There are two serotonin receptors that seem to play a prominent role in the emotional effects of psychedelics. These two receptors, 5HT2a and 5HT2c, may be able to explain good versus bad trips, at least this is what the research suggests, revealing many contrary patterns throughout the literature. These receptors are both involved in anxiety, aversion, endogenous opioid activity, and dopamine activity. This essay is an exploration of an early hypothesis that these two receptors have differential effects on valence with a special focus on psychedelics and the opioid system. Next we explore the very Pavlovian purpose of valence and how these receptors might be implicated in learning.
Researchers have narrowed down the anti-aversive effects of the psychedelic drug known as DOI to 5HT2a and 5HT1a receptors (1). Both of them seem to be necessary for anti-aversion and these effects seem to occur in the dorsal periaqueductal grey (DPAG). A similar study on the psychedelic drug MDMA found anti-aversive effects mediated by the 5HT2a receptor as well (2). CBD’s anti-aversive effects were also found to involve 5HT2a and 5HT1a receptors (3). 5HT1a and 5HT2a interact with each other and even depend on each other for their effects (4, 5, 7, 8) . One study suggested that activation of either of these receptors reduces anxiety but not panic (6).
The 5HT2a receptor agonist LSD was found to inhibit the depressive effects of KOR agonists (9), such as the endogenous opioid peptide dynorphin. This peptide is involved in pain (10) and stress-induced aversion (11, 12). Dynorphin is opposite of the kind of opioids we typically imagine, rather than euphoric, it is dysphoric (13). It also enhances fear circuitry in the amygdala (14), a region which is associated with the DPAG in fear responses (15). While serotonin enhancing drugs like SSRIs diminish reward and aversion processing (16), dynorphin enhances reward and aversion processing, which depends on the reuptake of serotonin via a pathway known as mitogen activated protein kinase (MAPK) (17). In this sense, serotonin (at 5HT2ar) and dynorphin’s effects oppose each other through their mechanisms, producing opposite effects on pleasurable and aversive experiences, serotonin (at 5HT2ar) diminishing the sensitivity to valence while dynorphin may enhance sensitivity to valence.
While dynorphin enhances fear-circuitry in the amygdala (18), LSD inhibits fear-recognition in the aymgdala (19). The long-lasting anti-depressant effects of psilocybin were found to correlate to the degree of blood flow reduction to the amygdala during the experience (20). Dynorphin and psychedelics also both relate to fear extinction. During fear extinction, KOR mRNA is found to be dramatically downregulated while fear conditioning shows a dramatic upregulation of KOR mRNA. Blocking dynorphin/KOR was found to block conditioned fear (21). DMT microdosing in mice was found to enhance fear extinction (22). Low doses of psilocybin were found to increase neurogenesis and enhance fear extinction, while high doses appear to do the opposite (23). There are studies on psychedelics (MDMA) exploring fear extinction in relevance to PTSD (24), which is a disorder that involves altered fear extinction (25).
This opposing interaction relationship between dynorphin and serotonin seems to occur at p38 MAPK, KOR signaling induces the serotonin transporter (SERT) to reuptake serotonin, producing a hypo-serotonergic state (26). This induction of SERT was necessary for dynorphin to produce some of its effects (27) which may be due to the anti-dynorphin/KOR effects of 5HT2a receptors. Blocking SERT is known to produce stress resilience (28). The removal of p38 MAPK on serotonergic neurons also produces stress resilience (29), likely by disrupting dynorphin and the reuptake of serotonin. Blocking dynorphin directly leads to stress resilience as well (13). Serotonin itself is known to downregulate SERT (30), so when dynorphin levels are high its’ induction of SERT will lower extracellular serotonin levels and prevent SERT from downregulating. This should be expected to perpetuate a stressed tone, until something else either decreases the stressful trigger or increase serotonin levels and disrupt the low serotonin tone. Repeated doses of the KOR agonist, Salvia, are thought to upregulate SERT (31). Ultimately, a pattern of low serotonin activity and high dynorphin activity seems to be consistent. It may be that disruption of KOR mediated effects invoked by psychedelics stops this loop in which SERT is induced, thus allowing serotonin to accumulate again and restore a resilient state of mind.
Much of this argument refers to impacts of these serotonin receptors on the opioid system. The opioid peptides may signal valence. Mu opioid receptor (MOR) agonists are reportedly euphoric. Meanwhile, KOR agonists are reportedly dysphoric and psychotic. The endogenous MOR agonists are endorphins and enkephalins, while dynorphin is the endogenous KOR agonist. Endorphins and enkephalins are essentially opposite to dynorphin in many ways (32). The MOR agonists stimulate dopamine and glutamate activity while the KOR agonists diminish dopamine and glutamate activity, for example.
5HT2a receptors interact with MORs (33), but it isn’t clear how. One study noticed that the 5HT2a receptor antagonist ketanserin could treat pain by raising the threshold needed for pain signaling (34). This was naloxone reversible, suggesting 5HT2a receptor modulation of opioids. An issue here is that antihistamines also potentiate opioid activity (35) and ketanserin has equal affinity for histamine receptor and 5HT2a receptor antagonism. It could be that the SSRI-induced reduction of pleasure and aversion processing is mediated by the 5HT2a receptor. In this sense, the 5HT2a receptor itself may usually reduce valence range. On the other hand, another study found that 5HT2a and opioid receptor antagonists prevented painkiller effects induced by stimulating the ventrolateral periaqueductal gray (36), suggesting that both mechanisms could be involved in pain relieving mechanisms. While 5HT2a receptor stimulation might be anti-aversive, it isn’t clear whether it promotes pleasure or positive feelings, it may also induce neutral feelings.
While these patterns suggest that serotonin may be very anti-aversive in most cases, there is one contradiction.
5HT2c receptors show exactly the opposite pattern of correlations as 5HT2ars. This receptor is shown to increase anxiety (37). Dynorphin mRNA is shown to pool most heavily in highly 5HT2c receptor dominant neurons, meanwhile it is lowest in 5HT2a receptor dominant neurons (38). While 5HT2a receptor activity helps with fear extinction, gene editing to increase 5HT2c receptor expression increases trauma sensitivity (39). 5HT2c receptor activity also enhances fear learning (40). There is also evidence that 5HT2c receptors induce CRH release (37). CRH is corticotropin releasing hormone and it is involved in stress and anxiety. It is actually a necessary co-factor in the production of aversion along with dynorphin (11), meaning both CRF and dynorphin are simultaneously needed to stimulate aversion. CRH also releases dynorphin (41), which suggests that 5HT2c receptors promote dynorphin release downstream through CRH release.
5HT2c and 5HT2a receptors seem to have an interaction with each other (42), which we may hypothesize is oppositional modulation of each other. 5HT2a receptors have an interaction with MORs (43), which produce many effects that are opposite of KORs (32), for example, increasing dopamine release (44), producing euphoria (45), and playing a critical role in reward learning (46). 5HT2c receptor stimulation also produces opposite mitogenic effects as MOR stimulation (47), showing another point of opposition in these systems. One study found somewhat oppositional effects of 5HT2a and 5HT2c receptors in relation to the reward system (48), but the results are nuanced and it’s unclear what to take away from this. Since many of the correlated effects of 5HT2a and 5HT2c receptors are opposite, it makes sense that they may modulate each other antagonistically somehow, producing both pro- and anti-aversive effects differentially. More research is needed to understand the interaction of these receptors.
This presents complications to the notion of treating schizophrenia with psychedelics. If these drugs increase aversion, CRH, and dynorphin activity, they might be psychotomimetic and antipsychotic depending on factors that influence receptor activity dominance of each receptor. Some researchers have noted these contradicting pro- and anti-psychotic effects of 5HT2ar and 5HT2cr in the literature (49).
From the abstract:
Phencyclidine, ketamine, and other agents that block NMDA glutamate receptors trigger a schizophrenia-like psychosis in humans and induce pathomorphological changes in cerebrocortical neurons in rat brain. Accumulating evidence suggests that a complex network disturbance involving multiple transmitter receptor systems is responsible for the neuronal injury, and it is proposed that a similar network disturbance is responsible for the psychotomimetic effects of NMDA antagonists, and might also be involved in the pathophysiology of schizophrenia. In the present study we present evidence that serotonergic agents possessing 5HT2A agonist activity prevent NMDA antagonist neurotoxicity in rat brain. It is proposed that 5HT2A agonists may also prevent the psychotomimetic effects of NMDA antagonists. Among the 5HT2A agonists examined and found to be neuroprotective are LSD and related hallucinogens. The apparent contradiction in proposing that these agents might have antipsychotic properties is resolved by evidence linking their hallucinogenic activity to agonist action at 5HT2C receptors, whereas antipsychotic activity would be attributable to agonist action at 5HT2A receptors.
5HT2c receptor antagonists are being explored as an overlooked mechanism in atypical antagonists (50), as some researchers believe that 5HT2c receptor antagonists may be useful in treating schizophrenia. The study notes that a potent 5HT2c receptor agonist known as meta-chlorophenylpiperize (m-CPP) enhances the positive symptoms of schizophrenia. They also note that many antipsychotics antagonize 5HT2c nearly as potently as they antagonize dopamine D2 receptors, which is the popular explanation for their efficacy. Adding to this, I’ve made the claimed that 5HT2a receptor agonists may treat psychotic symptoms, with evidence showing that impaired receptor function or decreased receptor density of the 5HT2a receptors has been linked throughout the research. It is important to mention that I would expect psychedelics can treat trauma and psychosis by downregulating 5HT2c receptors.
These two receptors may be key in determining whether a trip is good or bad. Perhaps when both receptors are stimulated we are granted a higher sensitivity to both positive and negative valence. When something good happens perhaps aversion processing shuts down, while scary or disturbing things quickly shut down bliss states.
It is important to note that I suspect 5HT2a receptors to be behind the visual distorting effects of psychedelics still. This seems to occur as a result of increasing glutamate activity (51), which I’ve proposed could accelerate learning mechanisms and produce stroboscopic-like effects within the brain here. I also argue that 5HT2a receptor stimulation produces manic effects rather than psychotic, where I have distinguished mania and psychosis as nearly opposites in Psychedelics and Schizophrenia. If you’d like to check out a more cultural-biological approach to distinguishing mania and psychosis mood dynamics, check out Memetic Mutation. This includes some of the same arguments from the Psychedelics and Schizophrenia post, but it goes further to explain the lifestyle, divergent thinking, and creativity differences between mania and psychosis.
A key utility of valence in our experience is to learn and associate these feelings to stimuli. The association of good or bad feelings to external events can help us to recall these feelings later so that we can either seek the pleasure or avoid the aversive feeling. Addiction and PTSD can be viewed as the extremes of seeking pleasure and avoiding aversive feelings. Psychedelics are thought to treat both of these. Valence helps us tag events, people, places, and anything you could think of with tags as a reference for future assessment of these stimuli.
Psychedelics are also known to enhance associative learning (52). Research shows that higher emotionality makes stimuli more memorable (53). So psychedelics may enhance associative learning partly by boosting emotionality.
First let’s consider addiction.
The stimulation of the 5HT2c receptor has been shown to reverse heroin addiction and withdrawals induced by naloxone (54). It may be important to note that CRH induces both dynorphin and enkephalin. Enkephalins are MOR agonists so perhaps 5HT2c receptor induced CRH enhances both positive and negative valence. Enkephalins can reduce withdrawal symptoms from morphine (55), as they have the same effects. Dynorphin is thought to be a key in withdrawal symptoms, especially dysphoria, lack of motivation, and potentially pain, so it seems strange for a dynorphin releasing mechanism to attenuate withdrawals. It also prevented the withdrawals induced by naloxone, which blocks enkephalin (MOR) and weakly blocks dynorphin, 12x more weakly than it does with enkephalin (56). I do not think this opioid releasing effect sufficiently explains the observed inhibition of morphine withdrawals by 5HT2c receptor agonists.
I suspect there might be other mechanisms involved, like the inhibition of NMDAr mediated addiction mechanisms (57). NMDAr seems to regulate a drug tolerance mechanism (58) and is involved in reward learning, associative learning, appetitive learning so perhaps the reinforced cues utilize NMDAr as a memory mechanism and 5HT2c receptors may disrupt the initiation of withdrawals by disrupting NMDAr mediated neuron activity (59). This also ties into the study that claims 5HT2c receptor activity worsens psychosis while 5HT2a receptor activity is anti-psychotic. The effect of 5HT2c receptors on NMDAr might be to decrease conditioned responses, like in the case of repeated drug use and addiction. While 5HT2c receptor activity might increase dynorphin release, it might shut down conditioned dynorphin responses that occur during withdrawals independently from 5HT2c receptor mechanisms. It may even disrupt a whole list of conditioned withdrawal responses by disrupting NMDAr mediated responses.
This is supported by studies showing that NMDAr antagonists inhibit morphine withdrawal as well (60). The NMDAr antagonist ketamine is able to disrupt recall and recognition memory (61). The disruption of NMDAr from 5HT2c receptor agonists was noted to relate to the nitric oxide pathway (59). The ketamine-induced recall impairment can be corrected by drugs that reduce the breakdown of nitric oxide (61). Though it is important to note that NMDAr antagonists impair associative learning (62) and psychedelics do not. Furthermore, 5HT2a receptor agonists have been shown to have both NMDAr enhancing (63, 64) and partial NMDAr attenuating effects, seemingly functioning as a kind of indirect NMDAr partial agonist (65), which means both agonizing and antagonizing properties depending on the dose. It might be that NMDAr-dependent conditioned responses are impaired but not NMDAr-dependent learning.
The 5HT2c receptor is also shown to mediate anxiety responses from unfamiliar and novel stimuli (37). There have also been reports that opioid addiction results in developing a conditioned response to many cues around them, kind of like a reward form of PTSD, perhaps a Post Reward Reaction Disorder (PRRD). This makes evolutionary sense because automated responses to stimuli may be dependent on cues, or familiar inputs. If introduce novel inputs, then the automated behaviors in response to the usual familiar inputs may not be useful anymore. We develop automated behaviors to deal with familiar and repeating situations. When something unfamiliar happens, we want to pay special attention to this stimuli until we understand it and determine if it is valuable or safe. When entering a new space, this 5HT2c receptor mechanism may wash away conditioned behaviors and activate an anxious cautious approach to new stimuli.
Meanwhile, the 5HT2ar receptor may mediate a more curious exploratory approach to new stimuli by reducing the fear of exploring novel experiences. The ratio of 5HT2a and 5HT2c receptors may determine the response to novel stimuli. This ratio could theoretically be determined by serotonin downregulating and desensitizing the receptors. Perhaps 5HT2c receptors tend to be dominant initially and spark a first cautious approach while later curiosity takes hold and then eventually numbness and familiarity. Different neurotransmitter systems likely modulate the ratio of these receptors as well, This receptor may activate learning mechanisms and enhance associative learning of new stimuli. This has been shown with LSD, which enhances Pavlovian conditioning (52).How generally safe the environment is, based on the good or bad outcomes of previous novel exploration may condition the serotonin receptor ratio of 2a:2c. Perhaps psychedelics help those with trauma by altering the ratio very quickly, allowing one to program their response to novel stimuli for future use. This is something that should be explored in the future. I would suggest looking at the way non-serotonergic drugs regulate serotonin receptors, perhaps especially opioids. In the case of addiction and general reprogramming of habits, the 5HT2c receptor might allow NMDAr activation but disrupt specific pathways normally trigger the conditioned response to the environmental cue. This could mean that the environment can overwrite the responses and allow us to change our behavior, free from the compulsion of prior conditioning. 5HT2a receptor stimulation increases glutamate release (51) and might enhance NMDAr activation so that conditioned responses are developed faster than usual. In the article Flicker, I argued that the motion aftereffect or drifting illusion observed on psychedelics is the result of enhanced conditioning to repeating stimuli. It is as if the incoming stimuli are loudened so much that they leave stains in our brain. Consider how brighter lights often leaves trails in our vision and psychedelics seem to enhance this mechanism. Here is a video that allows you to condition your visual perception so that it creates a kind of short-term memory of visual motion. I believe that this is nearly the same as the drifting illusion noticed on psychedelics. Seizure warning!https://youtu.be/OAVXHzAWS60If you enjoyed this, checkout the recent article The Phoenix Effect which explores how psychedelics may be similar to the childhood critical period of development. This kind of reprogramming effect is critical to the plasticity that is core to our development.
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