There has been a lot of praise for psychedelic and dissociative antidepressant treatments as they seem to work by inducing spontaneous recovery from depression, sometimes with a single dose. A new 2020 study found that ketamine restores long term potentiation (LTP) in the hippocampus, a mechanism impaired in depression (15). People wonder about the mechanisms and here we are to explore them. Here we explore the mechanisms that might help to explain the rapid antidepressant effects of ketamine and psilocybin (and probably psychedelics commonly).
These effects may come down to a chemical exorcism of the neuropeptide known as dynorphin.
Research has found a pattern of reduced plasticity to be associated with depression. This has led many researchers to suggest that the mechanisms of antidepressants may be due to restoring plasticity, especially in the hippocampus. Ketamine has been found to restore plasticity in the hippocampus (1), prefrontal cortex (1), and the mesolimbic pathway (2). I suspect any region impacted by ketamine that has the potential for neuroplasticity will likely express it.
The immediate effects of ketamine would reduce neuroplasticity, which has been shown in the research. Ketamine blocks LTP in the hippocampus (3). This suggests that the hippocampal plasticity restoration induced after ketamine is due to downregulating antiplastic mechanisms.
Dynorphin feels bad man.
Dynorphin is linked to the negative affect of stress (18) and pain (19). It is linked to addiction (20), depression (21), schizophrenia (22, 23, 24), PTSD (25), suppresses dopamine activity (21), reduces glutamate release (17), and directly blocks NMDA receptors (26). Dynorphin is the endogenous kappa opioid receptor (KOR) agonist.
It is clear that dynorphin mediates demonic energy. /s
The protracted antidepressant effects of ketamine were found to require immediate KOR binding and long-term desensitization (16). This is particularly interesting because dynorphin is shown to impair LTP in the hippocampus (17), which makes sense since it blocks NMDA receptors and agonizes KORs which also inhibit LTP (4, 5, 6).
So it makes sense that desensitizing KORs would restore plasticity in the hippocampus and other regions.
It isn’t talked about much but psychedelics share this anti-KOR mechanism too. Psychedelics (the serotonergic kind) have been explored as treatments for PTSD (27), addiction (28), depression (29), and anxiety (30). On the other hand, dynorphin/KOR has been explored as generating symptoms of PTSD (25), drug withdrawals (20), anxiety (31), and depression (21). Psychedelics also induce plasticity (32) and neurogenesis (33). So does serotonin: neurogenesis (34), plasticity (35).
Psychedelics (LSD) have been shown to disable KOR-mediated depressant effects (14). The mechanism of this may be a combination of effects involving 5HT1a, 5HT2a, and 5HT2c serotonin receptors. 5HT1a receptors have been found to suppress the dynorphin release that occurs from applying a dopaminergic (7). 5HT2a receptors have been shown to enhance acetylcholine release in the hippocampus and prefrontal cortex (8) which is significant because one of acetylcholine’s targets, nAch alpha7, suppresses dynorphin release (9). Both 5HT1a and 5HT2a have been linked to suppressing aversion (10, 11, 12, 13), which fits well since dynorphin is implicated in aversion and these mechanisms seem to suppress dynorphin.
Lastly, the 5HT2c receptor may also be involved in the tendency for psychedelics to influence dynorphin/KOR and treat the many associated psychological problems. 5HT2c receptor agonism is acutely anxious (36, 37, 38) and is associated to trauma (39), releases the stress hormone CRF (36), which is known to stimulate dynorphin activity (40) and be a necessary co-factor with dynorphin in the subjective experience of aversion affect (18). I’ve recently argued that this mechanism may help explain ‘bad trips’ on psychedelic drugs. It may be that psychedelics downregulate 5HT2c receptors, leading to long-term decreases in dynorphin activity. This would be functionally similar to ketamine’s ‘required KOR desensitization and immediate acute KOR activation’.
Taken together all of this suggests that both ketamine and serotonergic psychedelics may share overlapping mechanisms in the treatment of depression.
Another thing that isn’t often discussed is the potential for these drugs to help those with schizophrenia. Of course, ketamine may produce an immediate psychotic effect, but it may also be capable of desensitizing psychotic mechanisms.
KOR is the primary target that the extremely hallucinogenic drug, Salvia Divinorum, binds to (47). I’ve written a dynorphin/KOR hypothesis for schizophrenia that explores a lot of data to support this hypothesis. Schizophrenia is thought to involve impaired plasticity (76) and neurogenesis (75) in the hippocampus, a region shown to be atrophied in schizophrenia (77). On the other hand, ketamine seems to produce enhanced plasticity after the dose wears off and even has been shown to induce neurogenesis when dosed ‘subchronically’ (78). As a warning, chronic doses may shut down neurogenesis and if schizophrenia involves chronic NMDAr dysfunction, it isn’t clear whether dosing an NMDAr antagonist would upregulate NMDAr function. It is possible though.
Ketamine may not work as well for schizophrenia compared to psychedelics because repeated doses of KOR agonists having the risk of self-enhancing their effects. Those with schizophrenia may already be further along in the ‘repeated dosing’ of endogenous KOR agonists. It isn’t clear though, because theoretically so are those with depression. Still, either way, repeated ketamine use may prove to be as potentially unsafe as repeated Salvia Divinorum use.
Many reports of ‘reverse tolerance’ to the effects of the KOR agonist Salvia Divinorum exist on the internet (44, 45, 46). This may be explained by the way KOR agonism interacts with a mechanism known as p38 MAPK, which stimulates serotonin reuptake through serotonin transporters, thus reducing serotonin activity (41, 42). Salvia is thought to upregulate the serotonin transporters with repeated dosing (43), which would prevent the anti-KOR effects of serotonin, ultimately enhancing dynorphin/KOR mediated issues over time. Overtime, serotonin’s blunting of KOR will be downregulated, allowing for increasing KOR mediated effects.
Because of these patterns, activating serotonergic mechanisms that suppress dynorphin and desensitizing/downregulating 5HT2c receptors may produce a recovery from prolonged dynorphinergic disorders. Ketamine may also help, but repeated doses may risk producing long-term pro-dynorphinergic changes, or as the internet has described (with Salvia) ‘reverse tolerance’. In support of this, current frequent ketamine users were observed to have increased depressive symptoms (48).
Besides treating depression, PTSD (51, 52), addiction (53, 54), and maybe schizophrenia, might ketamine enhance cognition (sometimes)? I’ve suggested that classic serotonergic psychedelics are cognitive enhancing, possibly by increasing glutamate release and by disrupting dynorphin. There is research linking dynorphin to cognitive decline with aging and Alzheimer’s disease (55, 62, 63), cognitive decline from alcohol (56), and stress-induced memory and learning impairment (57). Scarcity and stress have associated with up to 14 IQ point drop (64). PTSD has also associated with low intelligence (58, 59, 60) and traumatic experiences have been observed to suppress IQ performance (61), which makes sense because stress impairs plasticity (65, 66) and involves dynorphin activity.
If ketamine acts by desensitizing KOR, then perhaps we will observe an attenuation of KOR mediated cognitive deficits. There is evidence of this with depressed patients who found an increase in cognitive ability, both processing speed and verbal learning, after ketamine use (49, 50). This seemed to especially occur in anxious depressed patients and not as much in non-anxious depressed patients.
It is important to consider that repeated frequent ketamine use is associated to cognitive decline (48). This seemed to not occur with occasional use but occurred progressively with frequent use. Ketamine can also be neurotoxic (67, 68, 69, 70, 71, 72), through NMDAr antagonism and possibly also KOR agonism. The acute effects involve a shut down of neuroplasticity, where benefits seem to emerge after as plasticity is restored or even enhanced. Children who used NMDAr antagonists for anesthesia also showed reduced IQ (73, 74). So be warned, frequent ketamine use will highly likely be a detriment to cognitive ability.
With all these other wonderful effects of ketamine, might we also observe a cure for allergies?
No, I’m joking.
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