A man posted on Facebook describing an experience with the nootropic drug Noopept, reporting that his vision was rendered 2-dimensional by the drug, indicating some problem with depth processing. He also described colors and brightness being turned up very high. When directly contacted, the subject noted insomnia and an inability to ‘calm down’. This post is a dissection of this man’s, as well as another women’s, subjective experience. Then we explore how kindling may occur with the use of many nootropic drugs and how this relates to intelligence. These ideas may help explain HPPD, tinnitus, and other perceptual disturbances.
The text below is crude (English is not the person’s native language), but it is a direct copy of what the man reported:
helloo I need your help please I have a bad side effects from noopept I took it 10mg twice in week for a month and now i feel detached from my environment, everything has this weird 2d look to it, colors are overly saturated and everything looks so bright. best way I can describe it is if im looking at life through a tv with the color turned all the way up. I calmed down a little since it happened im just waiting it out, hoping it will get better. and no im no longer on it im hesitant to try anything that messes with my brain again in all honesty. what do you recommend do you think that this effect will go, any advice please. I stopped since a two weeks?Facebook Link
When further pressing for questions in private messaging, the Noopept user reported that the effects developed over the course of weeks. The man reported using 300mg Alpha GPC along with noopept. The user didn’t notice any drastic acute effects, though they compared the effect of Noopept to be possibly stimulating, or at least able to attenuate caffeine crashes. They also noted an induction of headache. The user dosed 10mg 2x a week for a month and the visual effects set in slowly over the course of this time. Once the user was startled, they ceased the drug. The subject also reported occasional use of CBD.
A Crash From Enlightment
Noopept seems to be an NMDA receptor (NMDAr) and AMPA receptor (AMPAr) enhancing drug, possibly as an agonist at NMDAr (1). These mechanisms are involved in learning and plasticity (2), as well as the main mechanisms for excitotoxicity (3). Visual effects have been reported with Noopept on the internet (83, 84, 85, 86). Case 83 notes that Noopept produced comparable visual effects to psychedelic drugs. Case 84 notes that using Noopept only a few times resulted in lasting HD vision (visual acuity). Case 85 found that Noopept potentiated LSD immensely. Case 86 found “extremely enhanced vision” at the same dose as our subject. If you read the comments of these cases, many other report their own experiences with the drug.
Why do visual effects occur with Noopept?
Stimulating NMDAr is known to enhance dynorphin release (4), possibly as a neuroprotective measure to fight against NMDAr-mediated excitotoxicity (5). Dynorphin may achieve neuroprotection via two separate mechanisms. First, dynorphin is capable of blocking the NMDAr (6). Second, dynorphin is the body’s main agonist neurotransmitter for the kappa opioid receptors (KORs), which further decrease glutamate activity (7). It is important to note that dynorphin can also be neurotoxic and enhance excitotoxic events as well (8).
Seizures and migraines sometimes induce the kind of effects this man experienced, which is often dubbed a seizure ‘aura’. Seizures and migraines involve high NMDAr activity (9). In the case of migraines, the man reported headaches, which may be related to enhanced NMDAr activity. In the case of seizures, dynorphin may release during high levels of glutamate signaling in an attempt to curb damage (10). This may lead to cortical spreading depression (11 also see Desummation), but also psychotic effects (10). This is notable because dynorphin binds to the same system (KOR) as the drug Salvia Divinorum (12) and even ketamine (13), both being strongly hallucinogenic drugs. The cortical spreading depression might simulate cortical damage, which has been shown to induce a loss of stereoscopic vision (79, 80). Ketamine also shuts down cortical activity during its’ dissociative effects (81). Psychedelic drugs also enhance glutamate activity (14) and induce effects similar to aura as well.
My speculation is that Noopept lead to enhanced NMDAr activity quite generally at first. Then as more pathways of neurons became potentiated through long-term potentiation (LTP), it became easier to activate the same mechanisms that release dynorphin. Part of the observed effects may resemble seizure auras, possibly due to overstimulation of some neurons by glutamate, while other neurons are increasingly suppressed by dynorphin, resembling dissociative effects. This may lead to a mix of symptoms that are proesthetic (opposite of anesthesia; sensory enhancing), such as inreased colors and brightness, while also producing dissociative anesthetic effects, such as the loss of depth processing. In this case, proesthesia can be described as additive experience while anesthesia is subtraction of experience.
The loss of depth processing has been observed before in the effects of drugs. Most notably, cannabis has produced this 2D vision effect in myself and many others across the internet (15, 16, 17), and in one of these cases the effect was brought on from a single large dose and lasted 6 months (16). Salvia has been reported to induce 2D experience (18), which several psychonauts I’ve talked to and myself have experienced as well. There is also a report of this occurring at the tail-end of a psilocybin trip (19). I suspect the effect would occur with NMDAr antagonists as well. Many of the people with the dissociative disorders known as derealization and depersonalization seem to have 2D vision as well (20, 21, 22). The case in 21 fits the symptoms described in the salvia study in 18, described as Alice in Wonderland Syndrome.
Seizure auras can induce some of these strange ‘hallucinogenic’ effects as well. During seizure aura, some report distortions of the senses, enhanced colors, brightness, and other strange effects. Psychedelics are also commonly reported to enhance colors and make things appear brighter. Of course, psychedelics also produce a whole host of distortions and perceptual changes that they are famous for.
A complication: the subject has disclosed that they also recently tried CBD, which could theoretically be contaminated by THC. The man did not suspect CBD, which may suggest that the effect isn’t originating from the CBD product. The subject did not report any strong acute effects from CBD, only a light sleepiness. It is possible that CBD is upregulating sensitivity to endogenous THC like mechanisms since CBD antagonizes the effects of THC (23). CBD also seems to be a 5HT2a receptor agonist (24), which is the primary target for serotonin psychedelic drugs. There are reports of visual hallucinations (25) and both improvement and worsening of visual disturbances with CBD use on reddit (26). It is possible that Noopept combined with CBD resulted in the subject’s response.
If this notion of high glutamate triggering anti-glutamate mechanisms like dynorphin is true, then it would suggest that glutamate stimulating drugs could produce dissociative effects consequentially of their excitatory effects. The glutamate agonizing drugs may simulate seizures on some level to produce aura-like effects and then the dissociative/psychotic response may come after inhibitory anti-epileptic mechanisms set in. Depending on whether glutamate activity is decreased or increased, features of consciousness may be diminished or exaggerated. That includes the sizes of objects, distance, lack detail versus high detail, brightness, colors, and so on.
Case 2: Theanine Mania
Someone else recently got in touch with me due to the rise of some problematic symptoms after they dosed Melatonin gummies. They dosed quite a lot, 62.5mg in one night, and then 62.5mg the next night. The first night she experienced waking multiple times that night and finally waking for the day at 4:30 AM. There was a prominent headache, intense anxiety, and a crushing sensation in her chest. She noted feeling depressed and suicidal that day.
Later that night she dosed the rest of the melatonin and finally was able to sleep through the night. Upon waking, she noticed high energy, a rush of ideas, and she couldn’t sit still. A strange sensation of her limbs being pressed or torn apart was reported, though she found this hard to describe. That night she slept around 6 hours. Upon waking, a new symptom emerged: auditory hallucinations. This led her to a crying spell and she went jogging in an attempt to fix it. Her mood began cycling from depression to mania for the rest of the day. She experienced rage and self-harming. She also reported not eating much during this phase. Problems like this have lasted 6 days as of yet.
My first thoughts on this were that circadian rhythm genes are associated with bipolar disorder (76, 77) and that sleep deprivation induces mania (78). After finding out that the melatonin was in gummy form, I realized that it is very possible the gummies had L-Theanine in them. I wondered this because I’ve experienced mania and even withdrawal-induced panic disorder and hallucinations from using L-Theanine myself. Her description resonated with mine quite a lot. Both seemed like benzodiazepine-type withdrawals. When I asked about whether the gummies contained L-Theanine, she quickly replied in confirmation. She reported consuming 2.5 grams of L-Theanine across both days she took the gummies.
L-Theanine is another nootropic drug that enhances NMDAr activity (54) and LTP (57). It also has mild anxiolytic effects like the benzodiazepines, seemingly by enhancing GABA activity (82). L-Theanine withdrawals have been reported online by users (48, 49). So have strange ‘hallucinogenic’ effects (50, 51, 52, 53). Theanine is also reported to induce headaches (including in this very case) (55), which fits with the NMDAr mechanism and migraine link. Theanine also has been associated to a case of mania (56), meanwhile it is reported to treat the positive and negative symptoms of schizophrenia (58).
The individual started to recover after increasing calorie intake. Prior to this, the participant’s anxiety and manic symptoms were making eating difficult. When I experienced this strange reaction to theanine, I also noticed the same thing, that I was not eating sufficiently. Once I increased intake of food to 1800 calories, I became sleepier generally and started to recover. So I recommended this and it seemed to work. Likely it speeds up recovery if you maintain sufficient calories and sleep well during these kind of episodes. Without doing these, manic-like effects may persist or progress.
There is a possible element of similarity to the effects of kindling in this subject. Kindling is when sensitivity to excitatory transmission increases in response to excitatory transmission. It is usually talked about in relation to repeated withdrawal of sedative benzodiazepine drugs or when repeated sub-convulsant application of electricity results in convulsant effects and sensitivity (87). Here I’m using the term kindling to mean any push towards the kindled state, even if it hasn’t reached epileptic outcome yet. Kindling-type effects have been implicated in the development of seizures (27), panic disorder (28), and mania (29, 30). The process of kindling seems to involve an increase of AMPAr (31, 96) and NMDAr activity (94, 95, 96), [although kindling is possible with NMDAr blockade, such as with electricity (32)], which may explain what is observed in the subject after using Noopept. LTP and kindling seem to share some mechanisms in common (32, 95).
Benzodiazepine withdrawals are infamous for their disastrous effects. These drugs are sedatives and when the drug is stopped, often times extreme excitatory effects occur. All of the symptoms these individuals are facing are associated to the withdrawal syndrome of benzos. Mania, panic, seizures, and even psychosis are all possible effects of benzodiazepine withdrawals. Those experiencing such withdrawal states often report staying awake for days at a time, which fits with the subject’s reported trouble sleeping and calming down.
It seems possible that nootropic drugs, especially ones that increase glutamate activity, kindle us.
The effect of kindling on the senses, perception, and cognition might be like tinnitus, the effect of illusory ringing sound in the ears. Tinnitus is actually associated to both NMDAr agonism and dynorphin activity (88). NMDAr blockers also reduce tinnitus (89). Kindling has been compared to auditory insults that result in tinnitus (87). The author’s of that study suggest that desynchronizing neural activity could reverse the kindling, as they call it “anti-kindling”. HPPD (hallucinogen persisting perception disorder) could be an effect of kindling, like a tinnitus of something like pattern recognition, of spatial distance, of various specific elements of perception. Perhaps some HPPD effects are actually the opposite of kindling, an anti-kindling. It may even be a combination of kindling and anti-kindling.
Intelligence and Supersensitivity
Since LTP and kindling seem to share an overlap of mechanisms, might they also both be associated to intelligence? Disorders that are involved with a kind of neural supersensitivity often have associations with intelligence and cognitive function. For example, bipolar disorder (33, 34, 35, 36, 37, 38) and autism (39) are associated to intelligence and both involve problems with excess excitatory signaling (40, 41). There is even a model that has explored this idea that supersensitivity is linked to intelligence (42). This study showed that 27% of the above 132 IQ participants had mood disorders (such as bipolar disorder) and 20% had anxiety disorders. The association of autism and intelligence is highly theoretical and should be approached cautiously. The autistic spectrum seems very broad and sometimes vague. Interestingly, the autism study (40) brings up the association of autism and epilepsy.
GABA enhancing drugs are typically sedative drugs. GABA blocking drugs have been explored as cognitive enhancers (43, 47). Low GABA function is observed in autism (44, 45) and bipolar disorder (41). The withdrawals of GABA potentiates LTP (46). Though, the common nootropics used in today’s biohacking culture are more like noopept: glutamate enhancing drugs and sometimes acetylcholine enhancing drugs. GABA antagonists will probably frequently induce negative reactions like panic so they are not favored. It is also possible that GABA’s role in learning is far more nuanced than this, as both inhibitory and excitatory signaling seems to be involved (59).
Bipolar disorder may be a condition in which individuals cycle between states of ‘higher consciousness’ to lower zombie-like states of consciousness, ie between mania to depressive or psychotic states. Dynorphin has been associated to depression (60) and psychosis (61, 62, 63), meanwhile dynorphin agonists are being explored to reduce mania (64, 65) and have been shown to do so without their usual psychotomimetic effects in manic patients (64). This bipolar idea even fits with epilepsy, as the moments or sometimes days before seizure, individuals will experience stimulating effects, while the post-seizure state often involves depression, fatigue, amnesia and even psychosis.
Dynorphin has also been studied in various contexts that suggest dynorphin decreases cognitive function. Dynorphin mediates impaired learning and memory that emerges from stress (66), alcohol consumption (67), aging and possibly Alzheimer’s disease (68, 69, 70). Dynorphin also impairs LTP in the hippocampus (71).
Psychosis may be when stimulation goes too far and the dissociative anesthetic compensatory mechanisms step in to curb potential excitotoxic events in the brain. Seizures have been known to produce post-seizure psychotic episodes (10), supporting this model. Reduced GABA functioning is also associated to schizophrenia (41). Schizophrenia is associated to low IQ (75), as opposed to bipolar disorder. This idea of dissociation would also help explain the relationship of bipolar disorder and schizophrenia (41), where both phenotypes involve supersensitivity initially but then dissociative compensatory mechanisms set in with psychotic states. Schizophrenia may often be a state of dissociative subsensitivity.
Whether or not kindling or maybe even anti-kindling is useful in enhancing cognition probably depends highly on what the baseline is. The outcome may be highly variable and unpredictable (as of yet). There is research showing that kindling is bad for cognition in rats (90), though here it is a kindling than fully produces epilepsy. As previously mentioned, seizures induce dynorphin activity as an endogenous anti-convulsant. I suspect you could kindle someone and stop before epilepsy develops and the outcome may be hypomania and boosted cognition. The mechanism of electroconvulsive therapy (ECT) seems to paradoxically be anti-kindling (91). ECT is also found to decrease cognitive abilities immediately afterward (92).
Since dynorphin reduces plasticity (71), it may prevent recovery from the visually strange state. NMDAr blockade has been observed to prevent LTP from occurring, but it has also been shown to maintain current LTP (72). This means the effect of NMDAr blockade doesn’t turn LTP off, but instead it turns off the ability for the state to change.
I strongly suspect that serotonin psychedelic drugs bypass this problem by attenuating dynorphin (73), and inducing a potent plasticity effect (74). For some people, they can find themselves experiencing a different baseline perceptual state long after the psychedelic drug has worn off. For those stuck in some strange state, they may be able to ‘find their way back’ somehow, although this is reductionist. It is possible that psychedelics frequently leave people in a state that resembles one from their youth, by turning back the accumulation of changes that have occurred due to chronic caffeine use, social media addiction, alcohol use, or traumatic events that have sculpted the person’s adult state. My most read article, The Phoenix Effect, has explored that topic in depth if you are curious to learn more.
There is also evidence of broadband cortical desynchronization being key to the psychedelic state (93), which might suggest potential reversing of kindling. In The Phoenix Effect, I argue that psychedelics have a reverse learning effect, which might also tie into the kindling, LTP, and other ideas presented here.
There is actually some research that suggests LSD and other psychedelics may be able to treat migraines (97). One study noted that pentazocine, a KOR agonist like dynorphin, enhances the migraine scotoma, which is a common visual migraine aura (99). This study found that injections of naloxone, which blocks KOR but also MOR, was able to suppress the scotoma. On the other hand, a 15-year old girl that took LSD experienced migraine with recurrent cortical blindness (98). The cortical blindness developed in a matter of seconds and persisted for 48 hours. The patient experienced 3 other episodes of this blindness in the next few months. This suggests psychedelics could both help and hurt in these complex perceptual and cognitive issues such as HPPD, aura, and migraines.
There is no guarantee that treating this with psychedelics would work. Theoretically, psychedelics could also bring someone to a state like that. Perhaps psychedelics with specific combinations of other drugs could help with programming in the future. I have some suspicions of combinations that will be fruitful, though I won’t talk about that just yet.
I also did not recommend either of these individuals to try psychedelics. Instead, I simply reassured them that these effects will likely pass and that many drugs of convergent mechanisms have been observed to produce the same kind of effects they are experiencing currently and, of course, I told them they should talk to their doctors. The Noopept man already reported that some of the effects have faded.
. . .
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1. Vorobyov, V., Kaptsov, V., Kovalev, G., & Sengpiel, F. (2011). Effects of nootropics on the EEG in conscious rats and their modification by glutamatergic inhibitors. Brain Research Bulletin, 85(3-4), 123-132.
2. Lüscher, C., & Malenka, R. C. (2012). NMDA receptor-dependent long-term potentiation and long-term depression (LTP/LTD). Cold Spring Harbor perspectives in biology, 4(6), a005710.
3. Parsons, M. P., & Raymond, L. A. (2014). Extrasynaptic NMDA receptor involvement in central nervous system disorders. Neuron, 82(2), 279-293.
4. Hanson, G. R., Singh, N., Merchant, K., Johnson, M., & Gibb, J. W. (1995). The role of NMDA receptor systems in neuropeptide responses to stimulants of abuse. Drug and alcohol dependence, 37(2), 107-110.
5. Kanemitsu, Y., Hosoi, M., Zhu, P. J., Weight, F. F., Peoples, R. W., McLaughlin, J. S., & Zhang, L. (2003). Dynorphin A inhibits NMDA receptors through a pH-dependent mechanism. Molecular and Cellular Neuroscience, 24(3), 525-537.
6. Chen, L., Gu, Y., & Huang, L. Y. (1995). The opioid peptide dynorphin directly blocks NMDA receptor channels in the rat. The Journal of physiology, 482(3), 575-581.
7. Wagner, J. J., Terman, G. W., & Chavkin, C. (1993). Endogenous dynorphins inhibit excitatory neurotransmission and block LTP induction in the hippocampus. Nature, 363(6428), 451-454.
8. Lai, J., Ossipov, M. H., Vanderah, T. W., Malan, T. P., & Porreca, F. (2001). Neuropathic pain: the paradox of dynorphin. Molecular interventions, 1(3), 160.
9. Bausch, S. B., He, S., & Dong, Y. (2010). Inverse relationship between seizure expression and extrasynaptic NMDAR function following chronic NMDAR inhibition. Epilepsia, 51, 102-105.
10. Bortolato, M., & Solbrig, M. V. (2007). The price of seizure control: dynorphins in interictal and postictal psychosis. Psychiatry research, 151(1-2), 139-143.
11. Rogawski, M. A. (2008). Common pathophysiologic mechanisms in migraine and epilepsy. Archives of neurology, 65(6), 709-714.
12. Maqueda, A. E., Valle, M., Addy, P. H., Antonijoan, R. M., Puntes, M., Coimbra, J., … & Barker, S. (2015). Salvinorin-A induces intense dissociative effects, blocking external sensory perception and modulating interoception and sense of body ownership in humans. International Journal of Neuropsychopharmacology, 18(12), pyv065.
13. Nemeth, C. L., Paine, T. A., Rittiner, J. E., Béguin, C., Carroll, F. I., Roth, B. L., … & Carlezon, W. A. (2010). Role of kappa-opioid receptors in the effects of salvinorin A and ketamine on attention in rats. Psychopharmacology, 210(2), 263-274.
14. Moreno, J. L., Holloway, T., Albizu, L., Sealfon, S. C., & González-Maeso, J. (2011). Metabotropic glutamate mGlu2 receptor is necessary for the pharmacological and behavioral effects induced by hallucinogenic 5-HT2A receptor agonists. Neuroscience letters, 493(3), 76-79.
23. Bhattacharyya, S., Morrison, P. D., Fusar-Poli, P., Martin-Santos, R., Borgwardt, S., Winton-Brown, T., … & Mehta, M. A. (2010). Opposite effects of Δ-9-tetrahydrocannabinol and cannabidiol on human brain function and psychopathology. Neuropsychopharmacology, 35(3), 764-774.
24. de Paula Soares, V., Campos, A. C., de Bortoli, V. C., Zangrossi Jr, H., Guimarães, F. S., & Zuardi, A. W. (2010). Intra-dorsal periaqueductal gray administration of cannabidiol blocks panic-like response by activating 5-HT1A receptors. Behavioural brain research, 213(2), 225-229.
27. Löscher, W. (1998). Pharmacology of glutamate receptor antagonists in the kindling model of epilepsy. Progress in neurobiology, 54(6), 721-741.
28. Medel-Matus, J. S., Shin, D., Sankar, R., & Mazarati, A. (2017). Kindling epileptogenesis and panic-like behavior: their bidirectional connection and contribution to epilepsy-associated depression. Epilepsy & Behavior, 77, 33-38.
29. Subramanian, K., Sarkar, S., Kattimani, S., Rajkumar, R. P., & Penchilaiya, V. (2017). Role of stressful life events and kindling in bipolar disorder: Converging evidence from a mania-predominant illness course. Psychiatry Research, 258, 434-437.
30. Abulseoud, O. A., Camsari, U. M., Ruby, C. L., Mohamed, K., Gawad, N. M. A., Kasasbeh, A., … & Choi, D. S. (2014). Lateral hypothalamic kindling induces manic-like behavior in rats: a novel animal model. International journal of bipolar disorders, 2(1), 1-12.
31. Kamphuis, W., De Rijk, T. C., Talamini, L. M., & Lopes da Silva, F. H. (1994). Rat hippocampal kindling induces changes in the glutamate receptor mRNA expression patterns in dentate granule neurons. European Journal of Neuroscience, 6(7), 1119-1127.
32. Cain, D. P., Boon, F., & Hargreaves, E. L. (1992). Evidence for different neurochemical contributions to long-term potentiation and to kindling and kindling-induced potentiation: role of NMDA and urethane-sensitive mechanisms. Experimental Neurology, 116(3), 330-338.
33. Gale, C. R., Batty, G. D., McIntosh, A. M., Porteous, D. J., Deary, I. J., & Rasmussen, F. (2013). Is bipolar disorder more common in highly intelligent people? A cohort study of a million men. Molecular psychiatry, 18(2), 190-194.
34. Smith, D. J., Anderson, J., Zammit, S., Meyer, T. D., Pell, J. P., & Mackay, D. (2015). Childhood IQ and risk of bipolar disorder in adulthood: prospective birth cohort study. BJPsych open, 1(1), 74-80.
35. Tiihonen, J., Haukka, J., Henriksson, M., Cannon, M., Kieseppä, T., Laaksonen, I., … & Lönnqvist, J. (2005). Premorbid intellectual functioning in bipolar disorder and schizophrenia: results from a cohort study of male conscripts. American Journal of Psychiatry, 162(10), 1904-1910.
36. MacCabe, J. H., Lambe, M. P., Cnattingius, S., Sham, P. C., David, A. S., Reichenberg, A., … & Hultman, C. M. (2010). Excellent school performance at age 16 and risk of adult bipolar disorder: national cohort study. The British Journal of Psychiatry, 196(2), 109-115.
37. Shen, S. Q., Kim-Han, J. S., Cheng, L., Xu, D., Gokcumen, O., Hughes, A. E., … & Corbo, J. C. (2019). A candidate causal variant underlying both higher intelligence and increased risk of bipolar disorder. bioRxiv, 580258.
38. Smeland, O. B., Bahrami, S., Frei, O., Shadrin, A., O’Connell, K., Savage, J., … & Ueland, T. (2020). Genome-wide analysis reveals extensive genetic overlap between schizophrenia, bipolar disorder, and intelligence. Molecular psychiatry, 25(4), 844-853.
39. Crespi, B. J. (2016). Autism as a disorder of high intelligence. Frontiers in neuroscience, 10, 300.
40. Nelson, S. B., & Valakh, V. (2015). Excitatory/inhibitory balance and circuit homeostasis in autism spectrum disorders. Neuron, 87(4), 684-698.
41. Benes, F. M., & Berretta, S. (2001). GABAergic interneurons: implications for understanding schizophrenia and bipolar disorder. Neuropsychopharmacology, 25(1), 1-27.
42. Karpinski, R. I., Kolb, A. M. K., Tetreault, N. A., & Borowski, T. B. (2018). High intelligence: A risk factor for psychological and physiological overexcitabilities. Intelligence, 66, 8-23.
43. Chebib, M., Hinton, T., Schmid, K. L., Brinkworth, D., Qian, H., Matos, S., … & Hanrahan, J. R. (2009). Novel, potent, and selective GABAC antagonists inhibit myopia development and facilitate learning and memory. Journal of Pharmacology and Experimental Therapeutics, 328(2), 448-457.
44. Chao, H. T., Chen, H., Samaco, R. C., Xue, M., Chahrour, M., Yoo, J., … & Ekker, M. (2010). Dysfunction in GABA signalling mediates autism-like stereotypies and Rett syndrome phenotypes. Nature, 468(7321), 263-269.
45. Fatemi, S. H., Reutiman, T. J., Folsom, T. D., & Thuras, P. D. (2009). GABA A receptor downregulation in brains of subjects with autism. Journal of autism and developmental disorders, 39(2), 223.
46. Casasola, C., Montiel, T., Calixto, E., & Brailowsky, S. (2004). Hyperexcitability induced by GABA withdrawal facilitates hippocampal long-term potentiation. Neuroscience, 126(1), 163-171.
47. Yonkov, D. I., & Georgiev, V. P. (1985). Memory effects of GABA-ergic antagonists in rats trained with two-way active avoidance tasks. Acta physiologica et pharmacologica Bulgarica, 11(2), 44-49.
54. Sebih, F., Rousset, M., Bellahouel, S., Rolland, M., de Jesus Ferreira, M. C., Guiramand, J., … & Tassou, A. (2017). Characterization of l-theanine excitatory actions on hippocampal neurons: Toward the generation of novel N-Methyl-d-aspartate receptor modulators based on its backbone. ACS Chemical Neuroscience, 8(8), 1724-1734.
55. Haskell, C. F., Kennedy, D. O., Milne, A. L., Wesnes, K. A., & Scholey, A. B. (2008). The effects of L-theanine, caffeine and their combination on cognition and mood. Biological psychology, 77(2), 113-122.
56. Troyer, Emily & Marvin, Robert. (2016). A case report of over-the-counter L-theanine supplementation potentiating a manic episode in a patient with bipolar I disorder: Is L-theanine an antidepressant?.
57. Takeda, A., Tamano, H., Suzuki, M., Sakamoto, K., Oku, N., & Yokogoshi, H. (2012). Unique induction of CA1 LTP components after intake of theanine, an amino acid in tea leaves and its effect on stress response. Cellular and molecular neurobiology, 32(1), 41-48.
58. Ritsner, M. S., Miodownik, C., Ratner, Y., Shleifer, T., Mar, M., Pintov, L., & Lerner, V. (2010). L-theanine relieves positive, activation, and anxiety symptoms in patients with schizophrenia and schizoaffective disorder: an 8-week, randomized, double-blind, placebo-controlled, 2-center study. The Journal of clinical psychiatry, 72(1), 34-42.
59. Najafi, F., Elsayed, G. F., Cao, R., Pnevmatikakis, E., Latham, P. E., Cunningham, J. P., & Churchland, A. K. (2020). Excitatory and inhibitory subnetworks are equally selective during decision-making and emerge simultaneously during learning. Neuron, 105(1), 165-179.
60. Knoll, A. T., & Carlezon Jr, W. A. (2010). Dynorphin, stress, and depression. Brain research, 1314, 56-73.
61. Heikkilä, L., Rimón, R., & Ternius, L. (1990). Dynorphin A and substance P in the cerebrospinal fluid of schizophrenic patients. Psychiatry research, 34(3), 229-236.
62. Moustafa, S. R., Al-Rawi, K. F., Al-Dujaili, A. H., Supasitthumrong, T., Al-Hakeim, H. K., & Maes, M. (2020). The Endogenous Opioid System in Schizophrenia and Treatment Resistant Schizophrenia: Increased Plasma Endomorphin 2, and κ and μ Opioid Receptors are Associated with Interleukin-6.
63. Clark, S. D., & Abi-Dargham, A. (2019). The role of dynorphin and the kappa opioid receptor in the symptomatology of schizophrenia: A review of the evidence. Biological psychiatry, 86(7), 502-511.
64. Cohen, B. M., & Murphy, B. (2008). The effects of pentazocine, a kappa agonist, in patients with mania. International Journal of Neuropsychopharmacology, 11(2), 243-247.
65. Zarate Jr, C. A., & Manji, H. K. (2008). Bipolar disorder: candidate drug targets. Mount Sinai Journal of Medicine: A Journal of Translational and Personalized Medicine: A Journal of Translational and Personalized Medicine, 75(3), 226-247.
66. Carey, A. N., Lyons, A. M., Shay, C. F., Dunton, O., & McLaughlin, J. P. (2009). Endogenous κ opioid activation mediates stress-induced deficits in learning and memory. Journal of Neuroscience, 29(13), 4293-4300.
67. Kuzmin, A., Chefer, V., Bazov, I., Meis, J., Ögren, S. O., Shippenberg, T., & Bakalkin, G. (2013). Upregulated dynorphin opioid peptides mediate alcohol-induced learning and memory impairment. Translational psychiatry, 3(10), e310-e310.
68. Ménard, C., Tse, Y. C., Cavanagh, C., Chabot, J. G., Herzog, H., Schwarzer, C., … & Quirion, R. (2013). Knockdown of prodynorphin gene prevents cognitive decline, reduces anxiety, and rescues loss of group 1 metabotropic glutamate receptor function in aging. Journal of Neuroscience, 33(31), 12792-12804.
69. Jiang, H. K., Owyang, V. V., Hong, J. S., & Gallagher, M. (1989). Elevated dynorphin in the hippocampal formation of aged rats: relation to cognitive impairment on a spatial learning task. Proceedings of the National Academy of Sciences, 86(8), 2948-2951.
70. Ménard, C., Herzog, H., Schwarzer, C., & Quirion, R. (2014). Possible role of dynorphins in Alzheimer’s disease and age-related cognitive deficits. Neurodegenerative Diseases, 13(2-3), 82-85.
71. Wagner, J. J., Terman, G. W., & Chavkin, C. (1993). Endogenous dynorphins inhibit excitatory neurotransmission and block LTP induction in the hippocampus. Nature, 363(6428), 451-454.
72. Villarreal, D. M., Do, V., Haddad, E., & Derrick, B. E. (2002). NMDA receptor antagonists sustain LTP and spatial memory: active processes mediate LTP decay. Nature neuroscience, 5(1), 48-52.
73. Sakloth, F., Leggett, E., Moerke, M. J., Townsend, E. A., Banks, M. L., & Negus, S. S. (2019). Effects of acute and repeated treatment with serotonin 5-HT2A receptor agonist hallucinogens on intracranial self-stimulation in rats. Experimental and clinical psychopharmacology, 27(3), 215.
74. Ly, C., Greb, A. C., Cameron, L. P., Wong, J. M., Barragan, E. V., Wilson, P. C., … & Duim, W. C. (2018). Psychedelics promote structural and functional neural plasticity. Cell reports, 23(11), 3170-3182.
75. David, A. S., Malmberg, A., Brandt, L., Allebeck, P., & Lewis, G. (1997). IQ and risk for schizophrenia: a population-based cohort study. Psychological medicine, 27(6), 1311-1323.
76. Murray, G., & Harvey, A. (2010). Circadian rhythms and sleep in bipolar disorder. Bipolar disorders, 12(5), 459-472.
77. Mansour, H. A., Monk, T. H., & Nimgaonkar, V. L. (2005). Circadian genes and bipolar disorder. Annals of medicine, 37(3), 196-205.
78. Wehr, T. A., Sack, D. A., & Rosenthal, N. E. (1987). Sleep reduction as a final common pathway in the genesis of mania. The American journal of psychiatry.
79. Bridge, H. (2016). Effects of cortical damage on binocular depth perception. Philosophical Transactions of the Royal Society B: Biological Sciences, 371(1697), 20150254.
80. Holmes, G., & Horrax, G. (1919). Disturbances of spatial orientation and visual attention, with loss of stereoscopic vision. Archives of Neurology & Psychiatry, 1(4), 385-407.
81. Nicol, A. U., & Morton, A. J. (2020). Characteristic patterns of EEG oscillations in sheep (Ovis aries) induced by ketamine may explain the psychotropic effects seen in humans. Scientific Reports, 10(1), 1-10.
82. Nathan, P. J., Lu, K., Gray, M., & Oliver, C. (2006). The neuropharmacology of L-theanine (N-ethyl-L-glutamine) a possible neuroprotective and cognitive enhancing agent. Journal of Herbal Pharmacotherapy, 6(2), 21-30.
87. Eggermont, J. J., & Tass, P. A. (2015). Maladaptive neural synchrony in tinnitus: origin and restoration. Frontiers in neurology, 6, 29.
88. Sahley, T. L., Hammonds, M. D., & Musiek, F. E. (2013). Endogenous dynorphins, glutamate and N-methyl-d-aspartate (NMDA) receptors may participate in a stress-mediated Type-I auditory neural exacerbation of tinnitus. Brain research, 1499, 80-108.
89. Brozoski, T. J., Wisner, K. W., Odintsov, B., & Bauer, C. A. (2013). Local NMDA receptor blockade attenuates chronic tinnitus and associated brain activity in an animal model. PLoS One, 8(10), e77674.
90. Holmes, G. L., Chronopoulos, A., Stafstrom, C. E., Mikati, M. A., Thurber, S. J., Hyde, P. A., & Thompson, J. L. (1993). Effects of kindling on subsequent learning, memory, behavior, and seizure susceptibility. Developmental brain research, 73(1), 71-77.
91. Post, R. M., Putnam, F., Contel, N. R., & Goldman, B. (1984). Electroconvulsive seizures inhibit amygdala kindling: implications for mechanisms of action in affective illness. Epilepsia, 25(2), 234-239.
92. Frasca, T. A., Iodice, A., & McCall, W. V. (2003). The relationship between changes in learning and memory after right unilateral electroconvulsive therapy. The journal of ECT, 19(3), 148-150.
93. Muthukumaraswamy, S. D., Carhart-Harris, R. L., Moran, R. J., Brookes, M. J., Williams, T. M., Errtizoe, D., … & Feilding, A. (2013). Broadband cortical desynchronization underlies the human psychedelic state. Journal of Neuroscience, 33(38), 15171-15183.
94. Morimoto, K. (1989). Seizure-triggering mechanisms in the kindling model of epilepsy: collapse of GABA-mediated inhibition and activation of NMDA receptors. Neuroscience & Biobehavioral Reviews, 13(4), 253-260.
95. Yeh, G. C., Bonhaus, D. W., Nadler, J. V., & McNamara, J. O. (1989). N-methyl-D-aspartate receptor plasticity in kindling: quantitative and qualitative alterations in the N-methyl-D-aspartate receptor-channel complex. Proceedings of the National Academy of Sciences, 86(20), 8157-8160.
96. Kumar, A., Nidhi, S., Manveen, B., & Sumitra, S. (2016). A review on chemical induced kindling models of epilepsy. J Vet Med Res, 3, 1-6.
97. Andersson, M., Persson, M., & Kjellgren, A. (2017). Psychoactive substances as a last resort—a qualitative study of self-treatment of migraine and cluster headaches. Harm Reduction Journal, 14(1), 60.
98. Bernhard, M. K., & Ulrich, K. (2009). Recurrent cortical blindness after LSD-intake. Fortschritte der Neurologie-Psychiatrie, 77(2), 102.
99. Sicuteri, F., Boccuni, M., Fanciullacci, M., & Gatto, G. (1983). Naloxone effectiveness on spontaneous and induced perceptive disorders in migraine. Headache: The Journal of Head and Face Pain, 23(4), 179-183.