ingestion of ayahuasca decoction with their subsequent correlation to the effects of the plant ¹⁷⁹. Last but not least, thorough investigation of pathological changes on tissues and organs in cases of long-term use of ayahuasca is also insufficient and therefore requirable ¹⁷⁹.

DMT-containing ayahuasca appears to be less toxic while retaining psychological effects. Based on the studies of the health status of ayahuasca users, the use of ayahuasca may be considered safe and even beneficial to health ¹⁸³. Adverse results have been reported extremely rarely and are considered to be the result of uncontrolled intake of non-traditional ayahuasca preparations. However, there is still a need for more extensive clinical research on the use of these substances. Such studies should be done by recognized, credible researchers and must include a comprehensive recording of side effects as well as beneficial effects. These studies should be registered with the appropriate global clinical databases ¹⁹⁷.

Addictions treatment

Ayahuasca appears to be beneficial in treatment of addictions, and when used appropriately does not appear to carry risks of abuse or dependence ¹⁹⁸. Ayahuasca may enable sustained abstinence from alcohol, barbiturates, sedatives, cocaine, amphetamines, and solvents, though most continue to use marijuana ¹⁵⁶. Compared to matched controls, regular participants in Brazilian ayahuasca church ceremonies scored significantly lower on the Addictions Severity Index subscales of Alcohol Use and Psychiatric Status, although the authors noted that it is hard to separate whether these effects are from the ayahuasca, involvement in a supportive community, or both ¹⁵⁶. Barbosa et al. ¹⁵⁸ suggest that based on their findings, administration of hallucinogens in both clinical settings and religious settings can provide benefits.

Any drug that affects dopamine has potential for abuse, and although harmine does, it does not cause dependence ⁵. Ayahuasca does not show activation in reward-related regions of the striatum or ventral-tegmental area on SPECT imaging ¹⁵⁶, ¹²² and only causes increased blood flow in the frontal and paralimbic areas.

Liester & Prickett suggest 4 hypotheses to explain ayahuasca’s proposed antiaddictive properties ¹⁹⁹:

Ayahuasca reduces brain dopamine levels or activity in the mesolimbic dopamine pathway, decreasing the reward associated with an addictive substance. DMT is a known 5-HT2A receptor agonist and 5-HT2A receptor agonism is known to inhibit dopamine release in the mesolimbic, nigrostriatal, and mesocortical pathways. Reduced brain dopamine also fits with elevated prolactin levels with ayahuasca use ¹⁸. The opposite is also true as illustrated by atypical antipsychotics, which have 5-HT2A receptor antagonist activity and exhibit reduced dopamine blockade (70-80% blockade) compared to typical antipsychotics (90%) which have little action at serotonin receptors ²⁰⁰.
Reduced dopamine in reward pathways impairs the synaptic plasticity involved in addiction development and maintenance.
The introspection, self-realizations, and healing of past traumas afforded by an ayahuasca experience offer better understanding of consequences and improved decision-making, empowering the individual to abstain.
Ayahuasca facilitates transcendent experiences; the authors give the example of Bill Wilson, founder of Alcoholics Anonymous, having such an experience (not ayahuasca induced) and being able to give up alcohol.

Pain treatment and Opioid dependence treatment

Beta-carbolines may prove useful in treating opioid addiction. Harmine and harmaline act as imidazoline type 2 receptor agonists I2 ¹⁰⁵. Harmane and harmine have both been reported to reduce the symptoms of morphine withdrawal ²⁰¹. Miralles et al. ²⁰² assessed the affinity of various beta-carbolines for the I2 binding site in brain and liver and also found that norharmane prevents the stimulatory effects of opioid withdrawal as measured by withdrawal symptom severity, and attenuated L-3,4-dihydroxyphenylalanine (L-dopa) synthesis normally associated with withdrawal.

Cocaine dependence treatment

A study by Glick et al. ²⁰³ reported that harmaline led to significantly reduced cocaine and morphine self-administration in rats. While cocaine increases dopamine efflux and reuptake inhibition in both the shell and core of the nucleus accumbens, harmine only augments efflux in the shell of the nucleus accumbens ¹⁰², ¹¹², perhaps demonstrating one mechanism of harmine that is similar to cocaine that can be useful in treatment and has far less addictive potential. A Canadian study by Thomas et al. ¹⁷⁷ showed that ayahuasca holds promise as a potential treatment for cocaine dependence, with a statistically significant reduction in use (by self-report) that is greater than the reduction in either tobacco or alcohol use.

Alcoholism treatment

Halpern ²⁰⁴ touched on promising past research involving LSD in the treatment of alcoholism and anecdotal evidence of peyote containing mescaline used in the Native American Church being potentially useful in treating drug dependence and alcohol addiction, and suggested it is time to start studying hallucinogens again. As mentioned previously, Doering-Silveira et al. ²⁰⁵ found that adolescents from a Brazilian ayahuasca-using church had less recent alcohol use (32.5%) compared to adolescents who had never used ayahuasca (65.1%). Oliveira-Lima et al. ²⁰⁶ showed that in mice, ayahuasca inhibited some of the early behaviours that were associated with developing alcohol addiction.

Depression treatment

Osorio et al. ¹⁷⁶ in an open label trial in an inpatient psychiatric unit, found that a single dose of ayahuasca has rapid acting anxiolytic and antidepressant effects in patients with recurrent depression. dos Santos et al. ²⁰⁷ reviewed several clinical trials on ayahuasca, psilocybin, LSD, and their effects and concluded that all these drugs could be beneficial in treatment of depression (especially in treatment-resistant subjects), as well as anxiety and alcohol and tobacco dependence. The results also seemed to confirm that both the DMT and the beta-carbolines in ayahuasca show promise as effective depression and anxiety treatments. They highlighted findings that serotonin 5-HT1A receptor agonists have shown antidepressive and anxiolytic effects in both humans and animals, and 5-HT2A/2C agonists had antidepressive and anxiolytic effects in animal studies. In addition, 5-HT1A/2A/2C receptor agonists have shown anti-inflammatory properties, and there is growing evidence that inflammation is another process implicated in the pathogenesis of anxiety and depression ¹⁷³.

Several studies of harmine have shown an antidepressant effect ²⁰⁸, ²⁰⁹, ²¹⁰, ²¹¹, ²¹², ²¹³. One known mechanism through which harmine and harmaline may exert an antidepressant effect is reversible inhibition of MAO-A ²¹⁴, resulting in increased neurotransmission. Their reversibility for MAO-A inhibition makes them safer than the traditional nonselective, irreversible MAO inhibitors ²⁸. Fortunato et al. ²¹², ²¹³ have conducted several animal studies assessing the antidepressant effect of harmine. Using the forced swim test, it was shown that the animals treated with harmine had decreased immobility and more swimming and climbing, and they had increased levels of brain-derived neurotrophic factor (BDNF) which has an antidepressant effect in the brain ²⁰⁹, ²¹⁰, ²¹¹, ²¹², ²¹³. Harmine was also able to reverse the anhedonic effects of the chronic mild stress test ²¹³. Harmine acts to decrease synaptic glutamate via increased GLT-1/EAAT2 expression and subsequently increasing glutamate transport ¹⁰⁷.

DMT activates sigma-1 receptors. Other antidepressants, though not all, of the SSRI, MAOI and TCA classes have been found to do so as well. These receptors are found throughout the nervous system, and are concentrated in the hippocampus, frontal cortex, and olfactory bulb, consistent with a possible role in depression ²¹⁵. Past experiments have shown an antidepressant-like effect in mice administered sigma-1 receptor agonists ²¹⁶ and attenuation of these effects with sigma receptor antagonists [181]. Agonists of the sigma receptor are being studied as potential antidepressant drugs ²¹⁴. More work into the functions of sigma receptors and their role in depression treatment is needed. A possible connection lies in the inhibitory effect of DMT on the NMDA receptor through sigma receptor activation ⁸³.

Both I1 and I2 imidazoline receptors have been associated with the pathology of depression ²¹⁷. I1 sites are decreased in brains of depressed suicide victims, notably in the hippocampus and prefrontal cortex ²¹⁷. Imidazoline I1 binding sites are found throughout the human brain, and the highest density areas include in the striatum, pallidum, hippocampus, amygdala, and substantia nigra ²¹⁸. Imidazoline I1 receptors are thought to be involved in the central inhibition of sympathetic outflow, which can be altered in depression and hypertension ²¹⁹. Interestingly, the number of I1 binding sites are reported to be increased on platelets of patients experiencing depression and premenstrual dysphoric disorder. This effect was highly correlated with severity of symptoms, but there was a consistent return to normal levels following treatment with fluoxetine, citalopram, bupropion, desipramine, clomipramine, imipramine, and lithium, even though several of these drugs act through different mechanisms, which suggests platelet I1 density could be used as a possible biological marker of depression ²¹⁹. Halaris and Piletz ²¹⁹ also described an unpublished finding that in nondepressed patients, desipramine failed to produce the same effect. Therefore, platelet I1 sites could have potential as a biological marker of depression, as well as a measure of response to treatment. A downregulation of I2 binding sites has been found in frontal cortices and hippocampi of depressed humans postmortem. Harmine and harmaline have high affinity for the I2 binding site in rat brains [188]. In terms of clinical use, the selective I2 ligand BU224 showed antidepressant-like activity in rats and increased 5-HT levels in the frontal cortex and hypothalamus ²¹⁸. Antidepressant treatment caused upregulation of I2 sites in rat brains ²²⁰. Most I2 selective ligands have been found to be allosteric inhibitors of both MAO-A and MAO-B ²²¹.

Evidence is now suggesting that reactive oxygen species (ROS) may be involved in the pathogenesis of depression and anxiety ²²². Harmine has shown to be of benefit as it increased levels of both superoxide dismutase and catalase enzymes, and attenuated oxidative stress parameters of lipid and protein oxidation in rat brain hippocampus, a structure involved in mood regulation ¹²¹.

Anxiety treatment

Jacob and Presti ²²³ suggested that DMT action at a trace amine receptor may produce an anxiolytic effect. Anxiety, like depression, is another disorder which has been linked to oxidative stress ²²². Sarris et al.²²⁴ highlight ayahuasca as a treatment of potential use in their review of plant based medicines for anxiety. A double blind study showed a statistically significant reduction of hopelessness and panic-like parameters using standardized questionnaires, the Beck Hopelessness Scale and the Revised Anxiety Sensitivity Index upon acute ayahuasca ingestion ¹⁷³. Furthermore, it has been suggested that DMT acts in a manner similar to serotonin, and serotonin (5-HT2) receptor activation has been shown to alleviate panic symptoms ²²⁵. It is important to note that some beta-carbolines may have a possible anxiogenic effect, given their inverse agonist effect at the benzodiazepine receptor site of the GABA-A receptor ¹⁰⁸, dopamine (D(2)) and benzodiazepine receptors. Drug Alcohol Depend. 2000 Aug 1;60(2):121-32. doi: 10.1016/s0376-8716(99)00148-9)), ¹⁰⁹.

Psychotherapy

There are many reported psychotherapeutic benefits of ayahuasca, however most studies stress that this is only when it is used in specific settings ²⁸. Like LSD in the 1950s, ayahuasca is now being considered as a tool to facilitate psychotherapy, by dissolving the ego, promoting introspection, and aiding in processes of self-analysis ¹⁵². Barbosa et al. ²⁹ suggested that hallucinogens may also act to facilitate association and memory processing. However, regulations governing the use of psychoactive substances often limit the ability to undertake scientific investigations of such novel approaches.

Ayahuasca side effects

There is no safe level of Ayahuasca. Use of any drug always carries some risk. It’s important to be careful when taking any type of drug.

Ayahuasca affects everyone differently, based on ²²:

your size, weight and health
whether the person is used to taking Ayahuasca
whether other drugs are taken around the same time as Ayahuasca
the amount of Ayahuasca taken
the strength of the Ayahuasca decoction (varies from batch to batch)
the environment where Ayahuasca is taken.

The effects of ayahuasca can last between 4- to 6-hours and may include:

nausea and vomiting (induced by drinking the decoction). The most frequently reported adverse physical health effect was vomiting and nausea (68.2%), while the frequency of other adverse effects was 17.8% headache. It is important to clarify that vomiting and nausea is considered a normal effect of ayahuasca for experienced users. In the case of traditional ayahuasca ceremonies and even in non-traditional ceremonies, not only is vomiting and nausea not considered an adverse effect, but it is even sought out for its purging and perceived spiritual cleansing benefits ²²⁶
diarrhea
euphoria
feelings of connection and unity
introspection
intense visual and auditory hallucinations
experiencing powerful emotions
anxiety
panic and fear
moderate increase in blood pressure and heart rate
increased body temperature ⁶, ²²⁷

When Ayahuasca is taken in a traditional or ritual setting, these effects may be perceived as cleansing or purging and a part of the spiritual or healing journey ⁶.

Although there is consensus regarding the general safety of ayahuasca ²²⁸, ²²⁹, ²³⁰, ²³¹, the following reports of adverse effects have been identified in the literature:

The American Association of Poison Controls Centers’ (AAPCC) National Poison Data System (NPDS) collected 538 calls related to exposure to ayahuasca botanical products between 2005 and 2015 ²³⁰. Forty-one cases (7%) reported major clinical manifestations and 296 cases moderate ones (55%). The most common clinical effects were hallucinations (190, 35%), agitation (181, 34%), tachycardia (180, 34%), confusion (99, 18%), hypertension (87, 16%), mydriasis (72, 13%), and vomiting (32, 6%). The most severe effects were seizures (12, 2%), respiratory arrest (7, 1%), and cardiac arrest (4, 1%). Three fatalities were reported. In this study, patient’s characteristic, previous medical conditions, concomitant medication use, and what subjects actually took were unknown ²³⁰.
A systematic review of the published case reports describing psychotic episodes associated with ayahuasca use found three case series and two case reports describing psychotic episodes ²³² and at least three other cases have been reported since then ²³³, ²³⁴, ²³⁵. Although most of the cases had previous psychiatric diagnoses, a few did not. Some of the cases required antipsychotic medication, but all of them returned to their pre-crisis mental states after a variable amount of time.
A study involving 32 subjects of a US Santo Daime church also identified side-effects, most commonly nausea (11 subjects), vomiting (9 subjects), and exhaustion in the following days (9 subjects) ¹⁹. Other somatic effects, like headache, tachycardia, and muscle spasms, were reported by a few subjects [57]. In a recent retrospective study involving 614 members (regular uses) of the União do Vegetal, a Brazilian religion where ayahuasca is a sacrament, the most common physical effects, as expected, were vomiting (96.74%) and nausea (91.53%) ¹⁹. Diarrhea, shivers, rapid heart rate (tachycardia), tremor, and tinnitus were other common effects ¹⁹. Surprisingly, persistent physical effects were reported by 41.86% of the participants, among whom the daily lives of 3.89% (10 individuals) were reasonably (n = 9) or very (n = 1) affected in a negative way ¹⁹. Adverse psychological effects (anxiety, disorientation, or distress) were less common; however, persistent adverse psychological effects were reported by 20.68% of the participants (127 individuals), among which 11.81% (n = 15) indicated that their daily lives were moderately (n = 14) or very (n = 1) negatively affected by persistent effects ¹⁹. The total duration of the persistent adverse effects was not recorded. Participants with a reported psychiatric diagnosis experienced adverse effects more frequently than those without ¹⁹.
In a prospective longitudinal study involving 40 subjects who participated in ritual ayahuasca ceremonies ²³⁶, 7 referred to an extremely challenging psychological reaction, involving psychotic symptoms in some cases. Among those 7 subjects, 4 had a previous psychiatric diagnosis. The condition of all subjects with psychiatric antecedents improved, and none of those without were found to be worse during the follow-ups ²²⁹.
In a series of controlled clinical trials, while characterizing the pharmacology of ayahuasca with a total of 24 subjects using low (0.5mg/DMT/kg), medium (0.75mg/DMT/kg), and high (1mg/DMT/kg) doses of ayahuasca ²³⁷, ²³⁸, subjects scored active doses higher than a placebo in terms of the Visual Analogue Scales “liking,” and the ayahuasca was well tolerated. However, one subject who took the medium dose experienced an intensely dysphoric reaction with transient disorientation and anxiety that lasted 20 minutes without the need for medication ²³⁷, ²³⁹. In another clinical study using functional MRI (fMRI) and involving 10 subjects, effects were significant only at 40- and 80-minutes post‐intake in the brief psychiatric ratings scale (BPRS) used to detect psychotic symptoms and the Young Mania Rating Scale (YMRS) used to measure mania symptoms, but subjects were not incapacitated from performing the imagery task involved ²⁴⁰. A recent controlled clinical trial studying the effects of ayahuasca on the recognition of facial expressions of emotions in naive healthy volunteers did not find differences in clinical variables between ayahuasca and placebo ²⁴¹.

Ayahuasca Mental adverse effects

The frequency of adverse mental health effects was relatively high (55.4%), with a similar frequency being found for the emotional-cognitive and altered perception factors (42% and 38.3%, respectively) ²⁴². Although the frequency of any adverse mental health effects was high, only “hearing or seeing things that other people do not hear or see” commonly known as auditory and visual hallucination was observed in 28.5% of the ayahuasca users ²⁴². In relation to this response and also “visual distortions” it is important to note some respondents reporting these changes specifically mentioned in subsequent qualitative responses that they had considered these positive and not adverse effects ²⁴². Other mental health adverse effects were reported in less than 21.0% (“feeling disconnected or alone”) of the participants. However, there was a low frequency of severe adverse effects (4.4% was the highest frequency, for “visual distortions”). Moreover, 11.9% of the participants reportedly needed professional mental health support for the adverse effects they experienced. For most participants reporting adverse mental health effects, the duration was identified as being for less than a week. While previous research has found long-lasting, severe adverse mental health effects in rare cases ²³², other research has found that especially challenging adverse effects may improve psychiatric conditions ²²⁹, while other work from this study has reported the number of adverse mental health effects reported to be negatively associated with current mental health and perceived improvement in psychological wellbeing ²⁴³. Other research has also found that adverse effects can be important enough to interfere in individual daily lives ²³¹. So, future studies should focus on follow-up and the evolution of the adverse effects when they appear.

History of ayahuasca use, age at initial ayahuasca use and lifetime use were not related with the adverse mental health effects ²⁴². Regarding the clinical variables, only a previous diagnosis of anxiety disorder increased the likelihood of adverse emotional-cognitive effects, and previous physical health conditions increased the likelihood of altered perception adverse effects ²⁴². All non-religious contexts (traditional, non-traditional and non-supervised) increased the likelihood of emotional-cognitive and altered perception adverse effects ²⁴². Adverse emotional-cognitive and altered perception effects were more likely to be observed in females, younger participants, and those unmarried ²⁴².

Adverse mental health effects were not significantly associated with ayahuasca history of use variables. This finding, while intriguing, is in accordance with the early age of ayahuasca initiation in traditional contexts, both Indigenous and in ayahuasca churches, where researchers failed to find long-term neuropsychiatric alterations ²⁴⁴, ²⁴⁵, ²⁴⁶, ²⁴⁷. Over the last decade ayahuasca has increasingly been perceived to have therapeutic effects, leading to an increasing number of people accessing ceremonies as a complementary medicine or self-care practice. This situation has resulted in rare physical and/or mental health issues being more commonly seen in non-traditional contexts ²⁴⁸, ²⁴⁹.

Ayahuasca drug interactions

There is a possibility that any substances, including beta-carbolines, that act as MAO-A inhibitors can produce serotonin syndrome ²¹³. Serotonin syndrome is a potentially life-threatening drug reaction ⁶², ⁶³. Serotonin syndrome is caused by medications that build up high levels of serotonin in the body. Too much serotonin causes signs and symptoms that can range from mild shivering and diarrhea to severe muscle rigidity, fever and seizures ⁶², ⁶³. Milder forms of serotonin syndrome may go away within a day or two of stopping the medications that cause symptoms and, sometimes, after taking drugs that block serotonin ⁶². Severe serotonin syndrome can cause death if not treated ⁶².

McKenna ²⁸ suggested that DMT and the beta-carbolines in ayahuasca, when combined with an selective serotonin reuptake inhibitor (SSRI) antidepressant could cause serotonin syndrome. Callaway and Grob ²⁵⁰ also report a case of serotonin syndrome in a patient using the SSRI fluoxetine in conjunction with ayahuasca. The irreversible, nonselective MAOIs phenelzine and tranylcypromine are associated with serotonin syndrome, and there are also cases with opiates, analgesics, tricyclic antidepressants (TCAs), SSRIs, and antimigraine drugs, and it is suggested that those who have recently used any ginseng, St. John’s wort, dextromethorphan, or MDMA should be cautious ⁷. A chart of potential interactions exists on the harm reduction organization TripSit’s website (TripSit.me). Balikova ²⁵¹ reported on an incident of 30 people who ingested a brew containing harmine, atropine, and scopolamine in a meditation session, and found tachycardia, amnesia, hallucinations, hyperthermia, hypotension, mydriasis, collapse, coma, and even respiratory depression requiring mechanical ventilation. A synergistic effect was found with beta-carbolines in combination with atropine and scopolamine; the ingested doses of the three substances were all 8 to 13 times less than estimated lethal doses ⁷.

Harmine, harmol, and harmane have been found to be noncompetitive inhibitors of CYP3A4; they are also both substrates and inhibitors of CYP2D6. Harmaline, harmine and harmol showed competitive inhibition of CYP2D6 ²⁵². With two major CYP enzymes inhibited, users should be cautious of drug interactions. As well, genetic polymorphisms can affect the efficacy of these enzymes.

Ayahuasca bad trips

Some people may have negative experiences taking psychedelics, or experiences they find challenging. This can include experiencing:

frightening or confronting hallucinations
intense anxiety and confusion
fear and paranoia ⁶

These experiences may be understood or interpreted differently in a traditional or ritual context, where they may be seen as lessons and part of a spiritual or healing journey rather than wholly negative.

Ayahuasca dependence and tolerance

As a Schedule 1 controlled substance, DMT can be seen as an addictive substance, associated with substantial health risks ⁶⁶. Studies have been contradicting this finding, as no compulsive drug-seeking precipitated by consumption of DMT or ayahuasca has been reported in humans ²². Repeated use of Ayahuasca does not appear to result in tolerance to the effects, and it appears to pose an extremely limited risk for dependence ¹⁵⁶. Psychedelics, including DMT and ayahuasca, are seen as safer substances than cocaine, opiates, or even the widely used nicotine and alcohol, with the advantage of lacking the abuse potential, characteristic of these former drugs ²². As reviewed by Gable et al. ²², reports of abstinence syndrome after termination of DMT consumption are unknown.

Studies with repeated administration of DMT to volunteers have seen little or no drug tolerance ²⁵³, ⁹¹. Comparing long-term users and occasional consumers of ayahuasca, Bouso et al. ²⁵⁴ found that following ingestion of a single dose, both groups were associated with lower scores on working memory and performance improvement, but only the occasional users had an impaired performance in strategic planning. Therefore, greater prior exposure to ayahuasca by long-term users was associated with drug-induced neuromodulatory or compensatory effects, resulting in reduced cognitive incapacitation. Further reports on tolerance solely included slight changes in the release of growth hormone (GH), adrenocorticotropic hormone, and prolactin, which were found to be decreased following a second administration, and lower response in the systolic blood pressure and heart rate ²⁵⁵, ²⁵⁶. DMT did not elicit tolerance in animal models like squirrel monkeys ²⁵⁷ and cats ²⁵⁸. Additionally, LSD is not capable to produce cross-tolerance to DMT ²⁵⁹, contrary to what happens with other classic hallucinogens like mescaline or psilocybin ²⁶⁰, ²⁶¹. The absence of cross-tolerance suggests a distinguished pharmacodynamic behavior for DMT, which makes it a quite unique substance among classic hallucinogens.

Morgenstern et al. ¹⁹⁸ reported that almost no hallucinogen users had difficulty cutting down or controlling use, unlike many other drugs. In a study of rhesus monkeys, Fantegrossi et al. ²⁶² found reinforcing effects of the hallucinogens DMT, mescaline, and psilocybin, and suggest that the patterns of self-administration demonstrate weak reinforcing effects, and possibly mixed reinforcing and aversive effects. Ayahuasca does not seem to have the negative psychosocial implications caused by many drugs of abuse ¹⁵⁶. Mixed results were found in studies of drug tolerance in animal studies ²⁶³, ²⁵⁸, ²⁶⁴ as well as in human studies ⁷, particularly to the psychoactive effects, which is unique among other known hallucinogens. Callaway et al. ¹²⁰ found that some physical tolerance may develop in humans with regular use. In a study by dos Santos et al. ¹²⁸, acute tolerance failed to develop for any measures aside from growth hormone (GH), which showed decreased release on second administration, as well as a slightly lower response in the systolic blood pressure (SBP) and heart rate (HR). Another study similarly showed tolerance with heart rate, adrenocorticotropic hormone (ACTH) and prolactin ⁷⁹. Another study found that there was little to no tolerance with DMT in cats ²⁵⁸.

Is Ayahuasca safe?

The stem and/or bark of the Banisteriopsis caapi vine rich in beta-carboline harmala alkaloids can induce tremor in mice, thought to be due to the interaction of these compounds with tryptamine binding receptors ²⁶⁵. An experiment by Louis et al. ⁹⁸ suggests people should be cautious with beta-carbolines, as they are found endogenously in higher levels in essential tremor patients, and that harmine and harmane may be tremorigenic. Bouso et al. ²⁶⁶ compared two groups of ayahuasca users, one with long term experience and the other with occasional use. The study found that acute ayahuasca use does impair working memory, but having greater prior ayahuasca exposure was associated with less incapacitation during administration, and detrimental effects on cognition were mainly seen in the occasional ayahuasca use group. Those findings suggest there may be neuromodulatory or compensatory effects induced by long term ayahuasca use.

In an attempt to investigate ayahuasca toxicity, Pic-Taylor et al. ²⁶⁷ administered ayahuasca doses 30 and 50 times higher than that typically used in religious rituals to female Wistar rats. While the authors could not calculate an LD50 (the amount of a solid or liquid material that it takes to kill 50% of test animals in one dose) based on their findings, they determined that the lethal dose (corresponding to 15.1 mg/kg DMT) is higher than 50 times a typical Ayahuasca dose used during religious ceremonies. Pic-Taylor et al. ²⁶⁷ also found that the increased serotonergic activation from these high doses led to some neural degeneration, but no permanent alteration in brain structure or number of cells was found. Other rodent studies allowed to estimate that the LD50 values for humans are approximately of 1.6 mg/kg for DMT i.v. administration (a total dose of 112 mg for a typical 70 kg individual), and 8 mg/kg for DMT per os (a dose of 560 mg) ²², which is significantly higher than the average ceremonial dose of DMT (27 mg), giving DMT/ayahuasca a safety margin of approximately 20-fold.

The toxic dose of ayahuasca would be approximately 7.8 liters for a 75 kg person ³⁵. Given its highly unpleasant taste, it is unlikely anyone would ever reach this dose. In addition, vomiting and diarrhea occur long before this limit is reached ²¹.

In a literature search, Hamill et al ⁵ found no reports of deaths directly attributable to ayahuasca use. There are a few reported deaths associated with ayahuasca-like herbal preparations, but in these cases it appears coingestion with other substances was to blame. The only two cases of death reported in the literature that involved ayahuasca/DMT/harmala alkaloids were of a 71-year-old diabetic female who consumed B. caapi mixed with tobacco leaves (no information on quantities) ⁵⁰ and a 25-year-old man who consumed herbal extracts containing harmala alkaloids and tryptamines (no information on quantities) ⁵¹, with no anatomical cause of death found in the autopsies. In the first case, blood analysis revealed only the presence of nicotine (710–1900 ng/mL) and the cause of death was determined as acute nicotine intoxication. In the second case, reported by Sklerov et al. ⁵¹, the following concentration ranges were obtained in the blood analysis: 0.01–0.02 mg/L for DMT, 0.04–0.07 mg/L for harmaline, 0.08–0.17 mg/L for harmine, 0.24–0.38 for tetrahydroharmine (THH) and 1.20–1.88 mg/L for 5-MeO-DMT. The cause of death was undetermined. However, a few cases of suspected deaths involving ayahuasca consumption have been reported in the media.

A review by dos Santos ²⁶⁸ covers ayahuasca use in pregnancy, and concludes that while some animal studies show toxicity from in utero ayahuasca exposure, what little information there is on the topic indicates that there are no serious adverse effects of ayahuasca exposure in utero in humans, but more information is needed before its safety in pregnancy is fully understood ²⁶⁹. Pregnant rats consuming high doses of ayahuasca (10 times the normal human Ayahuasca dose) displayed decreased food consumption. The rats displayed decreased weight gain but increased relative liver weight, possibly indicating some liver toxicity ²⁷⁰. These researchers found a ayahuasca dose-response relationship, and fetal effects at 10 times the normal human dose include visceral and skeletal malformations, dilated lateral and third ventricles, along with decreased body weight, thought to represent intrauterine growth restriction (IUGR). A more recent study by Gardner et al. ²⁷¹ discussed congenital malformations in livestock in parts of South America and Mexico, which have long been attributed to ingestion of the Mimosa tenuiflora shrub containing N-methyltryptamine (NMT) and DMT. Their findings showed increased rates of cleft palate, scoliosis, and skeletal deformities in rat pups compared to controls when pregnant mothers were fed diets including DMT, N-methyltryptamine (NMT), both, or extracts of the Mimosa tenuiflora seeds and leaves.

In a recent study, Colaço et al. ²⁷² submitted Wistar rats to a chronic 28-day treatment using the same ayahuasca samples as a previous Pic-Taylor study ²⁷³ at doses 2 times higher (corresponding to 4.28 mL/kg of ayahuasca, 0.52 mg/kg of DMT, 5.16 mg/kg of harmine, 0.342 mg/kg of harmaline, and 0.66 mg/kg of tetrahydroharmine [THH]) than the common ritual dose of ayahuasca. Blood analysis (i.e., hemoglobin, total hematocrit, erythrogram, leukogram, corpuscular volumes), and biochemical analysis for hepatic function (aspartate transaminase, alanine transaminase, and alkaline phosphatase), kidney function (urea and serum creatine), and tissue damage (lactate dehydrogenase) were performed, with no reports on toxic effects ²⁷². Furthermore, a 1-year study comparing regular ayahuasca users with controls ⁹⁴ showed no indication that long-term ayahuasca use could induce psychologic maladjustment, mental health deterioration, or cognitive impairment. No decreased cognitive function nor increased mental health issues were associated with populations who have a life-time use of these mind-altering substances, particularly as part of religious ceremonies ²⁷⁴, ²⁷⁵.

There have been a few reported cases of poisoning from Peganum harmala seeds. These included a 35-year-old male with abdominal pain, low blood pressure (hypotension) and convulsions, but this was after ingesting 150 g of Peganum harmala seeds ²⁷⁶. His symptoms resolved after several hours ²⁷⁶. It is possible the convulsions could have been related to the inverse agonist effect of some of the beta-carbolines at the benzodiazepine receptor site on the GABA-A receptor ¹⁰⁸, dopamine (D(2)) and benzodiazepine receptors. Drug Alcohol Depend. 2000 Aug 1;60(2):121-32. doi: 10.1016/s0376-8716(99)00148-9)), ¹⁰⁹. Another case involved a 27-year-old woman who had ingested 50 g of Peganum harmala seeds in a cup of coffee. She presented with hallucinations, slow heart rate (bradycardia), nausea, and vomiting, but was discharged several hours later, and laboratory investigation results were all normal ²⁷⁶. Another case was a 45 years old woman who ingested about 50 grams seed of Peganum harmala for heavy periods (menorrhagia) ²⁷⁷. She suffered nausea, vomiting, dizziness, tremor, ataxia, and confusion. On physical examination, she had hypotension (BP=90/60 mmHg) with normal heart rate (60 beat/min) and impaired knee to heel test. Her consciousness was reduced without any hallucination. Her laboratory test was normal. She was discharged at good condition 18 hours later ²⁷⁷. Several similar cases have been reported ²⁷⁸, ²⁷⁹, ²⁸⁰.

Harmaline, which constitutes 3% of Peganum harmala seeds and is present in low amounts in ayahuasca, is two times more toxic than harmine, inducing tremor, convulsion, respiratory paralysis, hypothermia, central nervous system depression, visual trouble, delirium, loss of coordination, paralysis, and sometimes hallucinations, when consumed in high doses ²⁷⁷. Toxic effects usually appear 3 to 4 hours after ingestion, with the first symptoms being nausea and vomiting, followed by an altered mental state and other neurological presentations.

Pharmacological studies of acute ayahuasca administration to healthy volunteers and mental health assessments of long-term ayahuasca consumers suggest that ayahuasca is relatively safe ¹⁵, ¹⁶, ²⁶, ¹⁷³, ¹⁹, ¹⁵⁶, ¹⁷⁴, ¹⁶², ¹²⁷, ¹²⁸, ²⁸¹.

Ayahuasca during Pregnancy

As pregnant women also participate in ceremonial ayahuasca consumption, studies should be pursued in order to assess possible toxic effects that might occur during pregnancy ²⁶⁸. Experimental data recorded in pregnant rats dealing with the in utero toxicity of ayahuasca alkaloids are contradictory, with some authors suggesting toxicity ²⁸² while others do not ²⁸³. Oliveira et al. ²⁸⁴ first reported the evidence of toxic effects in pregnant rats due to chronic ayahuasca consumption during gestational days 6–20, at doses 10 times higher (14 mL/kg of ayahuasca) than the normal human dose. These animals presented decreased food consumption and weight gain, accompanied with increased relative liver weight, an indication of hepatotoxicity. Effects at the fetal level included visceral and skeletal malformations, dilated lateral and third ventricles, and decreased body weight ²⁸⁴. Nevertheless, such data appear to be of limited relevance and should be extrapolated to humans with caution since, from field observations, pregnant women attending the religious ceremonies tend to use ayahuasca less frequently, and in reduced quantity ²⁶⁸. Although more investigation on this subject is needed, there are a few scientific evidences suggesting that no psychiatric nor neuropsychological problems are seen in adolescents who were exposed to ayahuasca before birth ²⁶⁸.

Is Ayahuasca dangerous?

Yes, Ayahuasca is potentially dangerous if taken by people with certain health conditions or taking certain medications, particularly ones that also release serotonin. Deaths have occurred ⁵⁰, ⁵¹. People who should not take ayahuasca include those with:

A family history of mental health issues
Bipolar disorder
Depression taking antidepressants
Difficulty vomiting
Epilepsy
Fractures
Gastrointestinal disorders
Glaucoma
Infection
Recent surgery
Retinal detachment
Schizophrenia
Seizures
Serious liver, kidney, or gallbladder disease
Severe cardiovascular disease
Stroke
Tuberculosis
Parkinson’s disease
Psychosis
Uncontrolled or very high blood pressure
Ayahuasca is not recommended for pregnant or lactating women

There is no safe level for ayahuasca and the use of this plant medicine always carries some risk. How ayahuasca affects you depends on:

If you have taken it before
Other medications you are taking
The amount taken
The strength of the decoction (varies from batch to batch)
Your current state of health
Weight
Where you take it and the vibe.

Ayahuasca should only be taken under the supervision of an experienced shaman or curandero because a trip can change your state of consciousness for several hours and you need to be kept safe.

DMT, the active ingredient in ayahuasca is classed as a Schedule I substance in the United States and it is illegal to import, possess, sell, distribute, or consume ayahuasca.

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