Marijuana is a common drug of use in today’s culture. Some claim borderline supernatural effects from the drug. Spiritual, mind-expanding, or enlightening effects. Could these type of effects be explained with science? That’s what I’m going to attempt.
This paper will attempt to review, not only the literature on the subjective and objective cognitive effects of marijuana, but also correlations of cognitive effects derived from its relationship to other drugs with shared pharmacological mechanisms. The physiological mechanism of the cannabinoid receptors, the main target for the most commonly known active constituents of Marijuana, CBD and THC, has relationships to the physiological mechanisms of other drugs. There are also possible associations to visual and cognitive illusions that are commonly studied.
THC AND CBD
Currently, Cannabidiol (CBD) and (THC) are the most studied constituents of the Marijuana plant. This is not to disregard the long list of other biologically active constituents, such as CBN, CBG, and plethora of varying terpenes such as linalool, pinene, and myrcene, to name a few. For the sake of simplicity, this paper will focus on THC and CBD and their isolated pharmacological mechanisms in relation to various drugs and mental disorders. THC is known to be a potent CB1 receptor agonist, while CBD’s mechanisms involve anandamide increase, CB1 receptor antagonism, and 5HT1a serotonin receptor agonism (15). Both THC and CBD also interact with opioid receptors, acting as allosteric modulators (15).
Anandamide is the endogenous ligand that binds to CB1 receptors (15). The CB1 receptors form heteromers with receptors such as NMDA glutamate receptors (17) and D2 dopamine receptors (8). When CB1 ligands bind as agonists or antagonists to the CB1 receptor, it causes a reaction from NMDAr and D2 receptors as well. In this regard, CB1 agonists may produce many of their subjective effects via indirect neurotransmitter systems, such as NMDAr and D2 receptors. The following sections will discuss the implications that these heteromers have, and their possible relationship towards schizophrenic symptomology.
Many neurotransmitter receptors form connections to other neurotransmitter systems via connections called heteromers. For example, CB1 receptors form heteromers with NMDA glutamate receptors and D2 dopamine receptors. When THC binds to CB1 receptors, it will also activate effects in these heteromer systems as well. This includes downregulation (17). When CB1 receptors undergo receptor endocytosis, where the receptor is pulled into the cell, and becomes unable to bind, due to being internalized. The heteromers are also downregulated as well. It is known that THC results in NMDA endocytosis, and that NMDA endocytosis is implicated in the major theories for the pathology of schizophrenia (17).
The effects of the NMDA glutamate receptors are critical to understanding the effects of Marijuana. The NMDA receptor is involved in processing memory and sensation. Blocking the NMDA receptor is the function of anesthetic drugs such as ketamine, phencyclidine (PCP), and nitrous oxide. These drugs reduce or even block sensation entirely, as well as causing amnesia, and even many bizarre effects (12). For example, PCP has been used in experimental animal studies to produce ‘psychotomimetic’ effects, in order to study schizophrenia and psychosis (20). NMDA antagonists produce effects such as motor discoordination, paranoia, numbness, hallucinations, and sensory dulling or loss (anesthesia) (12).
The Ebbinghaus illusion. Do the center circles appear the same size? If they appear the same size, it may imply schizophrenia. This isn’t certain though, so don’t worry.
It is possible that hallucinations occur from both a loss of memory and loss of sensory acuity. Sensory acuity loss would produce errors in perceptual processing. Memory disruption may disrupt the recall of familiar and common visual themes, causing the individual to process perception as unfamiliar, possibly changing elements of judgment. The ‘memory illusion’, in which false memories can be implanted, shows a case where a meta-cognitive illusion can exist (2). A case could be made, that all illusions are a form of memory, and they form for efficient processing. Using memory constructs to form perceptions of familiar and common images that we are exposed to, such as faces, the corners of rooms, and 3-dimensional data, would allow faster processing and less time spent deciphering data as if it were novel. The ‘motion aftereffect’ illusion occurs when staring at a source of consistent motion, where eventually when looking at a static image, the perception of motion continues after the stimuli has ceased (3). This would show that the illusion is developed via exposure to the stimuli, and this would make sense of cultural differences found with optical illusions (10). Being exposed to grid-roads vs being exposed to forests, reveal drastically different stimuli that each group is exposed to on a frequent basis. Illusions are in some sense, memory-based abstractions, created from familiarity and exposure to common stimuli. Illusions would allow for faster processing, reduction of details, assumption-recognition-based processing as opposed to sensory-observation-based processing and interpreting of observations.
There is correlation between illusions failing, and proneness to schizophrenia, such as the case of depth inversion illusions, or ‘hollow mask illusions’ (7). It may be that, increasing doses of NMDA antagonists, would decrease perception, and that illusions are the highest form of perception, relying on a combination of stimuli and memory, as opposed to stimuli alone. So, with increasing doses of NMDA antagonists, we could expect the highest forms of perception to vanish first, which would put pressure on visual processing, and eventually visual failure, where an excess of details are surpassing the ability to distinguish and process the details.
Illusions, such as the hollow-mask illusion, fail in schizophrenic subjects.
NMDA agonists produce excitotoxic effects on neurons via neuronal calcium influx, whereas antagonists produce neuro-protective effects for neurons (4). Because of this, NMDA agonists are largely avoided in medicine. There are far less examples of human use of NMDA agonists. We could assume NMDA agonists, to theoretically oppose NMDA antagonists, and therefore, be the opposite of anesthesia. If NMDA antagonists result in sensory degradation and the loss of optical illusions, it could be that NMDA agonists prevent the loss of illusions and sensory degradation, or even more, enhance the development optical illusions as well as enhancing sensory quality on some level. By increasing illusions, visual data may be increasingly abstract and simplified, resulting in faster processing of novel stimuli, or simply that there is less novel stimuli to process, as it has been turned into illusions/memories already. The increase of illusions may negate benefits gained from the faster visual processing, as we know illusions are commonly perceptual errors.
The drug LSD-25 is known to have a glutamate release enhancing mechanism. It produces visual and dramatic cognitive effects via partial agonism of the 5HT2a serotonin receptor. This receptor forms heteromers with mGlu2 receptors, which inhibit the release of glutamate. When LSD binds to 5HT2a as an agonist, it inhibits mGlu2 receptors, which causes glutamate to release (13). This enhances NMDA receptor activity indirectly, as well as other glutamate receptors. Since LSD does not agonize NMDA receptors directly, the effect would not likely be as controlled, but instead, natural downstream effects and homeostasis effects would likely produce different effects than a direct NMDA receptor agonist. For example, AMPA glutamate receptors modulate the activity of NMDA receptors, and since LSD is increasing glutamate release, in general, it doesn’t necessarily favor NMDA over AMPA glutamate receptor binding.
(a) shows the brain sober, and (b) shows the brain under the effects of a 5HT2a agonist.
Motion effects that resemble the common motion aftereffect illusion, occur on LSD. For example, a common anecdotal visual response to LSD, known as the ‘breathing walls’ effect, permeates psychedelic drug culture, on websites such as erowid.org, or psychonautwiki.com. This effect may occur by the same mechanism as the motion aftereffect illusion, which is induced when staring at a source of consistent motion, for 30 or more seconds (3). The effect of motion adaption may be enhanced by the increased glutamatergic signaling that occurs under the influence of LSD, causing the illusion to develop more quickly, and more minutely as well. So it is possible that the ‘breathing walls’ illusion is actually caused by the motion your body makes while breathing, causing slight movements in your visual field, that get learned, and projected as an illusion in your visual field. Further experimental research involving NMDA agonists and optical illusion development would need to be done to confirm this concept, but considering that an NMDA agonist should reverse or counteract the effects of an NMDA antagonist, and vice versa, a strong hypothesis could be made. This also suggests that something like an NMDA partial agonist, could possibly be used to treat schizophrenia, and produce less neurotoxicity than a full agonist.
Motion after-effect illusion demonstration.
THC in marijuana, agonizes CB1, and indirectly modulates NMDA activity. It is thought that NMDA is disrupted by CB1 binding, especially with higher frequency, resulting in downregulation of NMDA receptors. NMDA receptor status becomes more disrupted by increased frequency of CB1 binding, especially because CB1 receptors upregulate at a faster rate than NMDA receptors (17). This likely can explain an array of effects, especially if lower doses or reduced frequency of CB1 activity results in NMDA stimulation. It is thought that CB1 activation inhibits NMDA receptors directly as well (11). Although, the other study implied that CB1 activation rapidly disrupts NMDA via downregulation (17). Another study found both neurotoxic and neuroprotective effects of THC, with the neurotoxic effects occurring in lower dosages, not higher (18). This could imply that very low dosages of THC act as NMDA agonists, but that downregulation and disruption occurs rapidly, and increasingly rapid at higher dosages. If this were true, the short duration of marijuana may result in dramatic effects on cognition and perception that quickly change as the drug peaks and comes down, effects of both NMDA agonism and antagonism, with preferences for antagonism with increasing dosages. Future studies should factor this mechanic into their research and compare and contrast the differences between the peak and the following ‘crash’ period, or even measure the same variables over time throughout the experience, to measure the changes of functioning throughout the drug’s effects on an individual. Another factor to consider is that CBD is a CB1 antagonist, as previously mentioned, which may add dynamics to the NMDA receptor that change the resulting effects of marijuana consumption. Since CBD antagonizes CB1 receptors, which inhibit glutamate release, it would follow that CBD increases glutamate release (15). NMDA antagonists are commonly psychotomimetic, so this mechanism of CBD may play a major role in treating psychotic disorders.
Vsauce explains how the Ebbinghaus illusion functions and how it is a learned phenomenon, as noted by the fact that young children do not yet have this illusion.
D2 is another major receptor target that is modulated by marijuana’s main constituent, THC (8). D2 dopamine receptors function in two major ways: as a stimulatory receptor, similar to D1, or as an inhibitory presynaptic receptor, preventing dopamine release. Stimulatory dopamine receptors are linked to intention and action (19). D2 (22), as well as other inhibitory dopamine receptors, such as D4, are linked to processing novelty (5). D2 receptors form heteromers with 5HT2a (14), the main target of LSD, as previously mentioned. This system of associated receptors (D2-5HT2a-mGlu2) may serve a role in novelty processing, where presynaptic D2 receptors shut down distracting impulses caused by stimulatory dopamine activity, and increase observation and sensory awareness via increased glutamate release via the 5HT2a-mGlu2 heteromer.
Some of marijuana’s major effects on cognition may result from the D2 receptor effects. Schizophrenia is correlated to increased activity of D2 receptors (21). Creativity is cited with both marijuana use (23) and schizophrenia (9), perhaps an effect of increased observation, and also the decreased NMDA function may result in less familiarity and assumption-recognition-based processing, resulting in the sense of novelty, even when being exposed to familiar stimuli. The result of this may be users becoming bewildered by seemingly ordinary things, or possibly gaining insight to things they have previously ignored due to overexposure in daily life. Users often report self-reflection as an effect of marijuana. Again, the impacts of CBD as a CB1 antagonist may provide contrasting effects.
This section is boring but necessary. Continue to the next section though, as the qwerky science gets pretty crazy.
GABA is an inhibitory neurotransmitter (6). It functions by preventing or slowing the binding of neurotransmitters such as dopamine, serotonin, norepinephrine, and glutamate. Anti-anxiety drugs such as benzodiazepines enhance binding to GABA receptors, and produce their effect by reducing activity of other neurotransmitters (16). THC, in marijuana, is capable of modulating the GABA system, by reducing GABA (6). CBD, on the other hand, might cause GABA release, based on research on CB1 antagonists, showing that CB1 antagonism causes GABA release (15). When GABA is decreased by marijuana, the result is anxiety and panic attacks, the expected opposite of anti-anxiety drugs such as benzodiazepines, and, in contrast, GABA release enhancement via CBD’s mechanism would reduce anxiety in a similar manner as benzodiazepines.
The Default Mode Network is the most used parts of the brain. I imagine that as children, we are constantly changing states of mind, exploring the weirder ways of processing reality. For example, shifting our perspective between multiple possible perceptions, instead of assuming one of them is correct. This is known as gestalt shifting. This illusion shows evidence of object recognition playing a role in illusion formation.
First image artifies Gestalt concepts. The second image shows two images that you can gestalt shift between on command.
There is a something known as context-dependent memory, where recall of episodic memory can be triggered by a context related to the initial experience is present. For example, listening to a song while studying for a test, and then listening to the same song while trying to recall the information for the test can enhance the recall of that information. Imagine that the default mode network is the soundtrack to our lives. It is the state of mind we decide to settle down with, because we must deal with the demands from school, stressful events, and ‘adult’ problems. Likely, we can stay within one state of mind for a large portion of the time, allowing us to associate most experiences and information to the same ‘soundtrack’ that is running in the background of our lives.
The default mode network gets overused in daily life. It is linked to depression. Psychedelics are known to temporarily dissolve the default mode network, and also relieve depression for up to months with a single dose.
But what exactly is the default mode network, really? Imagine as you grow, you are rationalizing each decision within a frame of the current data you have attained up to that age. Your worldview determines each decision you make. When you make a decision, you do not save a full memory of the rationalization that led to a conclusion. You only save the conclusion itself. This creates a pyramid of age, where the rationalities have different ages each. Every decision is assigned to a different worldview, and each worldview is created by rationalities and conclusions you have formed in the past. You can probably consciously access the paths of rationality that lead to conclusions you’ve made, but you also probably constantly assume that there is no need to do such.
Growing out of certain rational points of view may lead to contradictions within rationalities. Essentially, your child self will be outdated to your adult self, but since you only retain the conclusions, you will not pick up on the contradictions between rationalities.
This means you will behave in ways that produce negative consequences based on faulty decision-making based on faulty rationalities that you are unaware of. We all know what it’s like to be stuck in a rut, or at least most of us. Stuck within daily habits and loops. What if our habits cause us to suffer, but we are not consciously aware of the logic that lead us to these decisions because the conclusions are already formed? What if this is the link between the default mode network and depression?
This system of past rationalities could be what we term the sub-consciousness.
I propose to you that psychedelics re-awaken sub-consciousness, and that the elimination of the default mode network, is caused by turning on all of the neglected paths of ‘rationality’ from past decisions. I think the default mode network is just a list of all of our current and most up to date assumptions and conclusions, ones that often lead us to our perpetual negative feelings.
Upon taking 5HT2a agonists, changes in our constant background track could occur, or even a total stop, where you must re-rationalize every decision, which brings conscious awareness to the habits we have been making everyday. Abolishing our psychological context removes all the habitual rationalizations, or memories, associated to this context.
Perhaps psychedelics help treat depression by actually targeting problems occurring for reasons based on a person’s rationality, a rationality problem that could even be enhanced by some chemical mechanism that enhances some process of ideological aging and development.
Some of these are insane reads. If you have access to a school library, most of these should be available via psych articles or some similar resource.
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