A Brief Technical Image

The process of teasing out functions of the NMDA Receptor feels a lot like progressing through this “flowchart” (I ask that you ignore the logic of the image, just scan the vibe2). Using drugs with this protein complex seems to inherently lead to bizarre phenomena on both the level of the neuron (see; Hebbia, Homeostatica, and Magnesia) and the brain as a whole (see; Elon’s twitter feed). This is evident once you internalize that without NMDA Receptors, you fundamentally could not make self-referential memories, much less exist as a viable organism.

Quandaries

When you start taking two NMDA Receptor antagonists at once, medical wisdom dictates that you’re liable to check into a psych ward within the week. This is wrong… but I can’t really call the thought process itself irrational. After all, most doctors encounter these drugs in the context of, “there’s an ER patient going fucking insane off PCP (an NMDAR antagonist).”

They often forget how they treat the incoming patient, “we’ve got to sedate him! Lets use Ketamine (another NMDAR antagonist).” And this works.

Now, both PCP and Ketamine are dissociative anesthetics, so the first thought is that this is probably just a dose mediated effect. Surely overdosing them on PCP would also work as a chemical restraint… Phencyclidine was used as an anesthetic in the 1950s, but those same side-effects that led to its recreational use still occurred when people woke up from anesthetic doses. People on Ketamine wake up and get confused, but they don’t get violent.

The question here is Why? Why does the category of ‘NMDA Receptor antagonist’ mean nothing!

Microlevel Differences

Subunit Selectivity

The most important factor in determining the effects of a given NMDAR antagonist is the drug’s subunit selectivity. The NMDA Receptor is “heteromeric tetramer.” It is composed of four complexes, two of which are NR1 subunits, these are the obligatory units of the receptor and are responsible for its most basic properties.

The other two subunits are free to be composed of NR2A/B/C/D or NR3/A/B. The NR3 subunits can be discarded for our purposes because their mere presence causes the NMDAR to function as a completely different receptor (saving that for another post). Really briefly, this is what you need to know about the NMDA Receptor (I do this every post):

• It has a pore that lets Calcium ions flow through

• This pore is nearly always plugged up with Magnesium

• To open the pore, the Magnesium needs to leave, Glycine needs to bind to NR1, and Glutamate needs to bind to NR2

The role of the NR2 subunits is to bind Glutamate and to modify the properties of the receptor as a whole. Even among NR2 subunits there is heterogeneity; NR2A/B subunits have a codependent relationship with Magnesium, NR2C/D subunits… they can do without. This means that NR2C/D subunits let a lot more current into the cells (see; prior blog).

Trapping and Flickering

The second most important factor is how these drugs are unbinding from the NMDA Receptor. For instance, Ketamine is anesthetic because at high doses it never comes unbound, whereas Memantine dissociates from the receptor every single time the central pore opens. For this reason Ketamine is referred to as a ‘trapping’ antagonist whereas Memantine flickers in and out of the central pore.

The capacity for an NMDAR antagonist to trap the receptor is determined by how it interacts with the central pore; specifically, whether or not Magnesium occludes it from binding. Memantine is occluded in such a way but when you add a +2 charge to it (chemistry is strange) it will displace Magnesium and become a trapping antagonist… Weird!

NR2D subunits are uniquely easy to trap because antagonist binding is predicated on the receptor’s affinity Magnesium, of which, the NR2D subunit has very little. This phenomenon leads to a network state called disinhibition (not behavioral disinhibition, that’s a whole other thing). Nearly all NMDAR Antagonists produce disinhibition because they trap NR2D first (even without preferential binding) and trap the other subunits after reaching a certain dose threshold.

Excitatory or Inhibitory Targets

The final factor that I’ll speak of, is what type of neurons the drug binds to.3 This is important because where the drug binds changes the behavior of the whole network. NMDA Receptors are found on all types of neurons4, but the composition of te NMDA Receptor differs based on the type of neuron it’s expressed on.

This ties in very nicely with Subunit Selectivity and the Trapping/Flickering dichotomy. As previously mentioned, due to the NR2D-subunit NMDARs having really weak Magnesium block, this means that Memantine can become a trapping antagonist as opposed to a flickering antagonist on this type of NMDA Receptor. It just so happens that NMDA Receptors containing the NR2D subunit are expressed almost exclusively upon inhibitory interneurons.

Ketamine is a slightly different case…

Conclusion

You may have noticed in the flowcharts that the three factors; Subunit Selectivity, Trapping and Flickering, and Excitatory vs Inhibitory Targeting… all seem to overlap/correlate with one another. That is, a drug targeting NR2D subunits would also tend to target location on inhibitory neurons and high trapping (ceteris paribus of course). This is mainly because (for all NMDAR pore antagonists) ‘Subunit Selectivity’ is almost entirely predicated upon the presence of a Magnesium ion in the central pore (see; Kotermanski & Jonson and prior blog et. al).

There are some NMDA Receptors immune to the sort of heuristic I have here, these are mainly NR2C-containing receptors on the surface of glial cells, they aren’t as engaged in conventional signalling like evoked or spontaneous EPSCs (see; prior-prior blog et.al), but their role in homeostasis is important; just too complicated for an already convoluted post. As for how NMDAR Antagonists interact with them, they are targeted by Memantine and they do get trapped by it, they just don’t factor into the dissociative/disinhibited signalling as much due to their location.

Final Thoughts

Going back to the quandaries, I got into the literature on this because couldn’t figure out/predict what sort of state a given NMDAR Antagonist would produce. Memantine was quite different, it had an off-target effect on the α7-Nicotinic Acetylcholine Receptor (nAchR) but this was seemingly irrelevant for differentiating it from Ketamine. I call it irrelevant because Ketamine *anesthetizes you* and no amount of modulating the α7-nAchR will prevent that.

Next blog, I’ll probably take a break from NMDA Receptor-Mediated Neurotransmission. Despite how cool it is, attempting to understand it requires too much brain power for a Dance Major (and also would require some novel research). Unfortunately, I am drawn to the convoluted so… I’ll probably get sucked into the α7-nAchR or D2 receptor literature.

Basic (Hebbian) Plasticity

Can you remember a room from your childhood? If so; congratulations, you don’t have a neurodegenerative disease. Now, can you imagine yourself moving around in the room? This one’s a bit harder but hopefully I’ve only lost a few of you.

There’s a reason you remember these places, and it’s not just because they might have emotional significance; rather, the very fact of having been there multiple times makes them memorable. Every time you enter a room, you’re rehearsing a bit of information and so it becomes all the more simple to remember. The reason rehearsal (or repetition) is so important for learning is because it triggers…

LTP

Most explanations of Learning and Memory in the brain go as such:

“There are a bunch of cells in the brain that form connections with one another. The communication between these cells is what encodes sensory, spatial, and semantic information into memory.”

If you get really lucky, the person explaining this to you might even be familiar with terms like Long-Term Potentiation (LTP) or Long-Term Depression (LTD). Journalists in the pop-sci sphere like to throw around these terms in service of a number of different things.

The use of LTP in the journalistic context ranges from the credible, like hypothesizing about why antidepressants work; to the erroneous, like conflating the long-term effects of addiction (months to years) with the long-term of synapses (minutes to hours). It’s evident that people are using this term without really understanding what it means, which is a shame because of how important it is!

LTP is the name we give to what’s basically the biological equivalent of a Rube Goldberg machine inside the cell. This “machine” eventually leads to an increase in the sensitivity of the postsynaptic (receiving) neuron to activity and the likelihood that the presynaptic (sending) neuron will send it.

In LTP, a synapse is strengthened after receiving a burst of activity. This activity is represented by the influx of Calcium ions (Ca2+) into the postsynaptic neuron. Receiving this signal requires activation of the NMDA Receptor by Glutamate and depolarization of the postsynaptic membrane (detailed in a prior post).

This is one of the main reasons LTP requires bursts. To the synapse, a single ‘spike’ could just be electric noise, but rhythmic spikes indicate intentional (evoked) communication.

No prior depolarization? No activation of the NMDA Receptor. No LTP.

Why should you care?

LTP binds neurons together, allowing them to form what are called Engrams; sets of neurons that represent attributes of memories.

Lets stick with the example of the childhood room.

There’s a set of neurons in the Hippocampus whose job it is to encode the spatial coordinates of your body whenever you’re walking around a room. When they are activated sequentially, they represent a path. When LTP strengthens the connections between the cells representing this path, it becomes an engram.1 Without LTP, the neurons can’t remember if — much less when — they’re supposed to fire. This means that recall of this path becomes impossible.

Advanced (Homeostatic) Plasticity

Given what we’ve learned, what might life look like if LTP could continue to strengthen the synapse unabated? Examples include but are not limited to:

• Schizophrenia

• Rett’s Syndrome

• Low-Functioning Autism

It should be obvious by now that synaptic strength is not a simple thing. The ability for activity to trigger LTP is determined by the synapse’s history, not just present stimuli. You might notice in the graph below that the actual amount of activity doesn’t correspond to the amount of LTP induction. This holds true, not just with the amount of activity, but also the frequency of activity.

So what gives? Why is LTP induction so conditional?

The Antenna

Think of a synapse like the rabbit ear antenna on an old TV. This antenna can be moved into a few conformations that display an image on the TV, and a few hundred conformations that don’t.

Adjusting this antenna too much makes it way too hard to find that sweet-spot again, and sometimes if you move it too much, it just breaks. Metaplasticity is what prevents this from happening.

Metaplasticity was coined by Wickliffe Abraham and Mark Bear in their 1996 paper ‘Metaplasticity: the plasticity of synaptic plasticity’. It refers to changes “in the ability to induce subsequent synaptic plasticity” (Abraham and Bear 1996). In the paper, they detail a number of experiments that show how prior activity – regardless of whether or not it triggers LTP – can either increase or decrease the likelihood of LTP induction by later stimuli.

This is a pretty heavy table to look at, but I’d like to draw your attention to the left column titled ‘Effect of prior activity on synaptic strength’. Fix your eyes now on the rows to the right of “LTP”, you’ll notice that the examples of prior activity actually decrease LTP or increase LTD in all cases!

For some reason, the synapse seems to be really good at preventing external activity from breaking or bending the antenna. But how can we model this behavior?

Spontaneous NMDA Receptor Currents

We mentioned depolarization earlier as one of the means of opening the NMDA Receptor, but we didn’t actually go into why exactly depolarization functions this way.

At rest, the NMDA Receptor is blockaded by a single Magnesium ion (Mg2+) which is jettisoned during depolarization; as is the case with the ‘Open’ condition in the image below. It is only after the jettisoning of Mg2+ that Ca2+ can enter the cell and begin the LTP Rube Goldberg machine (hopefully we can expand on what this entails in a future post).

It’s not always the case that there’s sufficient Mg2+ to block all the NMDA Receptors of a synapse; as a result, quantal or spontaneous releases of Glutamate become sufficient to open the NMDA Receptor in the absence of activity. This is quite problematic! It means that Ca2+ is entering the cell and attempting to start the Rube Goldberg machine when there’s no real information to process.

Going back to our antenna allegory, this would be equivalent to the display of TV static. Obviously we want the synapse to be responding to signals and ignoring this noise, but the solution isn’t obvious. NMDA Receptor currents, regardless of spontaneity lead to Ca2+ influx. What differentiates spontaneous and evoked currents is the amount of Ca2+ that gets through.

Diverging Calcium Pathways

Ca2+ from the NMDA Receptor is sensed by a number of proteins within the cell, the main four of which are referred to as “Calcium Calmodulin” proteins; designated as CaMKs. CaMKII is the main protein active during burst firing, as a result it’s the main calcium sensor active during LTP.

Spontaneous NMDA Receptor Currents, however, are sensed by a different Calmodulin protein, going by what I can only assume is a pseudonym; EEF2k. In truth, the confusing name is due to the protein having been discovered in a different context; not as a calcium sensor, but rather as a protein that inhibits the nucleic protein “Eukaryotic Elongation Factor 2” downstream from it. From here on we’ll refer to EEF2k by its other name; CaMKIII, in keeping with the theme of Calmodulins.

When CaMKIII senses calcium it begins an opposing Rube Goldberg machine to the one we described earlier. Rather than producing LTP like its sister CaMKII, CaMKIII phosphorylates Eukaryotic Elongation Factor 2 (EEF2) and inhibits its activity.

The role of EEF2 is multifaceted, but in the context of the synapse, its role is to inactivate the transcriptional silencer MeCP2, promoting synaptic growth. EEF2 spends most of its time in its phosphorylated form; this prevents the synapse from strengthening independent of any relevant information.

The question that should be asked next is, how can we experimentally promote one CaMK vs the other?

Messing with Magnesium

I sort of hinted at this in the prior section, but the concentration of Mg2+ in the synapse can be manipulated to change the synapses threshold for plasticity induction. Abraham and Bear (1996) cite Coan et al (1989) as the first hinting of a metaplastic mechanism as the primary finding of the study was considered paradoxical.

The experiment in Coan et al compared the activity of two groups of rat hippocampal slices; one hippocampal slice was bathed in a medium without Mg2+ and the other in a medium with a 1mM concentration of Mg2+. The amount of 1mM was used as it is the average concentration in the rat brain.

It was expected that the hippocampal neurons prepared in the absence of Mg2+ would be more responsive to burst stimulation, allowing more Ca2+ to flow into the postsynaptic neuron, yet this was not the case. The expected response of LTP induction was only observed after the application of an NMDA Receptor antagonist.

Inna Slutsky’s Semi-Replication

At the time, Coan et al did not have the necessary tools to determine what was mediating the non-response of the Mg2+ absent condition. However, In 2004, Inna Slutsky’s lab published a paper reproducing the experiment, this time measuring both NMDA Receptor currents and response to burst stimulation.

The two conditions in this study were again rat hippocampal slices prepared with different concentrations of Mg2+; the primary difference was in the concentrations used, 0.8mM (a low but physiological range) and 1.2 (at the higher end).

As in Coan et al, the response to burst stimulation was greater in the hippocampal slices cultured in high Mg2+; more important for our purposes however, are the measures of NMDA Receptor currents.

The primary finding of this study was that synapses cultured in 1.2mM Mg2+ exhibited dramatically lower amounts of Spontaneous NMDA Receptor Currents and were more plastic as a result. This pattern of high Mg2+ concentrations leading to greater synaptic plasticity is found outside of ex vivo data and is even implicated in the pathophysiology of depression.

Concluding Remarks

There is a common, yet seemingly unknown finding that keeps replicating. Treatment Resistant Depressives (TRD) have incredibly2 low3 levels4 of magnesium in their cerebrospinal fluid relative to both healthy and treatment responsive depressives. This pathway serves as a means of understanding not just metaplasticity, but the pathophysiology and treatment of TRD.

I’d like to thank Adam Mastroianni for giving my post ‘The Best Antibiotic for Acne is Non-Prescription’ Second Place in his Blog Extravaganza. This generated a bunch of traffic to my blog and subsequently a bit of nervousness as to what I’d write about for my next post! I’ve settled on discussing a pretty specific topic/region in neurobiology, but it is one that I believe has generalizable insights to other brain regions like the Cortex and to frameworks like Predictive Processing.

Without further ado…

Priors

I believe many of my readers will be familiar with the term ‘Predictive Processing’ but for those who were among the first to start reading my blog (my friends and family) I will summarize it as such:

1. Your brain constantly maintains a model of the world that includes the spatial, emotional, and sensory information that make it up.

2. This ‘World Model’ runs in the background of your experience, whenever something new is encountered it is rendered into your brain as schemata

3. Sometimes this ‘World Model’ is not accurate to actual experience. An example of this is could be putting a random color generator in your peripheral vision and then realizing your guesswork is almost worse than chance

The brain has physical processes analogous to this; The Parahippocampal Cortex encodes the meaningness of objects in your vision, the Limbic System encodes the emotional reaction to such objects, and the Prefrontal Cortex (we can absolutely get more specific for all of these examples) determines the appropriateness of this response.

The continuous learning period of childhood and adolescence is a time in which the learning rate of this ‘World Model’ is highest. This means that new information will color experience with greater and broader strength until it is encountered with contradictory information. For instance, I believed for the longest time that the word mischievous was pronounced “Mis-Chi-Vi-Us” and my speech reflected this until I was around 17 upon which my mother informed me that the more common pronunciation was in fact “Mis-Che-Vus” (this is a very common mistake).

Some schema in the ‘World Model’ are nearly impossible to overcome, especially those of which relate to the visual system. Take for instance the Hollow-Mask Illusion; introduced to me by Scott Alexander’s hilariously titled blogpost, “Why Are Transgender People Immune To Optical Illusions?”

The brain has an incredibly strong prior/schema against viewing faces as anything but outside in, such that even when the hollow mask rotates inside out – it sort of “snaps” (I thought this was an Alexanderism, but I can’t find the post where he uses this term) back to being outside in again.

Further reading on Predictive Processing can be found by searching the term on Lesswrong, Slate Star Codex, or even my own blog. I will not be the first, nor the last to talk about how cool it is.

The Neurobiology (the horror) of it All

These 'World Models’ and Schema have to come from somewhere of course, and there is no better training data than reality itself! Looking further and further back into the primal parts of the human brain we can find exceptionally fun systems, made without complicated synaptic machinery like the “Triheteromeric NR2A/2B NMDA Receptor”.

These systems are hesitant to change as they make up the very basis of sense data, yet the computations they perform require rich and complicated morphologies. The 'Superior Colliculus’ – known in Owls and other animals as the ‘Optic Tectum’ – is one such brain region. I initially became interested in it because it lacked many of the synaptic mechanisms that are considered essential for the cortical processing of information, namely the NR2B-NMDARs mentioned above. This is because, without NR2B-NMDA Receptors, you simply could not remember the placement of items in a novel space (similar results can be attained by getting blitzed on Ketamine). The lack of complex plasticity mechanisms in this circuit (at least in adulthood) point to its importance as a signal transponder of visual stimuli.

In the absence of these mechanisms at the synaptic level, how can the Optic Tectum perform tasks like Motion Detection, Signal-Noise filtering, and Discrimination of Attention?

Structure

The Optic Tectum is a layered structure — much like the cortex — with smaller bundles of neurons at the very center. The outside layer of the Optic Tectum can be thought of like a slice of a sphere with numerous columns inside of it, each column representing a group of neurons that relay input from the visual field to the Brainstem and Thalamic Nuclei. If you imagine your visual field as a grid, the content of each one of the cells in that grid can be represented by one of these columns. The outputs to the Brainstem and Thalamic Nuclei (specifically the dorsolateral geniculate nucleus) make it such that signals in the Optic Tectum cause the eyes to move reflexively towards the object of excitation.

The inner layer of the Optic Tectum behaves similarly, however it also integrates signal from the auditory cortex and other sensory modalities. Outputs from the inner layer project to the Brainstem where excitation produces reflexive/“ballistic” movements in the rest of the body (this will be important later). It also sends information to the Thalamic Nuclei; however, only to those that guide voluntary movements.

This region can be subdivided further, but frankly there is not enough data to determine the function of each of the proposed FIFTEEN layers. Two will make due.

Circuits

In order to discriminate whether or not stimuli is actually meaningful or “salient” there must be a mechanism that allows only one or a few local columns to fire at any given time. If the whole Optic Tectum were to fire without rebound inhibition you could not direct your focus on any thing in your visual field. Thankfully for us – and for nearly every vertebrate with eyes – rebound inhibition is a huge part of this circuit!

At the very center of the Onion(Optic!) Tectum lie a bundle of neurons called the Isthimic Nuclei. Any time a column in the Optic Tectum fires, it causes this bundle of neurons to fire as well. Rather than inducing excitation in the whole region, the Isthimic Nuclei inhibits every column and prevents any of them from sending output to the aforementioned Thalamic Nuclei, Brainstem, and Basal Ganglia. The Neurobiology professor Eric I. Knudsen refers to this as “competitive surround”.

The blue neuron in this image represents one of the neuronal columns I referred to prior. The two Isthmic Nuclei – Imc and Ipc/SLu – are responsible for the global inhibition as seen by the black neuronal fibers that reach into the Optic Tectum. The Orange neuron depicted is a neuron that accompanies each column that senses excitation for the Isthmic Nuclei so it can induce the “competitive surround”.

Because the brain is a noisy place, there’s excitation in every column; however, the amplitude of this excitation is variable. Only one column, one cell of the visual field, with the greatest excitation, the greatest motion/light/color, is able to project beyond the onion and to the rest of the brain. In the case of the owl, upon sensing the slightest movement in the bottom-left corner of its vision, the eyes immediately shift focus, ballistic movements trigger direction turning in midair, and a surge of dopamine and noradrenaline hit, all within milliseconds. Moments later a dead mouse lies on the forest floor.

From Birds to Humans

The Optic Tectum is a primitive region of the brain that shows up in nearly every vertebrate with eyes, it turns out those organs are effectively useless if an organism doesn’t have the ability to visually focus. In humans and primates, the Optic Tectum gained extra functions and was given the name ‘Superior Colliculus’. The interior layer especially broadened its ability to integrate various sensory modalities, so much so – that some neurobiologists theorize that it is “Causally engaged in Abstract Higher-Order Cognition”. Given how recent the studies determining the higher functions of the Superior Colliculus are – I don’t feel comfortable drawing dramatic conclusions about them as I would with the Optic Tectum.

It is worth mentioning however, the synaptic mechanisms I mentioned were absent in the Optic Tectum are in fact present in the Superior Colliculus, owing to my suspicions of higher order function.

With that, I hope you enjoyed reading and I hope that you point out anything I missed in the comments!

Further Reading and Works Cited

Further Reading on the Superior Colliculus can be found in these articles:
- Primate superior colliculus is causally engaged in abstract higher-order cognition
- Pathways for Naturalistic Looking Behavior in Primate II. Superior Colliculus Integrates Parallel Top-down and Bottom-up Inputs
- Morphology of Superior Colliculus- and Middle Temporal Area-Projecting Neurons in Primate Primary Visual Cortex

Some Lesion studies are also helpful to get a feel for how important this region is:
- Visual Neglect After an Isolated Lesion of the Superior Colliculus
- Superior colliculus lesions preferentially disrupt multisensory orientation

And of course the work that inspired this blog:
- Neural Circuits That Mediate Selective Attention: A Comparative Perspective

Since coming back from art school—and ceasing my activities—my routine was pared down to washing my face with water, putting on a retinoid, and ending off with a light moisturizer. However! One day my routine was interrupted… unbeknownst to me, I had put Neosporin (instead of adapalene) on my lovely pores. What came the next morning was nothing short of a miracle.

Neosporin is a mixture of three antibiotics (Neomycin, Polymyxin, and Bacitracin) in a petrolatum carrier. It also happens to be highly efficient in combating a great annoyance: C. acnes bacteria (formerly known as P. acnes). Despite this, I've seen a lot of claims to the contrary, most stemming from this article. The only thing resembling a claim here is a feeble, “Neosporin’s three active ingredients... may not work against acne.” This is only about 2/3rds of a truth. Neomycin and Polymyxin are totally useless as anti-acne drugs, they’ve got that. But while they consider Bacitracin as potentially effective, they dismiss it for, uhhh undisclosed reasons? I guess?

The academic literature on this topic presents a very different story. Bacitracin is incredibly effective at suppressing C. acnes, “The susceptibility to triple antibiotic ointment (neomycin/bacitracin/polymyxin) and bacitracin alone was 100%.” (Ma et al., 2016) This study examined the effects of bacitracin vs. prescribed agents Of the samples collected from the population, over half had received prior antibiotic treatment. There was 0% bacterial resistance to Bacitracin observed at a breakpoint of ≤ 2 IU/ml (this is very small) as recommended by the Clinical and Laboratory Standards Institute (CLSI). Breakpoint refers to the minimum "concentration of an antibiotic at which bacterial growth is completely inhibited" (Kowalska-Krochmal & Dudek-Wicher, 2021). Rates of resistance to Clindamycin and Erythromycin were 33.4% and 49.3% respectively.

There are two maybe valid concerns about its use, 1-6% of people who use Neosporin may have a skin allergy to it, this however can be easily tested prior to use, or you can just use straight bacitracin. The other concern is a possible depletion of skinflora. Skinflora refers to the environment of bacteria on your skin, all of which keep each other in check to prevent infection. Unlike the gut microbiome, the ecosystem of the skin seems very resilient to antibiotic-induced dysbiosis. This is why people who undergo antibiotic treatment on their skin don't have long lasting deleterious effects. The only reports observing adverse effects have come with numerous caveats. The patients in these studies are often either taking them orally or are among a number of case reports which doctors erroneously prescribe strong topical antibiotics for open wounds (leading to systemic absorption and gut dysbiosis) or for… eczema???

With that spiel I hope more people become open to the usage of Neosporin/Bacitracin for Acne. Proof of concept on self:

TL;DR: Bacitracin Suppresses the bacteria responsible for acne at a rate of 100% in a petri dish. There was zero bacterial resistance observed. Concerns about skinflora and skin allergy are unfounded.

Bibliography

‌Sullivan, D., & Zambon, V. (2020, April 27). Neosporin for acne: Does it work and alternatives. www.medicalnewstoday.com. https://www.medicalnewstoday.com/articles/neosporin-for-acne

‌Ma, Y., Zhang, N., Wu, S., Huang, H., & Cao, Y. (2016). Antimicrobial activity of topical agents against Propionibacterium acnes: an in vitro study of clinical isolates from a hospital in Shanghai, China. Frontiers of Medicine, 10(4), 517–521. https://doi.org/10.1007/s11684-016-0480-9

Kowalska-Krochmal, B., & Dudek-Wicher, R. (2021). The minimum inhibitory concentration of antibiotics: methods, interpretation, clinical relevance. Pathogens, 10(2), 165. https://doi.org/10.3390/pathogens10020165

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There are two receptors that mediate this attractive force, the Kainate Glutamate Receptor (henceforth KAR) and the AMPA Glutamate Receptor (henceforth AMPAR). When Glutamate binds to an AMPA or Kainate Receptor it opens them to allow calcium to flow into the receiving cell. This Calcium Influx induces a cascade of effects inside the cell that lead to the exocytosis (expression at the surface) of more AMPA, Kainate, and NMDA Glutamate Receptors.

The NMDA Glutamate Receptor (henceforth NMDAR) is a unique receptor among its companions. It does not activate when Glutamate alone binds to it, rather three things must occur:

1. The synapse must already have received calcium influx (via AMPAR/KAR/α7-nAChR activation)

2. The co-agonists Glycine or D-serine must bind to the Glycine site on the NR1 subunit

3. The excitatory neurotransmitter Glutamate must to the Orthosteric site on the NR2 subunit

The peculiarities of this receptor are such that it induces wildly different responses to spontaneous neurotransmission, such neurotransmission would need to be excessive in order to trigger any response from the NMDAR. In this way, the NMDAR serves as a sensor for excessive excitation of a synapse.

When an NMDAR is activated by Spontaneous Neurotransmission— rather than inducing synaptic growth, it suppresses protein translation and translocation to prevent synaptic growth. The balance of NMDAR and AMPAR/KAR calcium influx can be sensed via electrophysiology, the measurement of electrical currents via an electrode placed on a neuron.

AMPARs show different Decay Kinetics—the time it takes for a current to weaken and for the receptor to close itself—than NMDARs. Whereas the AMPAR rapidly opens and closes, the NMDAR opens rapidly (although with less influx) and slowly closes its Central Pore.

The intracellular mechanisms that allow the NMDAR to prevent synaptic growth have only begun to be characterized in recent years, however the most promising pathway is that of inhibition by Calcium Calmodulin IV Kinase (henceforth EEF2K, don’t ask). This is a protein that upon sensing small amounts of calcium influx, phosphorylates the protein Calcium Calmodulin IV (henceforth EEF2. Again, don’t ask).

EEF2 phosphorylation makes it such that it cannot translate the transcription factor BDNF as it would during times of synaptic growth. Spontaneous neurotransmission that is sensed by AMPARs activates BDNF and induces synaptic growth whereas NMDARs oppose this process. Among other effects of EEF2 phosphorylation is dephosphorylation of the transcriptional regulator MeCP2.

MeCP2 is a master regulatory protein that suppresses transcription in the cell nucleus in order to prevent synaptic growth. Mutations in the gene encoding this protein can induce hyper or hypo-function, one such mutation is responsible for the autism-linked genetic disorder Rett’s Syndrome. When MeCP2 is dephosphorylated it is in its active state, suppressing transcriptional responses to prevent aberrant growth of the neuron.

Spontaneous currents sensed by the NMDAR maintain a balance of synaptic scaling and descaling in order to prevent excitotoxicity and to filter noise. However in some cases it can be therapeutic to transiently block the NMDAR with pharmacological interventions such as low-dose ketamine or MK-801 infusion.

Ketamine has recently been approved by the FDA as a rapidly acting antidepressant. A single infusion is known to induce a week-long antidepressant effect that increases with repeated infusions. Depression is associated more events of NMDAR-mediated spontaneous neurotransmission in its patients due to low levels of Kynurenic acid and increased levels of Quinolinic acid. The receptors become sensitized in order to protect against what it believes to be excitotoxic insult, consequently they weaken functional connectivity between the midbrain, hippocampus, and forebrain. This is responsible for symptoms such as anhedonia, brain fog, and disrupted memory retrieval.

In future posts I will characterize other functions of the NMDAR as it is also required for neuronal computation in the higher brain cortices.

A few nights ago I was browsing some drug forum to score some dope (i jest) and I came upon the name of a drug which, while new, was very familiar to me:

MethylPhenylPiracetam, henceforth referred to as MPP.

MPP is part of the racetam class of substances. Every member of this class is progeny of the drug Piracetam. This is an archaic substance, produced and marketed in 1970s France as the very first “cognitive-enhancing” drug; a nootropic if you will. Since its creation, it has continued to prove sub-par at achieving its indicated function, but people didn’t give up on it. The French tested it out on all sorts of conditions; hypoxia, motion sickness, and essential tremors to note a few. Eventually they decided that if they couldn’t make the main substance profitable, they could fuck with it just enough to make a bajillion different things with the same effect.

This did not pan out as the French had hoped. However, what they got was way cooler! Almost every single racetam operates differently from one another, yet, almost every single racetam is capable of cognitive enhancement. I like to keep track of when another one of these guys gets made, some frankenstein-esque creation made out of its own cousins. Eventually we got one; MPP, that targets the mysterious sigma-1 receptor, but in a way unseen in any other drug.

The Sigma Mind

Every single smackhead on r/drugnerds is obsessed with the sigma-1 receptor (S1R). Here we have a receptor with high binding affinity for nearly every psychedelic, antidepressant, psychostimulant, and antipsychotic drug. Near no one knows what the hell it does. If you expect me to explain it then you’re flat out of luck (give it a decade when the science is clearer), but we do have some current estimations of it’s function.

• Induces Autophagy in the face of Endoplasmic Reticulum Stress

• Reduces ER Stress via reducing oxidative stress (produced during anabolism)

• Maintenance and Upregulation of Mitochondrial Energy Production

What excites me about S1R is its function as regulator of ER Stress, the dis-regulation of which is unique to depression. People who research biological correlates of mental illness encounter a very common problem which is that, on the biological level, most disorders look the same. This is especially the case for depression. In illnesses like Alzheimers there are clear biological markers even outside of symptoms. For instance, you can reliably predict someone has the symptoms of Alzheimers if they have β-Amyloid plaques in their head.

There aren’t many biomarkers you can check to predict if someone is depressed. What we do have are correlates, three of which are:

• Glial release of the neurotoxin Quinolinic Acid, an NMDA agonist (activator)

• Dysfunctional glucose homeostasis via GSK-3β upregulation and TAAM41 downregulation

• Insufficient response to ER Stress measured via the proteins GRP78 and GRP94

The Sigma-1 Receptor and Depression

Given all this information, one would expect that most agonists at the Sigma-1 Receptor would alleviate depressive symptoms; Not So!

Only one of these, PRE-084, actually produces antidepressant effects. These effects however, come with the caveat that it must be supplemented with our real hero: SOMCL-668.

SOMCL-668 is what’s referred to as a positive allosteric modulator. As opposed to activating existing sigma-1 receptors, it causes the cell to produce more of them. Typically when you see a drug touted as a substance with “rapid antidepressant effects!!!” these effects are exclusive to mice, and even then they are marginal.

The gains presented in this study, however, were massive.

The most relevant part of this study was not the antidepressant endpoints but rather the measurement of proteins in response to SOMCL-668. In the mice given SOMCL-668 the authors observed:

• Vast reduction of ER Stress via measurement of GRP-78 and 94

• Inhibition of GSK-3β, which is vastly upregulated in depressed people relative to their peers

• Vast increases in Neuron growth via Brain Derived Neurotrophic Factor

Those last two effects may be due to the Trk-B protein pathway, the activation of which is common in most if not all antidepressants. As of now I await more research on the actual mechanism of the GSK-3β/BDNF side.

Piracetam - an overview | ScienceDirect Topics. (n.d.). Www.sciencedirect.com. Retrieved May 6, 2023, from https://www.sciencedirect.com/topics/neuroscience/piracetam

‌Myint, A. M. (2012). Kynurenines: from the perspective of major psychiatric disorders. FEBS Journal, 279(8), 1375–1385. https://doi.org/10.1111/j.1742-4658.2012.08551.x

‌Bown, C. (2000). Increased Temporal Cortex ER Stress Proteins in Depressed Subjects Who Died by Suicide. Neuropsychopharmacology, 22(3), 327–332. https://doi.org/10.1016/s0893-133x(99)00091-3

Wang, Y., Guo, L., Jiang, H.-F., Zheng, L.-T., Zhang, A., & Zhen, X.-C. (2016). Allosteric Modulation of Sigma-1 Receptors Elicits Rapid Antidepressant Activity. CNS Neuroscience & Therapeutics, 22(5), 368–377. https://doi.org/10.1111/cns.12502

‌Ji, J., Gao, C., Wang, Q., Jia, X., Tian, H., Wei, Y., Liu, Z., Wang, Y., & Guo, L. (2023). The sigma‐1 receptor‐TAMM41 axis modulates neuroinflammation and attenuates memory impairment during the latent period of epileptogenesis. Animal Models and Experimental Medicine. https://doi.org/10.1002/ame2.12341

‌Su, T.-P., Su, T.-C., Nakamura, Y., & Tsai, S.-Y. (2016). The Sigma-1 Receptor as a Pluripotent Modulator in Living Systems. Trends in Pharmacological Sciences, 37(4), 262–278. https://doi.org/10.1016/j.tips.2016.01.003

Dong Hoon Oh, Yong Chon Park, & Seok Hyeon Kim. (2010). Increased Glycogen Synthase Kinase-3β mRNA Level in the Hippocampus of Patients with Major Depression: A Study Using the Stanley Neuropathology Consortium Integrative Database. Psychiatry Investigation, 7(3), 202–202. https://doi.org/10.4306/pi.2010.7.3.202

‌Blunsom, N. J., & Cockcroft, S. (2020). CDP-Diacylglycerol Synthases (CDS): Gateway to Phosphatidylinositol and Cardiolipin Synthesis. Frontiers in Cell and Developmental Biology, 8. https://doi.org/10.3389/fcell.2020.00063

‌Blunsom, N. J., Gomez-Espinosa, E., Ashlin, T. G., & Cockcroft, S. (2018). Mitochondrial CDP-diacylglycerol synthase activity is due to the peripheral protein, TAMM41 and not due to the integral membrane protein, CDP-diacylglycerol synthase 1. Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids, 1863(3), 284–298. https://doi.org/10.1016/j.bbalip.2017.12.005

‌

A Brief History of Antidepressant Medication

Drug development and etiological theory proceed in lockstep; each influencing the other and yet requiring the other to be validated. It was not until the discovery of the tricyclic antidepressant (TCA) Imipramine, that the first consensus etiology of depression was formed. Harvard Psychiatrist Dr. Joseph Schildkraut stated in a lecture to his peers, “some depressions, if not all, are associated with an absolute or relative deficit of catecholamines, particularly noradrenaline, in important adrenergic receptors in the brain. Contrariwise elation may be associated with an excess of such amines.” (Schildkraut) The catecholamine hypothesis was the logical conclusion of most psychiatrists, given that the drugs most effective at treating depression acted by increasing the concentration of noradrenaline. The field–having been in its infancy–sought to find a simple mechanism that was not just convenient for explanatory power, but also for profit.

Selective Serotonin Reuptake Inhibitors appeared on the drug market in the 1980 and 90s. These drugs had a separate mechanism of action, but they were similar enough to the catecholaminergic drugs that the theory wasn’t abandoned. All the rise of Prozac did was expand the scope of neurotransmitters that could be released. The catecholamine hypothesis was became the popular monoamine hypothesis, or as advertised to laymen, the ‘chemical imbalance’. Dr. Christopher M. France and Dr. Paul H. Lysaker reviewed the use of this term in a 2007 article stating, “… this chemical imbalance explanation remains unproven and is potentially invalid. The significant limitations of the imbalance explanation, however, have not prevented U.S. laypersons (as well as some treating professionals and other stakeholders) from being urged (e.g., via DTC advertisements) to accept the explanation as a likely fact” (France et. al.). Their claim is that the chemical imbalance theory as advertised misleads the consumer as it posits the cause of depression as a switch that is yet to have been turned on. The switch in this scenario is the increase in concentration of “monoamine” neurotransmitters, including serotonin, norepinephrine, and to a lesser extent at the time — dopamine.

The ‘chemical imbalance’ was widely regarded by academia to be an unlikely explanation, not worth examining to determine pathology or etiology. Researchers consistently found that SSRIs failed to relieve depressive symptoms in nearly a third of the depressed population. In the attempt to compete with Prozac, a second boom of antidepressant drug development began in the late 1980s. Anti-serotonergic drugs such as Nefazodone and Mirtazapine­—introduced to the market in 1994 and ‘96 respectively—had efficacies similar to pro-serotonergic drugs. The success of these new drugs—many of which did not increase serotonin at all—prompted renewed interest in etiological research. It made little sense that both pro-serotonergic and anti-serotonergic agents could contribute to antidepressant effects. In the effort to tease out new pathologies, researchers used non-antidepressant drugs on the depressed patient population, one of which was ketamine.

Initial Uses of Ketamine

Ketamine is an anesthetic derived from the dissociative drug, Phencyclidine (PCP). It was first synthesized by the biochemist Dr. Calvin L. Stevens in 1962. His goal was to modify the PCP molecule to keep its anesthetic properties but eliminate its deleterious side effects: hallucination and paranoia. To this end he succeeded, it began to be used as a form of anesthesia and in the paramedic context, as a chemical restraint. Ketamine was first used in the treatment of depression as an accident. There were numerous case reports observing a pattern of paramedics using ketamine to restrain people attempting to kill or otherwise harm themselves; if the patient had a prior history of depression, they would often report that many of their symptoms were relieved within the week. Eventually, this pattern of ketamine administration and subsequent remission of symptoms was noticed by Dr. John Krystal – now Chair of Psychiatry at Yale.

Krystal and his lab published a series of pilot trials: studies that use designs of clinical trials but on smaller samples. The first trials established the safety of sub-anesthetic doses of the injected drug. A second wave of trials from 2000-2014 performed by other labs sought to establish the efficacy of the drug relative to placebo or other antidepressants. A retrospective published in 2014 by Dr. Alexander McGirr et. al. concluded that, “After 7 days, the pooled OR was 4.00 (95% CI 1.52-10.51, z = 2.81, p < 0.01) for clinical remission and 4.87 (95% CI 2.24–10.55, z = 4.01, p < 0.001) for clinical response, indicating a significant difference in outcome favoring ketamine.” (697) The odds ratio refers to the multiplier by which it is more likely that a patient reached an outcome. For instance, in this study the authors found that only one week after a single dose, patients receiving ketamine had a 400% greater likelihood of remission than patients receiving placebo. This was coupled with a mean effect size of 0.9 after one day, greater than what any other antidepressant had achieved in a randomized trial. While it was well established that ketamine could greatly attenuate suicidality; it was only after this second wave of trials that clinicians began to take the idea of ketamine as an antidepressant seriously.

Etiologies and Enantiomers

The publishing of these trials prompted scrutiny upon the current state of etiological research. While theoretical and mechanistic research accelerated after the introduction of the “atypical” antidepressants, there was little in the way of data verifying these ideas. A growing theory was that of glutamatergic dysfunction, an overexcitation of the NMDA glutamate receptor leading to an inability for cells to communicate. The advent of ketamine – an effective glutamatergic antidepressant – provided researchers with a tool they could use to validate their theories. In demonstrating therapeutic efficacy, the researchers using ketamine shifted the long-standing paradigm of depression away from a disorder of monoamines.

Following successful trials and a preponderance of mechanistic data, the lab of Dr. Kyle Lapidus and his colleagues at Yale published the results of a 2014 trial on a novel means of administering ketamine – via an intranasal spray of ketamine. Two years later, Dr. Ella Daly et. al. performed an identical trial titled, “Intranasal Esketamine in Treatment Resistant Depression - A Double-blind, Randomized, Efficacy and Dose Response Study”. This 2016 study used the “left-handed” isomer of ketamine – esketamine, in order to test the specific mechanism of its antidepressant effects. The trial found that, “[a]t the end of OL phase (day 74; n=34), the majority of remaining patients were responders (n=22/34; 64.7%), and 32.4% patients (n=11/34) met remission criteria.” (Daly et. al.) While not on par with intravenous ketamine, intranasal esketamine was similar in efficacy to—and quicker to activate than—traditional antidepressants. Many scientists maintained that the primary mechanism by which ketamine provided its antidepressant effect was that of NMDAR antagonism. Esketamine, as an enantiopure version of ketamine, was very specific in its targeting of this NMDA receptor. However it as unknown whether or not these effects could be achieved by NMDA-independent mechanisms.

The FDA designated intranasal esketamine as a breakthrough therapy for the indications of depression with suicidal intent. This designation gives a drug preferential treatment for clinical trials. The FDA footed a great portion of the bill by renting hospital space, gathering patients, and other trial related expenses. Within three years, the esketamine molecule was on the market as a nasal spray that could be administered every three days in a licensed clinic. While it was a success for clinicians, researchers reiterated that ketamine had a greater antidepressant effect and even reduced incidence of side-effects. A meta-analysis comparing the two written by the Chief of the NIH Pathophysiology Branch; Dr. Carlos Zarate stated, “… intravenous ketamine demonstrated more significant overall response and remission rates, as well as lower drop-outs due to adverse events. As well, more substantial response and remission rates were observed in crossover trials, while more significant improvements in depression rating scores were observed in parallel trials.” (Zarate et. al) The amount by which ketamine exceeded the performance of esketamine was greater than two-fold measured by rates of remission. Despite being only one-half of the full mixture that is racemic ketamine, esketamine seems to have a far greater likelihood of adverse effects, including those that may increase abuse potential.

Opposition to Therapeutic Ketamine

Opposition to the use of Ketamine as an antidepressant stems from a healthy amount of rational skepticism. There are two primary groups in opposition to the use of ketamine for depression. Many clinicians fear that depressive patients will become addicted to the substance and many researchers dispute the methodological quality of the ketamine trials. Both groups are important to the continuing practice of psychiatric ketamine use. Ethical and efficacious standards of care cannot be created without such critiques.

Ketamine Addiction

Ketamine is not physically addicting in the same sense that amphetamines or opiates are. Despite this, there is a preponderance of evidence showing that ketamine addiction is common phenomena. An article from Dr. Kokane and colleagues entitled, “Overlap in the neural circuitry and molecular mechanisms underlying ketamine abuse and its use as an antidepressant,” reviewed the history of ketamine’s abuse potential. He stated, “Illicit use of ketamine began in the United States in the 1970s [156] and soon spread more widely aided by the emergence of the “rave” culture [67].” (Kokane et. al.) Ketamine was used at raves due to its “psychotomimetic” effects which include scenery slicing, macropsia, and environmental cubism as described in the Effect Index’s catalogue: the “Subjective Effect Index” (Index). Dr. Kokane’s initial research on ketamine was not upon its antidepressant effects, rather he studied its chronic use among addicts. This distinction may seem small as it’s the same drug, however clinical and recreational use differ significantly both in dosage and dose frequency.

Dr. Kokane contends that the use of ketamine as an antidepressant will lead patients to develop dependence and deleterious cognitive side-effects. In his “Overlap” study, he states, “…reports have indicated that a subset TRD patients who were repeatedly treated with ketamine developed ketamine dependence, indicative of ketamine’s abuse potential [12,94,150]” (Kokane et. al.) The evidence he uses to indicate this claim is weak. Of the three citations he provides, two are case reports of depressives self-administering ketamine without clinical approval and the other is a narrative review that speculates upon potential risks using those same two cases. The first report was recorded by Dr. James Liu and colleagues, “Intensive ketamine use for multiple years: A case report.” The report follows up on a chronic abuser of ketamine, who claimed he was using it to cure his depression. It was noted, “… that he did not experience a withdrawal syndrome nor did he have any observable cognitive deficits upon cessation of use” (Liu et. al.) The lack of withdrawal or cognitive deficits after, “… large doses of ketamine (1-3 g) on a daily basis over a period of 5 years” (Liu et. al.) is both astounding and should be of great assurance to those who oppose the use of ketamine in psychiatry. After reading the report I have come to believe that Dr. Kokane either did not read it or he willfully misunderstood it. The lack of withdrawal or cognitive deficit is contrary to the very claims he cites this study to prove. Of importance is the dosage of ketamine used by this patient – over 50x that which is used in psychiatric practice. The report is frankly useless. 

Recreational and psychiatric ketamine have vastly different effects. While both types of administration use the same substance, the dosages are different by multiple orders of magnitude. This was explained by the Dr. Scott Alexander, a psychiatrist initially hesitant to prescribe ketamine due to its deleterious effects on the bladder and brain. Upon reviewing the literature, he found that no patient taking ketamine for depression had experienced these apart from the two case reports cited by Kokane. His position is explained in the 2021 blog “Drug Users Use A Lot Of Drugs.” In which he states, “This Chinese study and this UK study analyze recreational ketamine users, and both find they take about 3g daily, every day. That's 90,000 mg over the course of a month. Again, that's 280 mg for the psych patients and 90,000 mg for the recreational users.” (Alexander) The same pattern is observed between addicts taking 3.5 grams every month and the 90-gram figure above. Alexander paraphrased a review article from Morgan et. al stating, “They find that severe abusers, who are taking an average of 60,000 mg/month, experience cognitive problems. But mild abusers, who take more like 3,500 mg/month, don't.” (Alexander) As of 2024, he prescribes oral ketamine off-label in his practice to great efficacy and is yet to have seen any patient become dependent. Given the lack of evidence for the claim—that patients using psychiatric doses of ketamine will become dependent—and the preponderance of evidence that this is not the case, it is unlikely that this is a concern worth halting approval of ketamine for.

Issues of Methodology

The second argument is that ketamine trials are insufficiently blinded to accurate compare effects between a placebo and a treatment group. Blinding is the practice researchers use to keep secret which group a patient is part of. If a patient is aware they are part of the non-treatment group, they may not experience the placebo effect and would thus be an insufficient control for the patient receiving treatment. This issue was described by Dr. Stuart Ritchie in his essay “Everything you need to know about psychedelics and mental illness.” Dr. Ritchie is a science communicator primarily known for debunking studies regarded as too good to be true, quite a few of which come from the field of psychedelic medicine. In this essay he describes issues with psilocybin trials, but ketamine is hard to blind for the very same reasons, “If you know (or strongly suspect) that you’re in the experimental group, you might be motivated to report stronger results on the questionnaire. … Conversely, if you know you’re in the control group, your mood might slump, since you know that you’re taking a useless inert pill.” (Ritchie) The issue with blinding in ketamine trials is that patients know which group they’re in, 90% of the time. Ketamine at antidepressant doses induces a state in which the patient experiences dissociation and sometimes even visual distortion. In order to truly blind study participants: one would either have to give them an active control — a drug with similar acute effects to ketamine — or would have to anesthetize the patient so they don’t experience any acute effects.

Since the publishing of Dr. Ritchie’s essay, these studies have been done. In 2023 a study was performed in which patients were anesthetized during surgery and given either ketamine or an extra dose of the anesthetic propofol. Dr. Liu and colleague’s study, “Randomized Trial of Ketamine Masked by Surgical Anesthesia in Depressed Patients” reported, “a single dose of intravenous ketamine delivered during surgical anesthesia had no greater effect than placebo in acutely reducing the severity of depressive symptoms.” (Liu et. al.) There was zero significant difference between ketamine and the propofol control group. Despite this conclusion, the study is almost entirely useless. While there were no differences between ketamine and propofol, it was not the case that both were benign; both groups experienced dramatic antidepressant effects, the same sizes as those of ketamine trials. Dr. Scott Alexander reviewed the study in another blog entitled, “Does Anaesthesia Prove Ketamine Placebo?” He presents two main contentions with the study. Quoting an article by PsyPost Founder Dr. Eric Doyle, he claims, “The anaesthetic propofol, used in about 88% of these patients, “may trigger rapid, durable antidepressant effects”, with a purported effect size well above that of SSRIs” (Alexander) Using propofol artificially shrinks the relative effect sizes. To regard ketamine as useless, one must ignore the part where it states that it preformed just as well as another antidepressant drug. Dr. Alexander’s second contention is with the specific scale they used to measure depression, “MADRS asks - for example - about disturbed appetite… But surgery naturally disrupts appetite… MADRS asks about disturbed sleep, but sleep in a hospital ward is also naturally disturbed. MADRS asks about concentration problems, but post-surgical patients are often on lots of painkillers” (Alexander) That the control group was given an antidepressant on par with ketamine, that all subjects were assessed while on opiates, and that they were given a questionnaire not suited to hospital life; these factors confound the results to a degree such that the trial has no bearing on ketamine’s efficacy.

The second proposed way to blind patients is with an active control. These studies have borne more fruit than the anesthetic studies. Midazolam is a dissociative sedative—like ketamine—with little to no antidepressant effects. There have been multiple trials comparing midazolam to ketamine, the largest of which was published in 2023 by Dr. Colleen Lee and thirty-seven other researchers. The study, “Efficacy and safety of a 4-week course of repeated subcutaneous ketamine injections for treatment-resistant depression (KADS study)” found that relative to midazolam, “the reduction in mean MADRS score by treatment end differed between groups by 5.5 points (95% CI 2.1–8.7), and response rates (29% v. 4%, P = 0.001) and remission rates (MADRS ≤ 12) (22% v. 4%, P = 0.007) were greater, favouring the ketamine group” (Lee et. al.) Also of note was that both groups didn’t know which treatment they were receiving, only guessing correctly after 4 weeks into the study at which point antidepressant effect had already been noted.

Concluding Remarks

Ketamine is an effective antidepressant regardless of control, whether that be an active one like midazolam or an inert one like saline. Concerns of abuse potential or side-effects are unfounded, as are concerns with long term (>1y) use as studied in recreational users of lower doses. Concerns that insufficient blinding are responsible for ketamine’s antidepressant effects are similarly unfounded. The critiques of ketamine’s use in psychiatry, while rational, stem from misunderstandings about its effects at different doses and unfamiliarity with trials addressing methodological issues.

Of the drugs developed in the wake of the ‘atypical’ antidepressants, none have contributed more than ketamine to the science and treatment of depression. For the first time in decades, researchers and clinicians have been bridging the gap between neurobiology and the psychiatric phenomenology of depression. Without the discoveries about the glutamatergic system made using ketamine, theories of consciousness or perception such as Janina Hesse’s Brain Criticality or Karl Friston’s Free-Energy Principle would have no basis. While this paper focused upon its efficacy in the clinical context, ketamine has been similarly–if not more–influential in the study of how neurobiology gives rise to phenomena.

Works Cited

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McGirr, A., Berlim, M. T., Bond, D. J., Fleck, M. P., Yatham, L. N., & Lam, R. W. (2014). A systematic review and meta-analysis of randomized, double-blind, placebo-controlled trials of ketamine in the rapid treatment of major depressive episodes. Psychological Medicine, 45(4), 693–704. https://doi.org/10.1017/s0033291714001603

Bahji, A., Vazquez, G. H., & Zarate, C. A. (2020). Comparative efficacy of racemic ketamine and esketamine for depression: a systematic review and meta-analysis. Journal of Affective Disorders, 278, 12473. https://doi.org/10.1016/j.jad.2020.09.071

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• Dermatology in the 21st century is an academic complex ruined by beauty companies that do not have their consumers’ best interests in mind. This document does not seek to teach people how to achieve “Glass Skin” or “Invisible Pores’. I instead want to touch on the benefits of healthy skin, and how it is ultimately better at self …

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