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DMT - LSD - KETAMIne - AYAHUASCA
DMT
N,N-dimethyltryptamine (DMT) is an indole alkaloid widely found in plants and animals, including humans. DMT was first synthesized in 1931 by the German-Canadian chemist Richard Manske (1901-1977) and isolated in 1946 by the Brazilian chemist Oswaldo Gonçalves Lima (1908–1989) from the root bark of the black Jurema (Mimosa tenuiflora).
In humans, DMT is found at higher levels in the lungs, thyroid, and adrenal glands. At intermediate levels, it is found in the placenta, skeletal muscle, heart, small intestine, stomach, pancreas, and lymph nodes. Although the mechanisms of its biosynthesis, metabolism, function, and mode of action are largely unknown, evidence suggests that endogenous DMT participates in various processes across different systems and may act as a neurotransmitter.
DMT does not produce effects when ingested on its own, as it is degraded by monoamine oxidase (MAO) enzymes present in the gastrointestinal tract, making it impossible to reach the circulatory system and the central nervous system. In ayahuasca, however, the presence of MAO inhibitors, such as harmine, protects DMT from degradation and endows it with significant effects on the brain and other organs.
The first human studies with isolated DMT occurred in 1956, conducted by the Hungarian chemist and psychiatrist Stephen Szára, who administered DMT intramuscularly (i.m) to 20 healthy volunteers. Since then, more recent studies have suggested a safety profile associated with the parenteral administration of isolated DMT, such as vaporized or intravenous (i.v).
The acute effects of DMT are transient, lasting between 20 minutes (IV or inhaled) and 1 hour (i.m). No tolerance or overdose is observed. At lower doses (0.01 mg/kg i.v), it leads to states of relaxation and comfort, and at higher doses (0.4 mg/kg i.v), it produces rapid and intense effects, with significant changes in the state of consciousness, which in many ways resemble a dream-like state.
Recently, DMT has been linked to therapeutic effects, particularly in mental disorders such as depression and anxiety. Clinical trials with ayahuasca and isolated DMT suggest a rapid antidepressant effect, initiated as early as one day after intervention.
Central to the creation and evaluation of new therapies is the understanding of the mechanisms by which DMT exerts its effects. Our studies suggest that the therapeutic response results from the combination of modulation of neuroimmune, neuroendocrine, and neuroplastic pathways that are crucial for homeostatic regulation, as well as certain characteristics of the phenomenology of the acute effects of the substance, such as changes in visual and auditory perception during the ayahuasca experience.
LSD
Lysergic acid diethylamide (LSD), a potent hallucinogenic compound, was first synthesized by the Swiss chemist Albert Hofmann in 1938 during his research on ergot alkaloids derived from the fungus Claviceps purpurea. However, it wasn't until 19 April, 1943, that Hofmann discovered LSD's potent psychedelic properties after accidentally ingesting a small amount of the compound, marking the birth of modern psychedelic science.
The phenomenology of LSD's effects encompasses a wide array of subjective experiences, ranging from alterations in sensory perception to profound shifts in consciousness. Users often report vivid visual hallucinations, characterized by intricate geometric patterns, intensified colors, and enhanced perception of depth and texture. These visual distortions are frequently accompanied by synesthesia, where sensory modalities intertwine, leading to experiences such as "seeing" sounds or "hearing" colors.
LSD-induced states commonly evoke feelings of interconnectedness, intense emotionality, ego dissolution, mystical experiences and a heightened sense of awe and wonderment. Such profound alterations in subjective experience underscore LSD's capacity to facilitate profound introspection and spiritual exploration, contributing to its enduring fascination among scientists, artists, and mystics alike. Despite its potential for inducing profound alterations in perception, mood, and cognition, LSD also poses certain risks. The substance can trigger intense, unpredictable psychological experiences, commonly referred to as "bad trips," which may include hallucinations, paranoia, and anxiety.
Additionally, LSD can induce adverse physical effects such as increased heart rate, elevated blood pressure, and nausea. In rare occasions, LSD use can precipitate serious adverse effects, particularly in individuals predisposed to or with a history of psychotic disorders. In clinical settings, LSD has demonstrated promising therapeutic potential. Research conducted in the mid-20th century explored its applications in psychotherapy, showing efficacy in treating various psychiatric conditions, including anxiety disorders, depression, and substance use disorders. Recent studies have reignited interest in LSD-assisted psychotherapy, with preliminary evidence suggesting its effectiveness in alleviating symptoms of anxiety and depression. Clinical trials investigating LSD-assisted therapy have reported improvements in mood, cognition, and overall well-being following controlled administration of the substance. These therapeutic effects are believed to stem from LSD's ability to modulate serotonin receptors in the brain, leading to enhanced introspection, emotional release, and mystical experiences.
Furthermore, LSD-assisted therapy often involves a structured therapeutic framework, emphasizing psychological support, introspective exploration, and integration of psychedelic experiences into everyday life. As research into LSD continues to evolve, it is essential to navigate its therapeutic potential while mitigating associated risks. By elucidating the underlying mechanisms of action and refining therapeutic protocols, scientists aim to harness the therapeutic benefits of LSD while minimizing adverse effects, ultimately paving the way for its responsible and regulated use in clinical practice.
KETAMINE
Ketamine is a dissociative anesthetic that has gained popularity due to its safety profile, particularly in maintaining airway reflexes and blood pressure stability during anesthetic procedures. Its effects are primarily mediated through the antagonism of N-methyl-D-aspartate (NMDA) receptors, which are part of the glutamatergic neurotransmission system.
Ketamine is a chemical compound that can be found in various forms, with the most common and first to be synthesized and clinically used being racemic ketamine. This is a 50/50 mixture of two enantiomeric forms, S(+) ketamine and R(-) ketamine. Each enantiomer has different pharmacological properties and, in its isolated form, is also clinically used. S(+) ketamine (or Esketamine) is the more potent enantiomer and is generally considered more effective at lower doses than the racemic form. R(-) ketamine is less potent and therefore has been less studied.
The first reports of ketamine's antidepressant action emerged from incidental observations. In the 1990s, researchers began to notice that patients undergoing anesthetic procedures with ketamine often reported significant improvements in mood, which emerged rapidly after drug administration and persisted beyond the anesthetic effect. From the 2000s onwards, studies began to systematically investigate the antidepressant potential of ketamine in patients with treatment-resistant depression.
Early studies on ketamine's antidepressant action were characterized by intravenous administration and single-dose use. These studies revealed rapid action, with improvements within 24 hours and therapeutic response rates between 50% and 70% in patients resistant to conventional treatments, also demonstrating good safety and tolerability of the drug. Subsequently, research expanded to explore other routes of administration, including intranasal, oral, intramuscular, and subcutaneous. Additionally, studies were conducted to investigate the effects of multiple administrations of the substance. This progress culminated, from 2019 onwards, in the authorization of the use of Spravato® (esketamine), an intranasal form of ketamine, for patients with treatment-resistant depression or patients at high risk of suicide, in various countries, including Brazil. Since then, ketamine has been studied for a variety of mental disorders, including anxiety, bipolar affective disorder, post-traumatic stress disorder, obsessive-compulsive disorder, and substance use disorder.
The therapeutic protocol for the administration of Spravato® presents high costs, notably due to the costs associated with importing the substance and the need for intranasal application to be performed under medical supervision in a clinical setting. In response to these challenges, we are conducting a clinical study exploring the use of nationally produced subcutaneous esketamine, with the aim of reducing the costs associated with the patent for Spravato®. Additionally, the study aims to validate psychotherapy protocols as support for the substance's action, for example in managing dissociation, an effect whose categorization as an adverse event is still under debate. The research proposes that instead of minimizing this effect, it should be more deeply studied and managed with appropriate psychotherapeutic support.
Therefore, ketamine is promising due to its ability to act rapidly and for conditions that are resistant to other forms of treatment. However, despite its potential, further studies are needed to fully understand its effects, possible long-term adverse events, and the development of safer, more effective, and less costly treatment protocols.
AYAHUASCA
Ayahuasca, which in Quechua means "the vine of the spirits" (aya = spirit and waska = vine), is a psychedelic brew created by indigenous populations of the Amazon basin, who have been using it for centuries in shamanic ceremonies. Additionally, since the 1930s, it has been used as a sacrament by syncretic Brazilian religions such as Santo Daime, União do Vegetal, and Barquinha. Its preparation commonly involves the combination of the Banisteriopsis caapi vine, also known as jagube or mariri, with the leaves of the Psychotria viridis plant, known as chacrona. Mixed with water and boiled for hours or days, the result is a brown liquid with a strong and characteristic flavor. The primary active substance in ayahuasca is N,N-dimethyltryptamine (DMT), a potent psychedelic substance present in the leaves of chacrona.
However, when ingested, DMT is normally inactivated by the human digestive system, by enzymes known as monoamine oxidase (MAO). The presence of monoamine oxidase inhibitors (MAOIs) in the Banisteriopsis caapi vine is what allows DMT to become active when consumed in ayahuasca. These compounds temporarily block the action of monoamine oxidase enzymes in the digestive system, preventing the degradation of DMT and allowing its psychoactive effects. The acute effects of ayahuasca vary depending on factors such as dosage, the context of the experience, and individual user characteristics. Generally, effects begin about 20 to 40 minutes after ingestion and last around 4 hours.
Experiences can be deeply introspective, with alterations in body sensations, emotions, mood, and perception of oneself and others. Closed-eye visions are common and can range from geometric patterns to vivid and complex scenes resembling a dream. Effects such as nausea, vomiting, diarrhea, and mild increases in blood pressure and heart rate can also occur. Neuroimaging studies show that ayahuasca also induces effects in the brain. Acutely, ayahuasca promotes changes in the visual cortex, hippocampus, and frontopolar cortex, areas associated with visual perception, memory, and cognition, respectively. Additionally, ayahuasca reduces activity and connectivity in a set of brain regions known as the default mode network, related to introspection and self-referential processes. There is a growing interest in research on the potential therapeutic benefits of ayahuasca. Studies suggest that ayahuasca may be effective in treating conditions such as depression, anxiety, post-traumatic stress disorder (PTSD), and substance use disorder. Our group conducted the world's first randomized placebo-controlled clinical trial evaluating ayahuasca in the treatment of treatment-resistant depression.
Our results suggest that ayahuasca has a rapid antidepressant effect, beginning one day after a single intervention. With this study, we also demonstrated that ayahuasca modulates biochemical markers such as the stress hormone cortisol, the molecule BDNF related to neuroplasticity, and the protein c-reactive related to inflammation. However, it is important to note that ayahuasca is not a risk-free substance, and its use should be approached with care. Additionally, the context of ceremonies and the integration of experiences are considered crucial aspects to maximize the potential therapeutic benefits and minimize the risks associated with its use. In 1987, the Brazilian government authorized the ritualistic use of ayahuasca; however, it is important to remember that as a medical treatment, it has only been used in an experimental research context and is not approved for commercial clinical use.