Neurology of lithium-psychedelic interaction

[HOOH]

The dangers of mixing psychedelics with lithium are widely known (seizures being the primary adverse effect but fugue states and general bad-trippines being also common), but does anyone know why? I thought this was the most appropriate subforum, since I am chiefly interested in the biochemical reason for this interaction

 

[SpiralusSancti]

I would also really like to find out this. Lithium is fascinating.

 

[Neuroprotection]

Nice to see someone else is interested in this. please forgive me for this long post, but I’m just happy to share my explanations/theories with others and I hope it benefits you. actually I’ve been researching mood stabilisers and their interactions with psychoactive drugs over the past few weeks following my fascination with the amazing functions of GSK3Beta in the brain, including its role in dopaminergic receptor signalling and mood elevation. this is important because lithium is a powerful inhibitor of GSK3Beta and this is how it suppresses mania. however, it also means lithium has paradoxical effects when it comes to receptor signalling, neuronal excitability and seizure threshold. GSK3Beta is a strange enzyme which works overall to weaken glutamatergic synaptic strength by preventing delivery of new GLUR1 subunit containing AMPA receptors to the membrane. in contrast, it simultaneously stabilises AMPA GLUR1/GLUR2 complexes at the synaptic membrane and encourages their phosphorylation. these receptors have Little to no calcium conductance but do have significant conductance for sodium and other ions. this receptor complex is probably responsible for mania and lithium, through inhibition of GSK3Beta disrupts this receptor complex to stabilise mood. unfortunately, GSK3Beta inhibition by lithium could lower the seizure threshold, contribute to kindling or enhance seizure severity by enhancing calcium influx through various calcium channels and calcium permeable glutamate receptors.

This is very relevant to 5HT2A signalling and psychedelic affects. 5HT2A receptors have multiple downstream signalling pathways and if I remember correctly, only one of them is necessary for hallucinations and this pathway is strongly activated by psychedelics. on the other hand, another downstream pathway results in GSK3Beta activation and doesn’t contribute to hallucinations, but instead works with dopamine to modulate mood states. going back to the GSK3 independent pathway stimulated by psychedelics, this is the one responsible for flooding certain brain areas with glutamate which results in psychedelic affects. remember that lithium strongly enhances glutamate synaptic strength and in doing so would likely tremendously magnify the effects of psychedelics. given the protective role of GSK3Beta against seizures by weakening synaptic function and the fact that lithium inhibits this enzyme, this makes the combination dangerous. this is because the glutamate surge triggered by psychedelics would have more receptors and more synapses to act on along with higher permeability to calcium.

 

[Neuroprotection]

The dangers of mixing psychedelics with lithium are widely known (seizures being the primary adverse effect but fugue states and general bad-trippines being also common), but does anyone know why? I thought this was the most appropriate subforum, since I am chiefly interested in the biochemical reason for this interaction

Just out of interest, do you take lithium? if so, could you describe its effects on your general mood as well as your natural emotional responses like fear, anticipation, reward/pleasure and sadness etc. furthermore, have you used any recreational psychoactive drugs along with it and if so, how did they interact.

 

[HOOH]

Just out of interest, do you take lithium? if so, could you describe its effects on your general mood as well as your natural emotional responses like fear, anticipation, reward/pleasure and sadness etc. furthermore, have you used any recreational psychoactive drugs along with it and if so, how did they interact.

I dont take it

This is very relevant to 5HT2A signalling and psychedelic affects. 5HT2A receptors have multiple downstream signalling pathways and if I remember correctly, only one of them is necessary for hallucinations and this pathway is strongly activated by psychedelics. on the other hand, another downstream pathway results in GSK3Beta activation and doesn’t contribute to hallucinations, but instead works with dopamine to modulate mood states. going back to the GSK3 independent pathway stimulated by psychedelics, this is the one responsible for flooding certain brain areas with glutamate which results in psychedelic affects. remember that lithium strongly enhances glutamate synaptic strength and in doing so would likely tremendously magnify the effects of psychedelics. given the protective role of GSK3Beta against seizures by weakening synaptic function and the fact that lithium inhibits this enzyme, this makes the combination dangerous. this is because the glutamate surge triggered by psychedelics would have more receptors and more synapses to act on along with higher permeability to calcium.

You do have a lot of things about GSK3Beta memorized, but I am not convinced this is the right explanation — we can't qualitatively say that glutamatergic signaling causes psychedelia and glutamate suppression (e. ketamine) can also induce some psychedelic effects (and diminish others), and lithium doesn't merely increase psychedelic effects, but actively change them (for the worse)

Do you know what biochemical reaction GSK3B catalyzes (as it is an enzyme aka a biochemical catalyst)

 

[Neuroprotection]

I dont take it

You do have a lot of things about GSK3Beta memorized, but I am not convinced this is the right explanation — we can't qualitatively say that glutamatergic signaling causes psychedelia and glutamate suppression (e. ketamine) can also induce some psychedelic effects (and diminish others), and lithium doesn't merely increase psychedelic effects, but actively change them (for the worse)

Do you know what biochemical reaction GSK3B catalyzes (as it is an enzyme aka a biochemical catalyst)

Yes, you’re right, no one knows for certain how psychedelics work and no one is fully sure how lithium works either. however, there is very convincing evidence that both lithium and psychedelics share the the glutamate system as one of the final downstream effectors although they do affect it in different ways of course. as I mentioned earlier, since lithium strengthens synaptic connections in many brain areas and alters AMPA receptor composition, The effects of psychedelics are likely to be strengthened and altered. I think there’s pretty convincing evidence that glutamate release is vital for psychedelic actions, I’ll try and post some links related to this.
Regarding your question about GSK3Beta, The answer is it catalyses hundreds of reactions. however, its actions on glutamate receptors, Microtubules and synaptic vesicles are perhaps of the greatest interest for neurology. in most cases, it works to weaken synaptic connections and prevent new ones from forming and is important for NMDA receptor dependent LTD. i’ve made a thread about this enzyme but I do apologise, my posts are very long, I’m happy to post you the link if you like.

 

[Neuroprotection]

Me, myself, bye: regional alterations in glutamate and the experience of ego dissolution with psilocybin

There is growing interest in the therapeutic utility of psychedelic substances, like psilocybin, for disorders characterized by distortions of the self-experience, like depression. Accumulating preclinical evidence emphasizes the role of the glutamate ...

www.ncbi.nlm.nih.gov

Metabotropic glutamate mGlu2 receptor is necessary for the pharmacological and behavioral effects induced by hallucinogenic 5-HT2A receptor agonists

Hallucinogenic drugs, including mescaline, psilocybin and lysergic acid diethylamide (LSD), act at serotonin 5-HT2A receptors (5-HT2ARs). Metabotropic glutamate receptor 2/3 (mGluR2/3) ligands show efficacy in modulating the responses induced by activation ...

www.ncbi.nlm.nih.gov

Paradoxical effects of lithium on serotonergic receptor function: an immunocytochemical, behavioural and autoradiographic study - PubMed

Lithium is the preferred treatment for bipolar affective disorder, yet its mechanism of action is poorly understood. Our study was designed to investigate the effect of lithium on the 5-HT2A or 5-HT2C (5-HT2A/2C) receptor subtypes, by comparing the consequences of chronic pre-treatment of rats...

pubmed.ncbi.nlm.nih.gov