A new project to dose recently brain damaged individuals with DMT has made the news. The worrying part is that they may dose individuals “as soon as they hit the ambulance”. I don’t necessarily doubt that there will be observed cognitive improvement in the individuals dosed with DMT, the problem is actually that certain mechanisms of learning and memory that DMT enhances may also be the very mechanisms that lead to brain damage in brain injury events. That is, the glutamate NMDA receptors, which play a crucial role in learning, memory, and plasticity (Paoletti, Bellone, & Zhou 2013). We may very well observe an improvement, but at the cost of attenuated neuroprotective mechanisms. This may lead to a wider spread of excitotoxic damage if used during the acute phase of brain injury. We should be wary of this potential illusion.
To start, let’s note that DMT does appear to reduce brain injury and enhance recovery in brain injured rats (Nardai et al 2020). Although, this is under the condition of anesthesia, which blocks the mechanism of excitotoxicity that this essay explores. One of the anesthetics used was isoflurane, which directly antagonizes the mechanisms of excitotoxicity proposed here by blocking NMDA receptors and enhancing GABA activity. In fact, isoflurane was found to be protective during brain injury itself, with seeming lasting benefits (Sakai et al 2007). Isoflurane was used during the MRI part of the DMT study. During the brain injury, the rats were anesthetized with ketamine, which also has been observed to be neuroprotective in brain injury (Hudetz & Pagel 2010). Luckily, the authors of the DMT study dosed all of the rats with the anesthetics, so the improvement observed could be associated to the combination of anesthesia and DMT at the very least. Another issue is that they dosed the rats with DMT 60 minutes into the brain injury, at which point most of these excitotoxic mechanisms may have normalized, as you will soon see below. Let’s get into it.
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Mechanisms in Brain Injury
When the brain is injured, the sudden excess glutamate may produce secondary injury via excitotoxic mechanisms (Yi & Hazel 2006). During brain injury, glutamate was found to be elevated by 80+ fold in animals, which normalized after the acute (30 mins – 1 hour) phase (Palmer et al 1993). In humans, dramatically increased glutamate was found to predict worse outcomes from traumatic brain injuries (Bai et al 2017). One of the excitotoxic mechanisms of glutamate is via binding to the NMDA receptors, which are heavily involved in learning, memory, and neuroplasticity (Paoletti, Bellone, & Zhou 2013). This will be key later.
The NMDA receptor excitotoxic mechanism is also shared by seizure-induced brain injury (Fujikawa 2005). Most interestingly, dynorphins seem to function as endogenous anticonvulsants (Loacker et al 2007; Simonato 1996) and are even neuroprotectant against seizure-induced brain injury (Dai et al 2019). The mechanism of dynorphins may be neuroprotective via kappa opioid receptor (KOR) agonism (Simonato 1996), and possibly via NMDA receptor antagonism (Chen, Gu, & Huang 1995). Dynorphin activity has been found to decrease glutamate release and reduce hippocampal plasticity (Wagner, Terman, & Chavkin, 1993), and also to reduce learning and memory in animals (Carey et al 2009; Kuzmin et al 2013; McDaniel et al 1990). Post-seizure psychosis is thought to involve the dynorphin, as a ‘cost’ (Bortolato & Solbrig 2007), which makes sense since KOR agonists are very often hallucinogens (ie pentazocine, ketazocine, salvia divinorin).
During brain injury events, dynorphin levels increase in the injury areas (McIntosh et al 1987; Hussain et al 2012), which I suspect release as a neuroprotective mechanism that works by reducing glutamate release and by also blocking NMDA receptors directly. This is at the cost of cognitive ability, particularly learning, memory, and possibly sanity. It is worth noting that McIntosh et al hypothesized that the accumulation of dynorphins in damaged brain areas may have been a source of secondary injury, which is reasonable, since dynorphins contain not only neuroprotective mechanisms, but also neurotoxic mechanisms as well (Hauser et al 2005; Hauser, Foldes, & Turbek 1999). The neurotoxic mechanism occurs via enhanced NMDA receptor activity, meanwhile the neuroprotective mechanism is through KOR agonism. I would hypothesize that NMDA receptor antagonism may also be protective at times as well. Whether or not dynorphins are protective or toxic seems to depend on various factors: levels of dynorphin, whether it is during an excitotoxic event, etc.
DMT is a serotonin and sigma-1 agonist. The psychedelic effects of DMT are thought to partly be related to increased glutamate release that occurs via 5HT2a receptor agonism and possibly sigma-1 agonism (Barker 2018). DMT improves learning and memory in mice (Morales-Garcia et al 2020). DMT also may induce plasticity, as serotonin psychedelics appear to (Ly et al 2018). This is where the trouble begins though. In the past, I’ve argued that serotonin psychedelics may improve cognition, plasticity, and mood via anti-dynorphinergic mechanisms (In: Chemical Exorcism; Dynorphin Theory).
This poses us with a strange conundrum.
DMT may boost learning, memory, by disrupting dynorphinergic processes and enhancing glutamate activity, essentially functioning by disinhibiting cognitive ability and plasticity. This may be at the cost of removing neuroprotective anti-glutamatergic mechanisms.
5HT1a receptor agonism by DMT may inhibit dynorphin increases, similar to the way other 5HT1a receptor agonists have shown to (Tomiyama et al 2005). LSD, which binds to 5HT1a and 5HT2a receptors (and others), seems to suppress the behavioral effects of KOR agonists (Sakloth et al 2019). Also noteworthy is that the conditions that psychedelics are purported to treat are ones that dynorphin/KOR agonism may be capable of inducing. KOR agonism is dysphoric (Land et al 2008) and is studied in research on stress, depression, anxiety, addiction, and PTSD (Jacobson, Browne, & Lucki 2020; Knoll & Carlezon Jr 2010; Crowley et al 2016; Chavkin & Koob 2016; Rabellino et al 2018). Meanwhile, psychedelics have been studied for treatments of all of these problems (Kredeit et al 2020). In support of the possibility of anti-dynorphin effects of psychedelics, psilocybin and LSD have both been shown to induce seizures at higher doses (Adey, Bell, & Dennis 1962; Haden & Woods 2020), possibly an effect of lowering the seizure threshold by decreasing endogenous anticonvulsant mechanisms.
5HT2a receptors are thought to be a primary mechanism for the effects of psychedelic drugs. This mechanism appears to work via induced glutamate release (Barker 2018), which might potentiate the rise in glutamate induced in acute brain injury. This may also be part of the mechanism for the seizures induced by psychedelics. Another glutamate enhancing agent known as IDRA-21 was studied for cognitive enhancement. This substance was found to potentiate ischemic brain injury when glutamate is present by enhancing AMPA receptor binding (Yamada et al 1998). The authors even specifically note the importance of this for patients with seizures or stroke. The psychedelic drug LSD was found to partially work by potentiating AMPA receptor activity as well (De Gregorio et al 2021). It isn’t clear whether this potentiation is due to serotonin mechanisms, but I would expect this. Luckily, the paper also notes that NMDA receptors are not potentiated.
Other psychedelics appear to have a partial agonist like effect on NMDA receptors. One study revealed that serotonin boosts NMDA receptor activity via 5HT2a receptor mediated effects, in motoneurons (Dantsuji et al 2019). Another study found that partial agonists of 5HT2a receptors enhance NMDA receptor activity at low doses and inhibit the activity at higher doses, in the prefrontal cortex (Arvonav et al 1999).
The boost in learning and memory granted by DMT seems to involve neurogenesis and sigma-1 agonism (Morales-Garcia et al 2020). This is important because sigma-1 agonism potentiates NMDA receptor activity (Su, Hayashi, & Vaupel 2009). As far as we can tell, sigma-1 agonists may actually be neuroprotective (Franchini et al 2020). Furthermore, the sigma-1 agonists studied also appeared to be negative allosteric modulators of the NMDA receptors, meaning they suppress the action of the receptor. CBD appears to be a sigma-1 receptor antagonist and was observed to reduce stroke and seizure-induced brain injury, which the researchers argued was due to reduced NMDA receptor activity via suppression of sigma-1 receptors (Rodríguez-Muñoz et al 2018). This protective effect was reversible by sigma-1 agonists. A sigma-1 antagonist was also found to be protective in ischemia (Schetz et al 2007).
As mentioned, DMT is a 5HT1a receptor agonist. The agonism of this receptor was found to suppress increases of dynorphin due to dopamine D1 receptor stimulation (Tomiyama et al 2005). Antagonists of 5HT1a receptors actually potentiate the subjective effects of DMT in humans (Barker 2018). 5HT1a receptor antagonists also facilitate NMDA receptor inhibition via serotonin, mimicking the 5HT2a receptor partial agonists studied (Arvonav et al 1999). Also, the increase of dynorphin via D1 receptor stimulation seems to rely on the presence of the D2 receptor and fails in D2 receptor knockout animals (Solís et al 2021). D1-D2 heteromers colocalize on dynorphin neurons in a high affinity state in amphetamine abusers and schizophrenics (Perreault et al 2010), suggesting the cluster of these mechanisms may drive psychotic-like effects perhaps via potentiated KOR activity and NMDA receptor inhibition. Interestingly, 5HT2a receptors potentiate D2 receptor activity (Borroto-Escuela et al 2014), which might actually increase dynorphin release. This may suggest that 5HT2a receptor agonism is suppressing NMDA receptor activity by enhancing dynorphin release, although this is unclear still and would need to be explored in further research. It does seem that 5HT2a receptor agonism has differential effects on NMDA receptors depending on 5HT1a receptor activity, which might also alter the protective effects of DMT during brain injury.
In remembrance, NMDA receptor antagonists (ie ketamine, PCP, memantine) have long been thought to protect against excitotoxicity during brain injury, but they failed in clinical trials (Ikonomidou & Turski 2002). The authors of that paper argue that the excitotoxicity mediates damage in the acute phase of brain injury, but then after glutamate is stabilized, NMDA receptor blockade may prevent survival of neurons. Another reason might be that there is possible enhancement of excitotoxic mechanisms via increased glutamate release and the reduction of GABA release that occurs (Stone et al 2012). NMDA receptor antagonists have also been thought to protect against seizures, usually, except sometimes they produce paradoxical seizure induction (Bausch, He, & Dong 2010). We might see similar patterns from the serotonin psychedelics, if their protective effects share mechanisms with NMDA receptor antagonists, although psychedelics still have very many different mechanisms and effects, so we cannot really conclude anything yet. It wouldn’t be surprising if we find that DMT is not simple enough to be purely neuroprotective.
Another serotonin psychedelic, MDMA, was found to enhance neuroplasticity at neurototoxic doses (Morini et al 2011). This shows us that it isn’t as simple as good or bad effects of these drugs, but rather, seemingly good effects can occur simultaneously with bad effects. While DMT appears to be non-excitotoxic, the condition of stroke or brain injury may drastically alter the context.
It is important that we consider that the brain may have evolved mechanisms to reduce brain injury in the face of physical trauma. One such mechanism may be inhibitory dynorphin-mediated activity. Despite that dynorphins could be neurotoxic on their own, the brain likely didn’t evolve a response to induce further brain damage under these circumstances. If we decide to disrupt the brain’s normal reaction to trauma, we must pay special attention to the nuances in this area. For example, we must test whether using DMT is useful in the acute or post-acute phase. We must also consider that patients may appear to superficially recover their brain function much faster, at the cost of increased excitotoxic processes. So patients may appear to recover their brain function rapidly, but experience neurodegenerative effects that become apparent in the long run. Unfortunately, if we are not careful about this, we might become convinced that DMT is useful when it could in fact be harmful.
That said, I do think we should still study this, as DMT could very well be neuroprotective in the case of brain injury. During cardiac arrest in rats, DMT seems to elevate significantly (Dean et al 2019). DMT has also been shown to be protective against hypoxia via hypoxia inducible factor 1 (HIF-1) (Szabo et al 2016), which might suggest that it plays an endogenous protective role in the case of hypoxia. Nichols has argued against Dean et al’s points, suggesting that dynorphin may actually underlie the effects of near-death experiences (Nichols & Nichols 2019). Despite that DMT may not be synthesized a great amount under normal conditions, hypoxia may disrupt monoamine oxidase from metabolizing DMT (Stuart et al 2016), leading to an accumulation of DMT that happens to be useful under hypoxic circumstances.
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