Marijuana, Perception, and Cognition


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.


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, or 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.


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.

escherfishbirdgestalt 2

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.


BTC: 1MzzbqUSMUNZaopeRTdNh2s3Wre6bD1GBX

LTC: LZJhmv3m15BGpAQs2jJr2FxsCnDM22M7sD



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.

  1. Bentall, R. P. (1990). The illusion of reality: A review and integration of psychological research on hallucinations. Psychological Bulletin, 107(1), 82-95. doi:10.1037/0033-2909.107.1.82
  2. Besken, M. (2017). Generating Lies Produces Lower Memory Predictions and Higher Memory Performance Than Telling the Truth: Evidence for a Metacognitive Illusion. Journal Of Experimental Psychology: Learning, Memory, And Cognition, doi:10.1037/xlm0000459
  3. Carlson, V. R. (1959). Aftereffect of a moving pattern. Journal Of Experimental Psychology, 58(1), 31-39. doi:10.1037/h0048102
  4. Chang-Mu, C., Jen-Kun, L., Shing-Hwa, L., & Shoei-Yn, L. (2010). Characterization of neurotoxic effects of NMDA and the novel neuroprotection by phytopolyphenols in mice. Behavioral Neuroscience, 124(4), 541-553. doi:10.1037/a0020050
  5. Ebstein, R. P., Novick, O., Umansky, R., Priel, B., Osher, Y., Blaine, D., Benett, E. R., Nemanov, L., Katz, M., & Belmaker, R. H. (1996). Dopamine D4 receptor (D4R4) exon III polymorphism associated with the human personality trait of novelty seeking. Nature Publishing Group, 12, 78-80.
  6. Hoffman, A. F., Oz, M. Yang, R., Lichtman, A. H., & Lupica, C. R. (2017). Opposing actions of chronic D9-tetrahydrocannabinol and cannabinoid antagonists on hippocampal long-term potentiation. Learning And Memory, 14, 63-74. doi:10.1101/lm.439007
  7. Keane, B. P., Silverstein, S. M., Wang, Y., & Papathomas, T. V. (2013). Reduced depth inversion illusions in schizophrenia are state-specific and occur for multiple object types and viewing conditions. Journal Of Abnormal Psychology, 122(2), 506-512. doi:10.1037/a0032110
  8. Kearn, C. S., Blake, K. P., Daniel, E., Mackie, K., & Glass, M. (2005). Concurrent stimulation of cannabinoid CB1 and dopamine D2 receptors enhances heterodimer formation: a mechanism for receptor cross-talk? Molecular Pharmacology, 67(5), 1697-1704. doi:6882/1198169
  9. Keefe, J. A., & Magaro, P. A. (1980). Creativity and schizophrenia: An equivalence of cognitive processing. Journal Of Abnormal Psychology, 89(3), 390-398. doi:10.1037/0021-843X.89.3.390
  10. Keith, K. D. (2012). Visual illusions and ethnocentrism: Exemplars for teaching cross-cultural concepts. History Of Psychology, 15(2), 171-176. doi:10.1037/a0027271
  11. Liu, Q., Bhat, M., Bowen, W. D., & Cheng, J. (2009). Signaling pathways from cannabinoid receptor-1 activation to inhibition of n-methyl-d-aspartic acid mediated calcium influx and neurotoxicity in dorsal root ganglion neurons. The Journal Of Pharmacology And Experimental Therapeutics, 331(3), 1062-1070. doi:156216/3534605
  12. Lofwall, M. R., Griffiths, R. R., & Mintzer, M. Z. (2006). Cognitive and subjective acute dose effects of intramuscular ketamine in healthy adults. Experimental And Clinical Psychopharmacology, 14(4), 439-449. doi:10.1037/1064-1297.14.4.439
  13. Maeso, G. J., Ang, R., Yuen, T., Chan, P., Weisstaub, N. V., Gimenez, J. F. L., Zhou, M., Okawa, Y., Callado, L. F., Milligan, G., Gingrich, J. A., Filizola, M., Meana, J. J., & Sealfon, S. C. (2008). Identification of a novel serotonin/glutamate receptor complex implicated in psychosis. Nature, 452(7183), 93-97. doi:10.1038/nature06612
  14. Perreault, M. L., Hasbi, A., O’Dowd, B. F., & George, S. R. (2014). Heteromeric dopamine receptor signaling complexes: emerging neurobiology and disease relevance. Neuropsychopharmacology, 39, 156-168. doi:10.1038/npp.2013.148
  15. Pertwee, R. G. (2008). The diverse CB1 and CB2 receptor pharmacology of three plant  cannabinoids: D9-tetrahydrocannabinol, cannabidiol and D9-tetrahydrocannabivarin. British Journal Of Pharmacology, 153, 199-215. doi:10.1038/sj.bjp.0707442
  16. Rush, C. R., & Ali, J. A. (1999). A follow-up study of the acute behavioral effects of benzodiazepine-receptor ligands in humans: Comparison of quazepam and triazolam. Experimental And Clinical Psychopharmacology, 7(3), 257-265. doi:10.1037/1064-1297.7.3.257
  17. Sanchez-Blazquez, P., Rodriguez-Munoz, & M., Garzon, J. (2014). The cannabinoid receptor 1 associates with NMDA receptors to produce glutamatergic hypofunction: implications in psychosis and schizophrenia. Frontiers In Pharmacology, 4(169), 1-10. doi:10.3389/fphar.2013.00169
  18. Sarne, Y., Asaf, F., Fishbein, M., Gafni, M., & Keren, O. (2011). The dual neuroprotective-neurotoxic profile of cannabinoid drugs. British Journal Of Pharmacology, 163(7), 1391-1401. doi:10.1111/j.1476-5381.2011.01280.x
  19. Satoh, T., Nakai, S., Sato, T., & Kimura, M. (2003). Correlated coding of motivation and outcome of decision by dopamine neurons. The Journal Of Neuroscience, 23(30), 9913-9923.
  20. Svenningsson, P., Tzavara, E. T., Carruthers, R., Rachleff, I., Wattler, S., Nehls, M., McKinzie, D. L., Fienberg, A. A., Nomikos, G. G., & Greengard, P. (2003). Diverse psychotomimetics act through a common signaling pathway. Science, 302(5649), 1412-1415. doi:10.1126/science.1089681
  21. Ward, R. D., Winiger, V., Higa, K. K., Kahn, J. B., Kandel, E. R., Balsam, P. D., & Simpson, E. H. (2015). The impact of motivation on cognitive performance in an animal model of the negative and cognitive symptoms of schizophrenia. Behavioral Neuroscience, 129(3), 292-299. doi:10.1037/bne0000051
  22. Watson, D. J. G., Loiseau, F., Ingallinesi, M., Millan, M. J., Marsden, C. A., & Fone, K. C. F. (2012). Selective blockade of dopamine D3 receptors enhances while D2 receptor antagonism impairs social novelty discrimination and novel object recognition in rats: a key role for the prefrontal cortex. Neuropsychopharmacology, 37, 770-786. doi:10.1038/npp.2011.254
  23. Weckowicz, T. E., Fedora, O., Mason, J., Radstaak, D., Bay, K. S., & Yonge, K. A. (1975). Effect of marijuana on divergent and convergent production cognitive tests. Journal Of Abnormal Psychology, 84(4), 386-398. doi:10.1037/0021-843X.84.4.386

8 thoughts on “Marijuana, Perception, and Cognition

  1. Hi!

    So in the paper it has a chart showing the binding. I’m not sure that it states it’s partial agonist in the paper. I can’t remember. BUT it’s on Wikipedia. Also partial agonists to my knowledge haven’t led to overdoses before.

    Kratom for example hasn’t caused death on its own supposedly. And it is a partial agonist.

    I’m pretty sure the paper DOES state this. Search on google scholar though. I wasn’t able to get access to some papers without paying so I may have used this paper instead.

    I’ll do some researching once I get time. But I’m pretty positive that it is indeed a partial agonist at mu.


    1. I can’t believe I was conflating the partial agonism to allosteric modulation. I’ve been sleep deprived and it’s been a while since I was looking into those though to be fair lol.

      Thank you so much for helping improve my post! It means a lot.

      I remember the allosteric from many ampakines. Or probably glycine is consider allosteric modulator for NMDA receptors too.


  2. I’m glad to see you investigating these topics on these levels; disappointingly few writers on cannabis and drugs in general get into the molecular specifics. A couple quibbles though: you say that anandamide is “the” endogenous ligand for CB receptors, ignoring 2-AG. Distinguishing the effects of AEA and 2-AG is important because, contrary to how this article reads, 2-AG and not AEA is the primary agonist at CB1 receptors, and AEA is only a relatively weak partial agonist. This is particularly important when discussing THC, because THC has a similar binding potential to AEA (both are much weaker than 2-AG); if this weren’t the case, downregulation and desensitization would be a much greater risk. Full agonists are much more effective at internalising the receptors; are you quite certain that THC does in fact internalise NMDAr complexes? I’m not certain about this, I suspect that it may just pull down on them without fully internalising them, leading to reduced efficiency of the channel without some of the more drastic consequences of full internalisation.

    Another point I’d like to make is that effects on D2 receptors themselves from THC are probably not as important as downstream effects on AKT, which both CB and D receptors (and their heteromers) influence. This isn’t really a criticism of your article but just something to look more into.

    I’d caution that the citation on dual neurotoxic/neuroprotective effects is extremely weak and unreliable, being studies of cultured neurons and rodents, neither of which behave anything remotely like human brains. In general the murine literature should be taken with a grain of salt.

    Lastly I’d encourage you to consider the effects on glutamate systems in context of anti-inflammatory effects and particularly at glial cells. Explaining all that might have been too much of an info dump for this article so I can understand if you chose not to include it but it’s very important to recognise that cannabinoid activity at astrocytes and microglia profoundly changes synaptic dynamics, in general reducing glutamate signalling and excitotoxicity, and also the release of other neurotransmitters (including dopamine, choline and GABA) as well.

    Anyway that’s just some thoughts. Not trying to come off as hyper critical or anything but these just felt like oversights to me.

    Liked by 1 person

    1. Thanks for commenting, this is useful. I will include the 2-AG part as an addition soon.

      In the resources, there is a paper that discusses the mechanics of NMDAr endocytosis. My hope for this was actually that THC acts as a very short NMDAr agonist through heteromer activity. The paper seemed to suggest it isn’t the case. I’m still unsure because of other patterns I’ve noticed.

      I’m not sure if NMDAr activity is ever measured at the peak of THC binding. It could be that it rapidly downregulates but very shortly acts as an agonist.

      The paper mentioned something about the timing of THC and NMDAr activation where THC lasts long enough for many NMDAr to internalize before THC is no longer having its effect on that particular cell. If I recall correctly, it went into vivid detail on this topic. Check the source for the NMDAr endocytosis claim. The paper was really cool. It was also vague at certain points if I remember correctly.

      I think that with tolerance, it is very difficult to get anything like an NMDAr agonist effect. But when I was new to the drug it seemed incredibly similar to NMDAr agonists I have tried. It gets more difficult to pin this question down as blocking NMDAr with no previous exposure may also do something similar. It is known that NMDAr inhibition can increase glutamate release, so at certain doses it can appear as some quasi-agonist.

      Agonists of NMDAr I have tried are theanine, IDRA-21, psychedelics, and certain terpenes I do not remember at the moment. They usually cause a much more vivid experience of reality. Clarity. Whereas antagonists tend to cause difficulty processing vision for me.

      I wonder if THCa could give NMDAr agonizing effect?

      Also, from my early experiences, after dosing cannabis, I would be psychotic mildly for a week. More numb. Pain resistant. Lots of dissociative style effects.

      The stuff you’ve mentioned about the both neurotoxicity and neuroprotective effects in cannabis, is what I hoped showed evidence for NMDAr agonist activity. But also the research itself did seem not so logically clear. I think they used multiple studies together that might have not had consistent factors for example. I do not remember tho. I think the authors may have concluded this effect too quickly without investigating other explanations.

      I also wonder, have you investigated agmatine? I have been researching this lately. It seems that there is evidence relating to schizophrenia progression, cannabis potentiation (by a huge amount, I’ve done this personally and developed hallucinations afterwards), and much more. It is an imidazoline receptor agonist that exists endogenously and these receptors have heteromers with NMDAr and also CB1.

      On agmatine alone, I’ve had psychedelic effects. Similar to NMDAr agonists and also psychotic like CB1 agonists can sometimes be. I remember the first few times it brought meditative clarity, visual improvement, and drastic alteration to internal thinking that is more significantly weird than THC. My thoughts began to go on their own and speak to me almost. I knew it was myself but I felt I could let my own mind speak and do the work while I just watch. I actually quite enjoyed this. Things only got annoying when I developed crawling hallucinations. These mostly are gone. Another issue was catatonic like effects. And also hyper social awareness that caused me to freeze up in public and I wouldn’t look away from one spot, on a wall for example. That effect is horrible too.

      I’m started to experiment with agmatine again but with more caution. I’m trying to recover from anhedonia/depressive symptoms.

      I am bipolar and Schizotypal by the way.

      Thanks again for replying! I’d love to continue conversing on this topic. I rarely get to talk with others who know the topic as well as you seem to.

      Liked by 1 person

      1. I highly doubt that THC directly agonises NMDAr at any concentration. It may indirectly lead to more NMDAr activity, for example through stimulating hormone release elsewhere in the body — in particular there’s an inverse-U relationship between THC dose and cortisol signalling. Have you looked into the effects of cortisol on glutamate signalling?

        The main agonists of NMDAr are glutamate and glycine, which are both amino acids and present in food. You can’t have soup without NMDAr agonists. But that doesn’t mean it has the sorts of effects you’re thinking of or looking for. Some theorists have considered glycine supplements as a possible way to counterbalance the NMDAr underactivity in schizophrenia, because too much glutamate is significantly harmful (activating other glutamate channels too not just NMDAr and so driving excitotoxicity) whereas glycine is pretty benign, boosting tissue repair. I haven’t looked into agmatine but I’ll do so this evening, thanks for the tip.

        I’m up for talking more as well. I have an ADHD diagnosis and know a lot of people with bipolar and schizotypy.


      2. I was diagnosed officially as ADHD as a child but have had numerous manic and depressive episodes with complete grandiosity and, in the past, delusions. I am currently doing quite well though.

        I have not looked into the cortisol factor.

        I also know that the anti GABA effect of THC would promote glutamate activity as well. There is also the fact that NMDA antagonists increase glutamate release at a certain threshold.


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