|
 
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| REVIEW |
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| Year : 2023 | Volume
: 2
| Issue : 3 | Page : 53-62 |
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Neuromodulatory mechanisms of N,N-dimethyltryptamine: a narrative review
Javier Hidalgo Jiménez
Independent scholar, Calle Cuevas del Palomo s/n, 18009, Granada, Spain
| Date of Submission | 08-Feb-2023 |
| Date of Decision | 02-Mar-2023 |
| Date of Acceptance | 20-Jun-2023 |
| Date of Web Publication | 26-Sep-2023 |
Correspondence Address:
Javier Hidalgo Jiménez
Independent scholar, Calle Cuevas del Palomo s/n, 18009, Granada
Spain
 Source of Support: None, Conflict of Interest: None
DOI: 10.4103/2773-2398.386227
N,N-dimethyltryptamine (DMT) is the simplest psychedelic tryptamine and is produced naturally by many plant and animal species, including humans. While classical psychedelics, such as lysergic acid diethylamide, or psilocybin, are gaining interest because of their therapeutic potential, DMT has yet to be fully investigated. However, preliminary clinical evidence suggests that DMT and/or ayahuasca, a DMT-containing psychoactive beverage, both possess antidepressive, anxiolytic, and antiaddictive properties. In addition, the subjective effects of DMT are particularly potent. Both subjective and therapeutic cues can be largely explained via the neuromodulatory properties of DMT. In addition, DMT interacts with several neurochemical systems, including the glutamatergic, monoaminergic, and cholinergic systems. Consequently, large-scale brain dynamics can suffer acute and dramatic shifts in several networks, including visual and auditive networks, and the default-mode network. More broadly, top-down cognitive processes (predictive and contextual processing) can become restricted while bottom-up and stimuli-related processing is enhanced. Furthermore, the acute effects of DMT can crystallize to some extent by virtue of its plastogenic effects which are mediated by sigma 1 receptor, brain-derived neurotrophic factor, tropomyosin receptor kinase B, and serotonin receptor 2A. DMT-induced plasticity has been related mental well-being and therapeutic benefits. Here, I provide an updated review of the neuromodulatory effects of DMT and the mechanisms that underlie these effects. I consider the molecular targets that influence neurochemical systems, changes in large-scale cortical function and structure, and DMT-dependent neuroplasticity. Finally, I highlight the therapeutic relevance and/or risks associated with the neuromodulatory mechanisms of DMT.
Keywords: N,N-dimethyltryptamine; major depression disorder; molecular mechanisms; neuroimaging; plasticity
How to cite this article:
Jiménez JH. Neuromodulatory mechanisms of N,N-dimethyltryptamine: a narrative review. Brain Netw Modulation 2023;2:53-62 |
| Introduction | |  |
N,N-dimethyltryptamine (DMT) is a classical psychedelic that is naturally produced by many plant and animal species, including humans (Saavedra et al., 1973; Shulgin and Shulgin, 1997; Barker et al., 2012). Classical psychedelics activate the serotonin (5-HT) receptor 2A (5-HT2A) to elicit mind-altering effects. In this review, the term “psychedelic” refers exclusively to classical, serotoninergic psychedelics.
From a chemical point-of-view, DMT is the simplest psychedelic drug; the structure of this drug serves as a molecular backbone to psychedelics of the ergoline class (e.g., lysergic acid diethylamide) and tryptamine class (e.g., psilocin, or 4-hydroxy-DMT) (Nichols, 2016) [Figure 1]. Despite its simplicity, the subjective effects of DMT are particularly potent. The so-called DMT “breakthrough” experience is characterized by the feeling of visiting a completely different hyper-realistic world or dimension (Nichols, 2016). Internet forums, such as Reddit (https://www.reddit.com/r/DMT/), feature a significant number of trip reports relating to immersive and complex visions (Lawrence et al., 2022), out-of-the-body experiences, and encounters with strange entities (Michael et al., 2021). However, the use of DMT can be traced to ancient times. For example, indigenous Amazonian cultures, dating back to prehistorical times, harnessed the properties of DMT from ayahuasca, a medicinal concoction with psychoactive properties (McKenna, 2004). Ayahuasca gradually became popular in the 1990s and networks of ayahuasca users are emerging in Western countries, thus raising dilemmas relating to medical/religious freedom, health and safety (Apud and Romaní, 2017). On the other hand, endogenous DMT (i.e., DMT produced naturally by organisms) has been detected in the cerebrospinal fluid, blood, and urine of humans (Barker et al., 2012). Cortical, extracellular levels of DMT in the rat are known to be similar to those of 5-HT, noradrenaline (NA), and dopamine (DA) (Dean et al., 2019). However, whether endogenous DMT plays roles that are relevant to mammalian physiology is still a matter of intense debate (Jiménez and Bouso, 2022). | Figure 1: Dimethyltryptamine (DMT), psilocybin and lysergic acid diethylamide (LSD) molecules.
Note: The structure of DMT contained in psilocybin and LSD molecules is highlighted in green.
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The neuromodulatory effects of DMT are of significant therapeutic interest. A recent pilot study reported that DMT exerts rapid antidepressant effects, and is safe and well tolerated both by patients suffering major depression disorder and healthy controls (D’Souza et al., 2022). In addition, a large-sample, randomized, and double-blind clinical trial testing DMT-assisted therapy to treat major depression disorder has already completed phase II (NCT04673383). Furthermore, several open-label and/or randomized controlled trials have shown that ayahuasca exerts anxiolytic and antidepressive effects after a single dose (Santos et al., 2007; Osório et al., 2015; Sanches et al., 2016). The therapeutic potential of ayahuasca can be explained by the interactions of DMT with a variety of molecular targets (Rossi et al., 2022), and on a higher scale, by DMT-dependent modulation of brain networks, including the visual pathways or the default mode network (DMN) (Gattuso et al., 2023). Moreover, DMT promotes neural plasticity and drives long-lasting changes in brain structure. Furthermore, DMT is one of the very few known endogenous molecules that can bind to the sigma 1 receptor (σ1) (Fontanilla et al., 2009), which drives antinflammatory, tissue-protective, and immune processes that are beyond the scope of this review. These effects make DMT attractive for future therapeutic research on neurodegenerative diseases.
Although there is growing interest in DMT, this molecule has not been studied extensively when compared to other psychedelics. This review offers a detailed summary of the neuromodulatory mechanisms of DMT and their therapeutic relevance. First, I describe how DMT affects different neurochemical systems. Then, I discuss the molecular mechanisms of DMT-dependent neuroplasticity. Finally, I address neuroimaging studies that have investigated the effects of DMT on large-scale cortical function and structure [Figure 2]. | Figure 2: The modulatory mechanisms and targets of DMT.
Note: 5-HT1A Serotonin receptor 1A; 5-HT2A: serotonin receptor 2A; 5-HT2C serotonin receptor 2C; BDNF: brain-derived neurotrophic factor; DAT: dopamine transporter; DMN: default-mode network; DMT: dimethyltryptamine; FC: functional connectivity; GABA: gamma-aminobutyric acid; MAO: monoamine oxidase; mTOR: mammalian target of rapamycin; NAT: NA transporter; SERT: serotonin transporter; TAAR1: trace amine-associated receptor 1; TrKB: tropomyosin kinase B; σ1: sigma-1 receptor.
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| Search strategy | | |
Electronic research was performed using the PubMed database. The final retrieval was performed on the 10th of January 2023. The following search terms were used: (dimethyltryptamine OR DMT OR ayahuasca) AND (neuromodulation OR glutamate OR N-methyl-D-aspartate receptor OR NMDA OR alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor OR AMPA OR gamma-aminobutyric acid OR GABA OR monoamine OR serotonin OR 5-HT OR DA OR adrenaline OR NA OR epinephrine OR norepinephrine OR SERT OR NAT OR DAT OR vesicular monoamine transporter OR VMAT OR monoamine oxidase OR MAO OR trace amine receptor 1 OR TAAR1 OR acetylcholine OR sigma OR plasticity OR brain-derived neurotrophic factor OR BDNF OR tropomyosin receptor kinase B OR TrkB OR electrophysiology OR excitability OR electroencephalography OR EEG OR magnetoencephalography OR MEG OR neuroimaging OR magnetic resonance OR fMRI OR MRI OR positron emission tomography OR PET OR single photon emission tomography OR SPECT OR low-resolution brain electromagnetic tomography OR LORETA OR network OR visual OR auditory OR DMN OR cognition OR perception). We also activated filters for clinical trials, meta-analyses, and randomized controlled trials with available abstracts. Because the literature relating to this topic is not extensive, the publication date was not restricted.
A total of 155 articles were identified. I screened all titles and pre-selected 34 articles. After reading their abstracts, 12 articles were selected of which 10 were finally included in this review. Further references were retrieved from a personal library developed to write previous articles; all of these papers are available on PubMed.
| Mechanisms modulating neurochemical systems | | |
Cortical glutamate modulation via 5-HT receptors
DMT activates 5-HT2A with nM potency (Blough et al., 2014; Eshleman et al., 2014; Rickli et al., 2016). 5-HT2A is an excitatory Gq/11 G protein-coupled receptor (GPCR) that is expressed at high levels in cortex layer V pyramidal, glutamatergic neurons (Aghajanian and Marek, 1997, 1999). 5-HT2A activation enhances membrane excitability, thus facilitating the release of glutamate (Glu) (Scruggs et al., 2003; Muschamp et al., 2004). When a psychedelic ligand binds to 5-HT2A, but not when 5-HT does, the induced excitatory postsynaptic currents exhibit an unusual, late and prolonged component due to the activation of extrasynaptic N-methyl D-aspartate (NMDA) receptors (Lambe and Aghajanian, 2006). In rodents, DMT is known to block the behavioral effects of phencyclidine, an antagonist of NMDA (West et al., 2000). In addition, agonists of the inhibitory metabotropic Glu receptor 2/3 are known to be potent partial blockers of DMT behavioral cues in rats; in turn, metabotropic Glu receptor 2/3 antagonists have been shown to facilitate the effects of DMT (Carbonaro et al., 2015). Furthermore, DMT has high binding affinity to 5-HT1A (Ki value around 180 nm) (Keiser et al., 2009), an inhibitory GPCR which exerts effects on membrane excitability that oppose those of 5-HT2A (Araneda and Andrade, 1991). The co-administration of pindolol, an agonist of 5-HT1A, potentiates the effects of DMT in humans (Strassman et al., 1996). DMT is also known to bind to 5-HT2C (Keiser et al., 2009; Ray, 2010; Eshleman et al., 2014), an excitatory GPCR that is expressed in deep, cortical GABAergic interneurons (Nocjar et al., 2015). 5-HT2C agonists have also been shown to block DMT-dependent behavioral cues in rats (Carbonaro et al., 2015). Nevertheless, ayahuasca has been shown to reduce the levels of Glu in certain brain areas 24 hours after intake, including the posterior cingulate cortex (PCC) (Beliveau et al., 2017; Sampedro et al., 2017). The PCC is a major node of the DMN (Fox et al., 2005); reduced activation of the PCC is considered to underlie some aspects of the psychedelic experience, including ego dissolution, which are believed to lead to positive therapeutic outcomes (Carhart-Harris and Friston, 2019).
These previous findings indicate that DMT modulates cortical excitability in a complex manner, simultaneously acting on several 5-HT receptors that promote or reduce the release of Glu. Glutamatergic modulation is becoming paradigmatic in new models that attempt to explain depressive disorders due to the efficacy of fast-acting antidepressants such as ketamine, an NMDA antagonist (Duman et al., 2019). DMT and ketamine show some similarities in their subjective effects and neuroimaging recordings (Daumann et al., 2010). This, in combination with DMT-dependent neuroplasticity, makes DMT a promising candidate to become a fast-acting antidepressant.
Modulation of monoaminergic systems
DMT is an endogenous monoamine (Barker et al., 2013; Dean et al., 2019) and binds to several 5-HT receptors, DA receptor D1, adrenergic alpha receptors 1B, 2B, and 2C, and histamine receptor H1 (Ray, 2010; Rickli et al., 2016). In addition, DMT modulates monoaminergic systems through monoamine transporters, monoamine oxidase (MAO), and trace amine-associated receptor 1 (TAAR1), all of which have known effects on dopaminergic transmission.
Monoamine transporter binding and substrate release
DMT binds to 5-HT, DA and NA transporters (SERT, DAT, and NAT, respectively) with Ki values of approximately 6 μM with SERT and NAT, and 22 µM with DAT (Rickli et al., 2016). Some drugs, such as d-amphetamine and 3,4-methylenedioxymetamphetamine are carried inside the cell by monoamine transporters and subsequently force these transporters to work backwards, thus pumping out neurotransmitters into the synapse (Hasenhuetl et al., 2019). In vitro, DMT releases 5-HT via SERT, and NA via NAT, with average concentration for 50% of maximal effect (EC50) values of 114 nM and 4166 nM, respectively (Blough et al., 2014). However, it is unknown if this mechanism operates outside of experimental conditions (i.e., abnormally high cytoplasmic levels of 5-HT), whether we need to perform in vivo experiments to ascertain the relevance of this mechanism to the pharmacology of DMT. In addition, DMT binds to the vesicular monoamine transporter 2 with a Ki of 93 µM (Cozzi et al., 2009). Whether vesicular monoamine transporter 2 binding permits the storage of DMT inside synaptic vesicles and its subsequent synaptic release or rather underlies a 3,4-methylenedioxymetamphetamine-like effect that depletes neurotransmitter reserves, is still debated and needs further investigation (Nichols, 2018; Jiménez and Bouso, 2022). Thus, DMT increases the synaptic levels of monoamines via SERT, NAT, and vesicular monoamine transporter 2 competitive inhibition and/or reverse transport. From a clinical perspective, SERT and NAT inhibitors, such as fluoxetine and venlafaxine, are currently being used to treat depression. Hence, DMT shares molecular mechanisms with first-line, monoaminergic antidepressants.
MAO
MAO catalyzes the degradation of 5-HT, DA, and NA. MAO also metabolizes DMT in an extremely fast manner; research has shown that DMT has a half-life of only 6 minutes in the rat brain (Barker et al., 1980; Sitaram et al., 1987). In ayahuasca, DMT is combined with beta carbolines (harmala alkaloids) that act as MAO inhibitors (MAOIs) to render orally adminstered DMT active. Otherwise, DMT is efficiently degraded by MAO in the gut and liver, so it cannot reach the brain and is not psychoactive (McKenna, 2004; Riba et al., 2015). In addition, the subjective effects of DMT are extended from approximately 20 minutes when administered intravenously (Timmermann et al., 2019) to several hours when ingested in ayahuasca (Callaway et al., 1999). One alternative, MAO-independent metabolic pathway, yields 2-methyl-1, 2, 3, 4-tetrahydro-beta-carboline through DMT cyclization (Barker et al., 1984), a potent and selective MAOI with an IC50 of 3 µM (Meller et al., 1977). Moreover, DMT can act as an MAOI in the brains of rats at very high doses following intraperitoneal administration at a dose of 25 mg/kg (Waldmeier and Maître, 1977).
MAOIs increase the overall levels of monoamine in the brain by hindering their metabolization. Drugs such as iproniazid were commonly used to treat depression between the late 1950s and the 1970s; however, this practice has been terminated, among other reasons, due to dangerous drug-drug and drug-food interactions. Thus, MAO inhibition is a mechanism by which ayahuasca and high doses of DMT may exert antidepressant proprieties; however, risk factors must be taken into account.
TAAR1
TAAR1 binds to trace amines with high specificity. Trace amines are minor monoamines that are derived from the metabolism of 5-HT or DA/NA and found in scarce amounts within the brain. One example is tryptamine, a metabolic precursor of DMT. TAAR1 is a modulatory receptor that has been compared to a cellular rheostat of dopaminergic, glutamatergic, and serotoninergic transmission (Gainetdinov et al., 2018). In rodents, DMT binds to TAAR1 with the efficiency of a full agonist and with an EC50 of 1 µM (Bunzow et al., 2001). It has been proposed that DMT may have anxiolytic effects in humans via TAAR1 (Jacob and Presti, 2005). However, more recent research showed that DMT activates TAAR1 in a species-dependent manner and does not induce activity with human TAAR1 at a concentration of 10 μM (Simmler et al., 2016). However, further investigations should be performed before discarding the potential role of TAAR1 in the pharmacology of high-dose DMT in humans.
Dopaminergic transmission
Some of the peripheral effects of DMT, like increased blood pressure, mydriasis, and hyperthermia, and some aspects of central effects, like electroencephalography (EEG) activation, can be antagonized by DA receptor blockers such as chlorpromazine and methiotepin (Moore et al., 1975; Domino et al., 1977). DMT binds to DA receptors 1 (D1 excitatory GPCR), 2 (D2; inhibitory GPCR) and 3 (inhibitory GPCR) with μM affinities (Rickli et al., 2016); there is also one study that reported binding to D1 at the nM level (Ray, 2010). However, despite these findings, there is evidence to suggest that DMT does not exert direct dopaminergic activity in the rat brain (Pieri et al., 1974; von Hungen et al., 1975). Nevertheless, owing to its MAOI properties, high doses of DMT (50 mg/kg by intraperitoneal injection) has been shown to cause the accumulation of DA and 3-methoxytyramine in the rat striatum, but without notable effects on the levels of NA and normetanephrine. DMT is also known to reduce the levels of 3,4-dihydroxyphenylacetic acid and homovanillic acid. Because the levels of 3,4-dihydroxyphenylacetic acid are affected more extensively than those of homovanillic acid levels and because homovanillic acid metabolism occurs extracellularly while that of 3,4-dihydroxyphenylacetic acid occurs intracellularly, these results suggest a combined MAOI + DA release effect (Waldmeier and Maître, 1977). In addition, DMT (20 mg/kg by intraperitoneal injection) has been shown to reduce the levels of DA in the rat forebrain; these effects were thought to be caused by the release of DA from presynaptic stores rather than the inhibition of DA synthesis (Haubrich and Wang, 1977). Alternatively, the activation of TAAR1 reduces the firing rate of mesolimbic dopaminergic neurons projecting to the cortex (Revel et al., 2011); this may explain the DMT-dependent reduction of DA in the forebrain of rodents. Furthermore, 5-HT2A can form heterodimers with D2 in HEK293 cells and both receptors co-localize in the medial prefrontal cortex (mPFC) and the pars reticulata of the substantia nigra (Lukasiewicz et al., 2010); however, the functional consequences of these receptor complexes have yet to be elucidated.
Collectively, these findings show that DMT modulates dopaminergic activity in an indirect manner. Although DMT promotes the release of DA at high doses, it does not exhibit dependence potential when used in a well-established social context such as clinical administration (D’Souza et al., 2022) or ritual ceremonies (Gable, 2007; Bouso et al., 2012). In contrast, several observational studies of ritual ayahuasca users report remissions of substance-use disorders (Halpern et al., 2008; Fernández et al., 2014; Loizaga-Velder and Verres, 2014; Winkelman, 2014). Considering the central role of DA in addiction, DMT-dependent dopaminergic modulation could facilitate the development of new antiaddictive treatments.
Cholinergic and endocannabinoid systems
Very little research has addressed the effects of DMT on the cholinergic and endocannabinoid systems. DMT is known to reduce the levels of acetylcholine in the striatum of rats but not in the cortex. These effects are probably due to the stimulation of acetylcholine release rather than the inhibition of synthesis (Haubrich and Wang, 1977). In addition, indolethylamine N-methyltransferase, the key enzyme responsible for the synthesis of DMT, has been detected in close proximity to σ1 in the cholinergic postsynaptic terminals of spinal motoneurons in the rat (Mavlyutov et al., 2012). Because DMT binds σ1 with low µM affinity and DMT injections can stimulate locomotion in wildtype but not σ1 knockout mice (Fontanilla et al., 2009), it has been proposed that DMT regulates motoneural excitability through σ1 (Mavlyutov et al., 2012). However, this speculation was challenged by recent research showing that rat indolethylamine N-methyltransferase is unable to synthesize DMT (Glynos et al., 2023). On the other hand, a pilot study reported that ayahuasca enhances the plasma levels of anandamide, a major endocannabinoid, in participants with social anxiety disorder, but not in healthy volunteers. However, high interindividual variability in both groups and small samples preclude definitive conclusions (Dos Santos et al., 2022).
| Mechanisms that promote neuroplasticity | | |
DMT activates the early growth response proteins 1 and 2 via 5-HT2A activation in the mouse cortex; these are transcription factors that play key roles in neural plasticity that cannot be recruited by non-psychedelic 5-HT2A agonists (González-Maeso et al., 2007). DMT is known to activate phospholipase A2 through 5-HT2A with 105% efficacy when compared to 5-HT. In turn, phospholipase A2 recruits mitogen-activated protein kinases (extracellular signal-related kinase 1/2 and p38) (Eshleman et al., 2014). Furthermore, DMT and other psychedelics, but not 5-HT, are known to increase the number of branches and mature spines in the dendritic trees of cortex layer V pyramidal neurons in mice. This is accompanied by an increase in amplitude and frequency of spontaneous excitatory postsynaptic currents 24 hours after the administration of DMT, even at low doses (1 mg/kg). DMT-induced cortical dendritogenesis depends on the mammalian receptor of rapamycin and can be blocked by 100 nM ketanserin, thus suggesting the 5-HT2A is also involved, although the engagement of 5-HT2C, adrenergic or histamine receptors cannot be ruled out. Interestingly, of all drugs tested, the dose-response curve of DMT was the only one that possessed a Hill coefficient > 1 (approximately 7.6), thus indicating the engagement of unique and highly cooperative mechanisms (Ly et al., 2018). In addition, subsequent experiments in the same paper showed that blockade of the tropomyosin receptor kinase B (TrkB) abolished the dendritogenic effects of DMT and other psychedelic molecules in cortical cells. Furthermore, DMT treatment doubled the protein levels of brain-derived neurotrophic factor, the agonist of TrkB, although this effect was not statistically significant (Ly et al., 2018). An alternative mechanism for DMT/TrkB interaction that does not exclude the potential release of brain-derived neurotrophic factor could be the facilitatory and allosteric binding of DMT to TrkB; this effect has been demonstrated for ketamine (Casarotto et al., 2021).
DMT promotes the complete differentiation of mature neurons, astrocytes, and oligodendrocytes from the neurogenic niche in the subgranular zone of the hippocampus in adult mice. This process is accompanied by improvements in the performance of spatial learning and memory tasks. Unlike cortical synaptogenesis, hippocampal neuro- and glio-genesis depends on the activation of σ1 and is not restricted by 5-HT1A/2A antagonists (Morales-Garcia et al., 2020).
Thus, DMT-induced plasticity has been demonstrated in a highly robust manner at the molecular, cellular, functional, and behavioral levels. Neuroplasticity deficits have become axiomatic in our understanding of major depression disorder and its treatment. Emerging therapies, such as ketamine treatment or transcranial magnetic stimulation have been shown to exhibit notable plastogenic effects (Ly et al., 2018; Pan et al., 2023). Moreover, the enhancement of plasticity is known to account for the endurable and fast-acting effects of ketamine when compared to other antidepressants (Casarotto et al., 2021). In this regard, the effects of ketamine and DMT on plasticity are comparable (Ly et al., 2018); however, while psychedelics do not seem to have addictive potential, ketamine does (Nutt et al., 2010; Dos Santos et al., 2018). Finally, DMT and other psychedelic tryptamines are known to have anti-inflammatory, immunomodulatory, and tissue-protective capabilities (Szabo, 2015); when combined to their plastogenic properties, these effects render these as promising drugs for the treatment of neurodegenerative disorders (Kozlowska et al., 2022).
| MODULATORY EFFECTS ON LARGE-SCALE FUNCTION AND STRUCTURE | | |
EEG studies: acute modulation of cortical waves
EEG recordings provide a high temporal resolution that is needed to keep track of the rapid-onset and short-lasting psychoactive effects of DMT in humans (Timmermann et al., 2019). One consistent EEG finding when administering DMT or ayahuasca is the suppression of alpha waves; these events correlate with the intensity of subjective effects and plasma levels of DMT when tested at doses of 7, 14, 18, and 20 mg of DMT administered intravenously (Timmermann et al., 2019; Alamia et al., 2020); 0.75 and 0.85 mg/kg DMT in ayahuasca (Riba et al., 2004; Valle et al., 2016). Alpha waves are commonly registered in the occipital lobe of adult humans with their eyes closed and are associated with higher order cognitive processes such as visual perception (Lorincz et al., 2009), attention, or semantic orientation in space, time and context (Klimesch, 2012). Ketanserin, a 5-HT2A antagonist, is known to prevent alpha depletion in humans (Valle et al., 2016). DMT also depletes beta waves, while waves in the theta and delta bands are potentiated during the peak effect of DMT (Timmermann et al., 2019; Alamia et al., 2020). The combination of alpha/beta collapse and delta/theta emergence has been compared to the situation of dreaming during rapid eye movement sleep (Timmermann et al., 2019). In addition, brain oscillations form travelling waves that propagate through contiguous regions. In visual perception, cortical travelling waves propagating forwards (from the occipital to the frontal lobes) are linked to bottom-up sensory processing while those propagating backwards (from the frontal to the occipital areas) are associated with top-down processing carrying information relating to context and expectancies. Normally, top-down processing predominates during quiet restfulness. DMT, which can elicit vivid visual hallucinations, produces a remarkable shift in travelling waves during eyes-closed rest, reducing backwards in favor of forwards flows in a similar way to that registered during eyes-open perceptual stimulation. The magnitude of these shifts is known to be correlated with plasma levels of DMT and subjective intensity (Alamia et al., 2020).
A similar shift in the hierarchies of information processing following the administration of ayahuasca (0.75 mg/kg DMT) has been registered by magnetoencephalography. Frontal-to-occipital information transfer, reflecting top-down processing, is hindered, while occipital-to-frontal information transfer, which carries bottom-up sensory information, is potentiated (Alonso et al., 2015). These reports are congruent with the localization of 5-HT2A, which is densely clustered in a portion of dendritic trees in layer V pyramidal neurons receiving abundant thalamic bottom-up inputs (Weber and Andrade, 2010).
Other neuroimaging studies: acute and post-acute functional modulation of brain areas and the long-term modification of cortical structure
Functional magnetic resonance imaging (fMRI) provides high spatial resolution. A previous fMRI study reported significantly less activation of visual and, to a lesser extent, auditory brain regions during a target-detection task with visual and auditory cues following the administration of DMT (an intravenous bolus of 0.15 mg/kg over 5 minutes followed by a break of 1 minute, followed by continuous infusion with 0.01 – 0.01875 mg/kg/min over 20 minutes). The visual areas affected were the left inferior and right middle occipital gyri, the right inferior temporal gyrus, the left cuneus, and the right culmen. In addition, auditory effects were noted in the right middle temporal gyrus (Dos Santos et al., 2022).
Other neuroimaging approaches have assessed the effects of ayahuasca during resting state; these approaches will be discussed in the following paragraphs. However, it must be noted that the beta carbolines that are present in ayahuasca are also psychoactive (Airaksinen and Kari, 1981; Rossi et al., 2022) and apparently plastogenic (Dos Santos and Hallak, 2017). Single positron emission computed tomography after ayahuasca intake (1 mg/kg DMT) detected a significant increase in blood flow in the anterior insula (with greater intensity in the right hemisphere), and to a lesser extent, in the right anterior cingulate cortex (ACC) and the right mPFC. These are regions related to somatic and emotional perception (Riba et al., 2006). Furthermore, an fMRI study recorded increased metabolism in several occipital, temporal, and frontal areas, as well as in the parahippocampal cortex. Photographs of people, animals, and trees were shown to the participants, who were then asked to mentally visualize them with their eyes closed. The intensity of activation in the primary visual area during the task was comparable to that recorded during eyes-open viewing. In addition, non-primary visual areas (the cuneus and lingual gyrus) that are activated during psychopathological hallucinations or rapid eye movement dreaming were activated. Functional connectivity analysis (FC; the coordinated activation between or within brain networks) supported the idea that normal, frontal-to-occipital information transfer in the brain shifted to an occipital-to-frontal pattern (1.76 mg/kg DMT) (de Araujo et al., 2012).
Research has shown that psychedelics can modulate the DMN. The DMN is a group of interconnected brain regions that are more active at rest than during task performance. The DMN has been associated with top-down cognitive processing (Gattuso et al., 2023). The expression levels of 5-HT2A are particularly high in the main hubs of the DMN: the mPFC, the PCC, the angular gyrus and, to a lesser extent, the precuneus (Beliveau et al., 2017). fMRI studies have shown that ayahuasca causes an acute reduction of activity in the PCC and the mPFC. FC within the PCC is also reduced, while FC within the ACC, between the ACC and PCC, and between the ACC and limbic structures in the right medial temporal lobe is increased [1.76 mg/kg DMT (Palhano-Fontes et al., 2015) and 0.36 mg/kg DMT (Pasquini et al., 2020)].
Similar fMRI results can be registered 24 hours after the intake of ayahuasca, with increased coupling from the PCC to the ACC, and to the visual cortex, increased coupling from the ACC to the right limbic structures, including the hippocampus, parahippocampal gyrus and amygdala, and decreased coupling from the ACC to the visual cortex [0.64 mg/kg DMT (Sampedro et al., 2017)]. Some researchers argue that DMN silencing is a central process that can explain the subjective and therapeutic effects of psychedelics (Carhart-Harris and Friston, 2019; Gattuso et al., 2023). Indeed, increased FC within the DMN has been correlated to rumination, a core trait of depressive disorders (Rosenbaum et al., 2017), although more recent research, using a different analysis method, was unable to replicate this result (van Oort et al., 2022). Furthermore, an open-label single positron emission computed tomography study of patients with recurrent depression reported that participants scored better on several depressive symptom scales after a single dose of ayahuasca. Improvements were detectable during the acute effects of ayahuasca and up to 21 days after intake. Concomitant blood flow increases were detected in the nucleus accumbens, the subgenual area, and the insula (Sanches et al., 2016).
With regards to long-lasting effects on cortical structure, a previous magnetic resonance imaging crossed-sectional study revealed differences in the cortical thickness of long-term ritual ayahuasca users (50 administrations over the previous 2 years) in comparison with controls. The former group possessed a thinner cortex in three main DMN structures, the PCC, the mPFC, and the precuneus, as well as in the superior frontal and occipital gyri. Furthermore, these patients possessed a thicker ACC and precentral gyrus. Cortical thickness in the PCC is inversely correlated with the duration and intensity of previous experiences of ayahuasca. Cortical thickness is also correlated with scores relating to self-transcendence, a personality trait that accounts for the tendency towards spirituality and religiousness, thus suggesting that the long-term use of ayahuasca can affect personality. Given the plastogenic effects of DMT, it is possible that the sustained use of ayahuasca results in macroscopic changes in the anatomy of the brain. However, because this study was not longitudinal, no causal relationship could be established between the use of ayahuasca and cortical thickness and/or changes in personality; it is possible that individuals were more likely to become long-term ayahuasca users because they had such a brain structure and/or personality traits (Bouso et al., 2015).
| Conclusion | | |
DMT is a complex neuromodulator with significant therapeutic potential. Although its main targets are 5-HT receptors, DMT modulates glutamate release and cortical excitability, and can affect monoaminergic neurotransmission via monoamine transporters, metabolic enzymes, and TAAR1. Furthermore, DMT interacts with the cholinergic system and may modulate the levels of endocannabinoids. In addition, DMT is a powerful neuroplastogen by virtue of the combined activation of 5-HT2A and σ1 DMT modulates brain waves and the activity of several cortical areas. More generally, DMT shifts the hierarchies of information processing in the brain: top-down processing loses strength against bottom-up processing. Collectively, these findings indicate that DMT is a promising drug for treating several psychiatric disorders and could facilitate the treatment of neurodegenerative diseases. Finally, DMT is a simple compound that is ubiquitous in nature and cheap to produce. Future research should aim to translate DMT to the forefront of psychedelic research.
Acknowledgments
Thanks to my colleague and friend Sergio Pujante-Gil for the long and enriching hours of chatting about 5-HT and arrhythmia.
Author contributions
All the search, selection and reading of bibliography, as well as the manuscript writing done by JHJ.
Conflicts of interest
The author declares no conflicts of interest.
Open access statement
This is an open access journal, and articles are distributed under the terms of the Creative Commons AttributionNonCommercial-ShareAlike 4.0 License, which allows others to remix, tweak, and build upon the work non-commercially, as long as appropriate credit is given and the new creations are licensed under the identical terms.[95]
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