N,N-Dimethyltryptamine (DMT) is a chemical compound known as an indole alkaloid which pertains to the shape of the molecule core which makes up a larger molecule called a tryptamine alkaloid. Tryptamine alkaloids are the one of the primary molecules found in all Earth Medicines and are best known for producing brief and intense psychedelic effects when ingested. Endogenous is the word meaning produced from within or naturally produced. Exogenous means it comes from a source outside the body. There is increasing evidence suggesting that endogenous DMT plays important roles for a number of processes in the human body and in the central nervous system (CNS), and also acts as a neurotransmitter. Neurotransmitters are chemicals in the brain that play a specific role when transferred from one neuron to another. Neurons are the cells that make up the nerve tissues in the brain and spinal cord. The brain and spinal cord are what make up the central nervous system in our body.
History of DMT
The first synthetic forms of DMT were created in a lab by a Canadian chemist named Richard Manske, in 1931 (Manske, 1931). Natural forms of DMT were first discovered in modern day society by Microbiologist Oswaldo Gonçalves de Lima in 1946 (Goncalves de Lima, 1946). It wasn't until 1956 that DMT’s hallucinogenic properties were discovered by Stephen Szara, a Hungarian chemist and psychiatrist, who extracted DMT from the Mimosa hostilis plant and administered it to himself via an intramuscular injection (Szára, 1956). It wasn't until then that DMT became an object of interest in the study of modern day science and entheogens and a subject of investigation for many different reasons.
The serotonin system within the brain has been thought to be the main contributor to the psychedelic effects of DMT. In 1988 JC Callaway of the University of California published one of the first scientific articles with supporting evidence of the existence of DMT in humans and that it naturally occurs in altered states of consciousness, such as psychosis, dreams, creativity, imagination, religious and/or spiritual phenomena, and near-death experiences. In 2009 Dr. Jason Wallach of Rowan University in New Jersey found that the primary receptor in the brain responsible for naturally and externally induced altered states of consciousness related to hallucinogenic effects of DMT were via serotonin 5-HT2A pathway. The 5-HT2A Pathway is the receptor site to which serotonin binds and exerts its effects.
Serotonin, also known by its molecular name as 5HT, is the naturally occurring chemical or neurotransmitter found in the human body that impacts every part of who we are, from our emotions to our body, to motor skills, appetite, and even digestion. Serotonin is also called the “happy hormone” or the “natural mood stabilizer”. It is also the precursor to the chemical melatonin which means that it helps produce melatonin which then helps regulate sleep-wake cycles, and our internal biological rhythmic clock. Serotonin is primarily produced in the gut and smaller amounts are produced in the brain.
In the article by Dr Wallach published in the Journal of Medical Hypotheses in 2009 he discusses the subject of the “Waking reality” that is created in a similar way to altered states of consciousness except that the normal state correlates with events in the “physical” world. Basically stating that a waking reality can be thought of as a regulated psychedelic experience that can be integrated in everyday life vs the psychosis that is found in schizophrenia and the inability to integrate or process extrasensory information. The model he developed states that the sensory-altering effects of exogenous psychedelics are a result of the compound acting directly in the neurotransmitter regions of the CNS. Meaning that DMT acts as a neurotransmitter that signals parts of the CNS involved in sensory perception that ultimately and significantly enhances our existing natural senses. This essentially means that we are not receiving an external source of hallucinations or psychedelic experiences, they are induced by chemical reactions from our own body that are triggered by an external source.
Synthesis Of DMT
Endogenous DMT is synthesized from tryptophan and then broken down into tryptamine. Tryptamine is then transmethylated (transfer of a methyl molecule) by an enzyme called INMT which catalyzes the addition of molecular methyl groups resulting in the production of DMT (Vitale et al.,2011). INMT (indolethylamine-N-methyltransferase) is the enzyme that converts tryptophan into DMT.
Tryptophan is an essential amino acid (molecules that combine to form proteins) used to make proteins in the body. It is not naturally produced in our body and must be consumed through food. After tryptophan is consumed it is metabolized by the enzyme TPH that converts it into 5-HTP which is then converted into Serotonin. Tryptophan is also broken down into the chemical compound known as NAD (Nicotinamide adenine dinucleotide). NAD helps convert food into energy and plays a role in maintaining DNA integrity to ensure proper cell function to protect against aging and disease.
DMT is biosynthesized by INMT that is widely expressed throughout many parts of the body. Large amounts of it can be found densely located in the spinal cord. Within the human brain, highest INMT activity has been found in the uncus, medulla, amygdala, frontal cortex, and in the fronto-parietal and temporal lobes. INMT is also found in the pineal gland (Vitale et al.,2011).
The Uncus is the part of the brain that is involved in the sense of smell, emotions, and forming new memories. The Medulla is the part of the brain involved in processing memory and emotions, primarily fear. The Amygdala is the part that produces physiological responses to the emotions and fear. The Frontal Cortex is the part of the brain that is associated with higher cognitive states of consciousness. The Parietal Lobes are the parts of the brain that allow us to process the information we receive through our senses. The Temporal Lobes are the part of the brain that is primarily associated with processing language. The Pineal Gland is the part of the brain that produces melatonin and DMT.
Pharmacokinetics of DMT
DMT has a rapid onset of action, intense effects, and a short duration of action. DMT can be injected, ingested orally with an MAOI or inhaled, and its effects depend on the dose and the administration route. The metabolism and pharmacokinetics of DMT depend on how it is administered. The Bentham Science Journal published a study in 2011 that found ways in which DMT works in the body. They found that IV (intravenous) administration of radio-labeled (the attachment of radioactive molecules that illuminate on scans to follow the molecules journey) DMT in rabbits entered the brain within 10 seconds and was eliminated by the kidneys. In this study no traces of radio-labeled DMT were found or measured in urine 24 hours post administration (Vitale et al.,2011). However, unlabeled DMT could still be detected at 2 and 7 days later. In the same study, tryptamine was also eliminated within 10 minutes after IV administration of DMT. These findings show that even after complete clearance of a dose of exogenous DMT from the blood, non radiolabeled DMT is still present in the CNS, thus providing tangible evidence that DMT is being produced in our bodies.
In a study done by Dr. Rick Straussman published by The Journal of Behavioral Brain Research in 1996 found that IV administration of DMT had an onset of 10-30 seconds, peaked at about 5 minutes, and was eliminated within 30 minutes. Intramuscular administration had an onset of 2 – 5 minutes and could last up to 30 - 60 minutes with the effects being generally less intense than IV or inhalation routes of administration. Inhaled administration of DMT is rapid, similar to that of IV administration, but lasts less than 30 minutes. Smoked DMT effects are also extremely intense, more so than IV administration. Intranasal free-base DMT was inactive, as was DMT administered rectally in the same form. DMT is rapidly metabolized or broken down by monoamine oxidase A (MAO-A), as well as by liver enzymes in mucous membranes (Simão et al., 2019). The half-life of DMT is approximately 5–15 min and can be extended by ingesting an MAO inhibitor (Cameron and Olson, 2018). DMT is inactive after oral ingestion due to a rapid degradation under the influence of MAO in the intestine and liver (Barker, 2013). In the case of ayahuasca use, the medicine can be orally ingested because it also contains MAO-A inhibitors like harmine, enabling large amounts of orally-administered DMT to be retained.
DMT interacts mostly with a variety of serotonin receptors, but also found to interact with glutamate, dopamine, acetylcholine, and sigma-1 receptors. 5-HT2A is the receptor site to which serotonin binds and exerts its effects. Glutamate receptors bind glutamate which is the neurotransmitter involved in human conditioning such as shaping learning and memory. Dopamine receptors bind to dopamine which is the neurotransmitter involved in the ability to feel pleasure and known as the “reward hormone”. Acetylcholine is a neurotransmitter that plays a role in memory, learning, attention, arousal and involuntary muscle movement.
Sigma-1 Receptors are another receptor family that has been found to interact with DMT. One of the possible roles of the sigma-1 receptor appears to act as an intracellular conduit between the endoplasmic reticulum (ER) and mitochondrial parts of a cell (Carbonaro and Gatch, 2016). The Endoplasmic Reticulum is the part of a cell that plays a role in the production of proteins and fats. The Mitochondria are the energy centers of cells.
Other Roles of DMT
To establish that DMT acts as a neurotransmitter rather than being a by-product of the metabolism of other bioactive molecules, it was necessary for researchers to establish that DMT was synthesized, stored, and released in the human body. To establish this, a study published in the Journal of Neural Transmission in 2013 suggested that DMT may have biological roles in the body in addition to psychedelic effects. They found that the body biologically prioritizes DMT as it does other processes such as the transport of glucose and amino acids in the body, meaning that the body identifies it as an important molecule and that it is present for more than just its psychedelic effects and plays a role in biological processes and cellular protective mechanisms.
In 1996 Dr. Straussman found that single doses of DMT produced a rapid onset of marked sympathetic effects such as increased heart rate and blood pressure. Sympathetic Effects are known as symptoms associated with “flight or fight” responses. During the experiments beta blockers (a type of blood pressure medicine that decreases heart rate and blood pressure) were co-administered with DMT and resulted in a diminishing of the increased heart rate, however the blood pressure increases continued to enhance.
In Straussmans 1996 study he additionally found that as DMT levels increased in the body so did the levels of corticotropin, cortisol, prolactin, and growth hormone when administered to human volunteers. When DMT was given repeatedly to human volunteers (4 times at 30 min intervals), tolerance to the increases in the endocrine hormone levels were noted. These findings are similar to the effects of serotonin on the endocrine system.
Corticotropin is a hormone released by the pituitary gland that stimulates the adrenal glands to release steroids such as cortisol in times of stress and also secretes androgens (sex hormones). Cortisol is the hormone responsible for supplying the body with the energy necessary during times of stress. Cortisol levels tend to be at their highest right after people wake up in the morning. This perhaps may be because when we sleep we have increased levels of DMT being secreted as we journey through our subconscious in dreamland.
Acute/Short-term Effects of Cortisol on the Body
Glucose Metabolism-Increases glucose levels and decreases the use of glucose by the body
Protein Metabolism-Increases the breakdown of proteins causing protein levels to rise allowing them to be readily available for energy
Fat Metabolism-Increases mobilization of fatty acids and increases the body's use of fats
Anti-inflammatory-Prevents the release of inflammatory mediators and suppresses the immune response
Psychological-Increases emotional instability (liberation of emotions)
Prolactin is the hormone involved in milk production in women, perhaps symbolic of the new energies we will be feeding or giving life to that occurs during transformational experiences. Growth Hormone is the hormone responsible for cellular growth and maintenance of cells and tissues in the body, perhaps symbolic of the personal and spiritual growth that occurs during and after spiritual ceremonies. Androgens are sex hormones that are involved in reproduction, for purposes of spirituality and their release during DMT administration, perhaps serving as a symbol of the rebirth and the new life we are giving way through our transformation.
DMT has been reported to decrease the percentage of CD3 and CD4 lymphocytes and increase the number of natural killer cells (Dos Santos et al., 2011). Lymphocytes are the primary cells responsible for the body's inflammatory response, which is why DMT has been found to suppress inflammatory responses as mentioned earlier. Natural Killer Cells are cells within the human body with the ability to recognize and kill abnormal cells or tissues; they are different from other immunologic cells in that they do not require specific antigen recognition to be activated. They are always active and kill on contact with abnormal cells. Because of the increased levels of natural killer cells after DMT administration it has been hypothesized that DMT might increase activity of the immune system and could potentially be useful in the treatment of cancer.
In 2013 Tourino et al., discovered that DMT increased cellular toxic activity of both monocytes and lymphocytes (immune cells) in human glioma cell lines (Gliomas are cancerous cells found in the brain and spinal cord). Other studies have found that DMT and similarly related compounds are anti-inflammatory as they have the ability to inhibit the production of certain interleukins (Szabo et al., 2014). Interleukins are signaling proteins that modulate and instruct immune cells on how to act. Additionally, DMT can increase the levels of secreted interferon-β and interferon-γ (Frecska et al., 2013). Interferons are potent protein compounds that inhibit viral multiplication, thus preventing the growth of viral infections in the body.
Neurogenesis is the process by which new brain cells called neurons are formed in the brain. Neuroplasticity is the ability of the brain to adapt and change through the growth and reorganization of existing neural networks. That is, making new connections and behaviors in response to new information, sensory stimulation, development, or even through externally or internally induced damage, or dysfunction.
Stimulation of 5-HT2A receptors appears to underlie the plastogenic effects of DMT. In a study done by Ly and Company they were able to demonstrate that DMT increases and promotes increased dendritic spine density. Dendrites are part of the nerve cells in the brain that give and receive information, they are the part that forms connections to other nerve cells. They look like the roots and branches of the nerve cells, symbolically in spiritually serving as the parts of the tree (roots and branches) that form connections. This DMT-mediated neural plasticity occurred through a mechanism involving the activation of 5-HT2A receptors. In their study they also found that when they blocked the 5-HT2A receptor, DMT was unable to bind, and therefore no neuronal genesis was observed. Neural plasticity in the prefrontal cortex (Front part of the brain) is critical to the behavioral effects of fast acting antidepressants like ketamine, and they also concluded that it is possible that the 5- HT2A receptor binding underlies the known antidepressant effects of psychedelics with a tryptamine center.
DMT can affect the rate of genetic replication and trigger immediate early gene stimulation in DNA replication by encoding for the production of factors that are associated with synaptic plasticity (Frankel and Cunningham 2002; Gonzalez-Maeso et al., 2007). Synapses are the ends of nerve cells that form the connections to other nerve cells. Increases in expression of brain-derived neurotrophic factor (BDNF) are also observed after DMT administration (Gewirtz et al., 2002). BDNF plays an important role in neuron survival and growth, serves as a neurotransmitter modulator, and participates in neuronal plasticity, which is essential for cognitive learning and memory.
When DMT bind with sigma-1 receptors the process results in the enhanced production of anti-stress and antioxidant proteins, with the activation of sigma-1 there is a reduction in the possible damage done by hypoxia or oxidative stress (Szabo et al., 2014, 2016; Szabo and Frecska, 2016). In addition it was found that DMT greatly increases the survival of certain cell types in severe hypoxia by way of its interaction with sigma-1 receptors. DMT also decreased the expression of hypoxia induced compounds and chemicals that increased cellular stress thereby increasing the survival of brain tissue. Such reactions have potential frontiers in conditions such as stroke, heart attack or similar arterial occlusive blood clot disorders, cardiac arrest, and perinatal asphyxia, all conditions associated with hypoxia consequences (Carbonaro and Gatch, 2016). Szabo et al. (2016) have speculated that DMT may also contribute to neuroregenerative and neurorestorative processes by modulating the survival of brain cells and concluded sigma-1 receptor activation is potentially neuroprotective. DMT has been also been shown to reduce brain swellings via the sigma-1 receptor and can also induce neuronal plasticity, a long-term recuperative process that goes beyond neuroprotection (Tsai et al., 2009; Ruscher et al., 2011; Kourrich et al., 2012). Sigma-1 receptors can also influence brain cell survival and proliferation (Collina et al., 2013) and Frecska et al. (2013) have suggested that DMT is protective during cardiac arrest and perinatal development.
Morales-Garcia et al. (2020) have reported that the N,N-dimethyltryptamine regulates adult neurogenesis implying a possible pharmaceutical agent in the treatment of stroke, dementia, Alzheimer’s, and other forms of brain cell disease, damage, and injury.
Death and Suffering
Frecska and colleagues (2013), suggest that during physical states of pain, suffering, and agony, the lungs synthesize large amounts of DMT (primarily through the removal of INMT inhibitors) and can release DMT into arterial blood within seconds. Once in blood circulation DMT is safe from getting broken down. Because of this scientists have theorized that DMT could potentially keep the brain alive without the brain having to produce DMT on its own. Exogenous (meaning coming from outside the body) DMT-like psychedelic effects are similar to near or after clinical death experiences. Leading to the belief that DMT is involved in the process of dying.
DMT and Psychosis
There have been adverse effects of hallucinogens that are physical such as intense fear, paranoia, anxiety, grief, and depression, that can result in putting the user or others in physical harm or danger. In laboratory controlled studies it is found that approximately 30% of psychedelic experiences are psychologically challenging. Even though DMT may not produce physical toxicity, severe psychological adverse effects can occur.
Other theories propose that DMT may be important in psychiatric disorders. An article released by the Journal of Psychopharmacology in 2007 found data suggesting that DMT may be a schizotoxin, and various contributors hypothesized that DMT was a key factor in causing schizophrenia. This hypothesis is no longer accepted, but it is still thought that DMT plays a role in psychotic symptoms. DMT was thought to be neurotoxic, but more recent research suggests that DMT may actually be neuroprotective.
As we can see there is a spectrum in the world of DMT, and that spectrum requires balance. Too little leads to symptoms of severe depression and loss of connection to self and the world we live in and on the other spectrum, too much can cause severe psychosis. In those spectrums, the middle ground is the so-called “Waking Reality” which is the state of balanced consciousness that allows for the proper integration of psychedelic experiences in the reality that we live in, that is, integrating the experience in the physical world around us.
Other Bodily Effects
DMT causes dose-dependent elevations in pupil size (Dos Santos et al., 2012). The amplitude of the pupillary light reflex was reduced and its latency was increased with DMT use (Dos Santos et al., 2011). Compared to placebo, DMT can cause a statistically significant decrease in body temperature during the first hour, followed by a gradual increase (Dos Santos et al., 2012).
WHAT PRODUCES A EUPHORIC JOURNEY vs. CHALLENGING JOURNEY?
DMT is found to be naturally produced in the human body and shares a similar tryptophan core with other psychedelic medicines. Research has found that it works primarily on the 5-HT2A receptor which is similar to the way serotonin behaves and has also been found to play several roles or influence other physiological processes that occur in our body. DMT may be a medicine of significant adaptive mechanisms in spiritual transformation, but can also serve as a promising substance in scientific applications of westernized medical therapies involving anxiety, substance abuse, inflammation, cancer, or healing damage to the tissues of the brain and spinal cord via neurogenesis and neuroplasticity. More scientific research is being conducted to validate hypotheses surrounding DMT with supporting evidence.
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