Lithium, the GOAT: Revealed: Therapeutic Benefits of Lithium Micro-Dosing

Ethan: Let's talk about a couple of other potential uses for lithium, and a couple of its lesser-known properties. Lithium in Neurodegenerative disorders. Chen did a retrospective study on 30,000 patients, only 550 on lithium, but had a difference in the development of major cognitive impairment, formerly known as dementia. (In the) lithium group, it was 9.7% versus 11.2% in the non-lithium group. This is despite the lithium cohort having several additional risk factors, including more smoking, more antipsychotic [00:01:00] use, depression, diabetes, hypertension, vascular disease, and hyperlipidemia. I don't know if you've listened to Ghaemi’s podcast. Ghaemi had a former NFL player's father on his podcast, and the NFL player had CTE, Chronic Traumatic Encephalopathy. (He was) using lithium as an anti-neuroinflammatory to slow or prevent the progression of CTE to dementia. What do you know about dementia and lithium's potential role?

Rif: It's complicated, as you would expect. So, lithium does these super things by being an antiapoptotic. Drug apoptosis is programmed cell death. Cells normally, they're told to commit suicide and they will turn on a pathway that leads them to die. [00:02:00] When a cell dies, an apoptotic death, it vanishes without a trace. There's no scar. If a cell dies in any other way, it leaves a scar. You can always see how cells have died. If they died apoptotically, the tissue looks clean, although it might be smaller than what you would expect. Like, for example, as we age, our brain gets smaller, but when we look inside a normal old brain, there are no scars. The cells have died clearly, but they've died an apoptotic death. Lithium will do 2 things, it reduces death from apoptosis. The word that we use to define that is neuro-protective, cells that would normally die don't. And part of our loss of brain tissue is probably pathologic. So there are probably some [00:03:00] cells that we don't want to have die. Overall, Lithium can be anti-dementia. And as you pointed out in folks who are prescribed lithium, you can really see that effect. You listed a whole bunch of problems that people with bipolar illness are more likely to have, high blood pressure, diabetes, those sort of things, so if I have bipolar illness and I have all of those extra risk factors, I would develop dementia earlier than the general population. If I was on lithium though, lithium delays that, protects me from all of these extra things. It doesn't prevent dementia, but now I will develop dementia at the same age as the general population. Lithium will actually replace calcium in your bone and reduce your risk of fracture. I mean, there's tons of these [00:04:00] benefits to lithium and all sorts of things that you can get with relatively low concentrations. And Ghaemi actually talks about micro- dosing with lithium because you can buy lithium orotate off the Internet. It's a low enough lithium concentration that it's not likely to cause too many problems and probably has some benefits. It's not necessarily bad to microdose even if there's nothing wrong with you. I don't go out of my way to do it cuz I think just living a good life is probably going to protect me in its own right. But sure, if you're worried about that, you have a family history, it might be reasonable to do. The thing to not get carried away with (is) remember that lithium does all of its benefits, and its harm for that matter, through [00:05:00] the intracellular fraction. And, not everybody accumulates lithium in the same way. It is important to understand, people who say I have some kind of bad disease, my neurons are dying and you decide to give me lithium, I will have a fairly small likelihood of being a good lithium responder just because I'm in the general population, and so you might give me lithium and it doesn't actually do a very good job of protecting my dying neurons. In actual controlled studies where you give it to non-psychiatric ill patients, people that have a neurologic degenerative condition, it actually doesn't seem to be particularly effective. It works in people who have bipolar illness, but bipolar illness itself is [00:06:00] probably a disease that increases lithium entry. If I have bipolar illness, I will accumulate more intracellular lithium, and that will protect my cells. If I don't have bipolar illness and I'm on lithium, I may not have a very high concentration of intracellular lithium, and now lithium doesn't really protect me.

Ethan: So in that same line of thinking, if you were somebody who is predisposed to the cysts, microcysts in the kidney, then you also may be predisposed to having a benefit in terms of your dementia risk with lithium. (Rif: Absolutely) And, vice versa, if you are not somebody who has a high intracellular sodium content at baseline, you're less likely to develop kidney problems, but you're also less likely to get reasonable benefit. (Rif: Right). Now, would you be able to get benefit with lithium as an antiviral? The (virus) with the most evidence is Herpes Simplex… Going back to 1990, JD [00:07:00] Amsterdam had 10 healthy women, bipolar patients who had chronic recurrent genital herpes infections, 10 on lithium and 10 not on lithium. (The ones on lithium) had reductions in their total monthly duration of outbreaks, the average duration of outbreaks over time. The longer they were on the lithium, they had an increased prophylactic ability over the 1-year duration of this study.

Rif: You have to remember that herpes is not a peripheral problem, it's a CNS problem. What happens with herpes is the virus actually infects the neurons and it's sitting generally inside the neurons in your spinal cord so if you get shingles, for example, the shingles match the distribution of the neurons in that particular segment of the spinal cord. And when you're talking about genital or oral herpes, again, it's the [00:08:00] neurons that feed that area. The herpes actually travels through the neuron up to the spinal cord where it lives. So the herpes actually gets the best real estate in the body and it lives a nice, comfortable life. And, until it perceives that something wrong, is happening in the CNS, a lot of times herpes outbreaks are associated with some kind of distress that the body is going through. And you can certainly transmit that distress to the neurons, whatever the distress is. It could be a physical illness, frequently actually, it's a psychological issue and you're making brain chemicals that are reflective of that stress, and the virus then perceives that and decides to leave. So the reason for the outbreaks is actually distress in the CNS and of [00:09:00] course the anti-apoptotic effect and maybe other things, remember it reduces the firing of really fast neurons. All of these things probably tell the virus, ultimately, ‘No problem here! You can hang out in this neuron and you're okay.’ And so, that's probably how you get the prophylaxis in terms of reducing the duration of the outbreak. Again, that's probably related to stuff that's happening in the neurons rather than in white cells, but it may very well be related to white cells. Lithium does increase the number of neutrophils that you have and sort of, when things are quiet, they just find a small blood vessel, and just sit on the side of the blood vessel, a behavior we call margination. And when you have a signal that needs neutrophils to do something, we activate these cells and, it [00:10:00] literally increases the number of neutrophils that you have. That translates into reduced infections. So it's been demonstrated with people who have AIDS, people who have cancer, that if you give them lithium and increase the number of neutrophils, that they'll actually have fewer infections.

Ethan: There's an ongoing clinical trial by a guy in Buffalo, Thomas Guttuso, who treated 12 patients in his outpatient clinic with long COVID symptoms with low dose lithium, and had significant improvement or remission of their symptoms in 11 of them.

Rif: Lithium accumulates in cells that fire. White cells do maintain a larger difference of intracellular sodium versus extracellular sodium than say, red cells. And, definitely the releasing of the vesicles inside the white cells requires calcium, which [00:11:00] lithium reduces. So that whole activity may indeed reduce inflammation because a lot of inflammation is mediated by interleukins, and interleukins are released by white cells in the same way that neurotransmitter is released in the brain. Lithium clearly will have an anti-inflammatory effect by reducing the likelihood of these interleukins to be released. And you actually get fewer infections. We're doing a small study, we've collected all the data, we just need to do the analysis. People have proposed that lithium may reduce the likelihood of people getting COVID.

Ethan: I saw that in bipolar populations.

Rif: We're actually doing a study only in bipolar populations to see if the people taking lithium have fewer infections than the people with bipolar illness that aren't taking lithium.

Ethan: Last thing to touch on, kind of more of a [00:12:00] theoretical, but all the razz is about immortality, living forever, and there are some studies in lithium, the Drosophila Fly, where Drosophila that are on lithium have a longer lifespan. It does have some sort of effect preventing the shortening of telomeres, which we associate with the aging process. What can you say about lithium and possible anti-aging effect?

Rif: First of all I, don't know if I want to live forever.

Ethan: I'm right there with you.

Rif: Telomeres of course are very important cuz they determine really, essentially, how many times a cell can divide. Telomeres, particularly in progenitor cells, tell you essentially how much spare tissue you have. To some degree, we need newer cells because our old cells have [00:13:00] worn out, and I think lithium reduces the wearing out, if you will, cells. It's the anti-apoptotic effect, the need for replacing cells is less. And I think that's one of the reasons that our telomeres get preserved if we're on lithium, because we have fewer cell divisions. I don't have any evidence for what I just said. I don't know the mechanism of how lithium might actually do that, independent of its anti-apoptotic mechanism. There's nothing that I know specifically that lithium does directly to the telomeres. I think the effect is more indirect. When we were talking about the mites on bees, these are mites that are parasitic on honeybees. And, if you feed the honeybees lithium, it actually it kills the mites, at concentrations that are harmless to the [00:14:00] bees. I don't know if it's necessarily prolongs lives of all creatures.

Ethan: You're saying there could be a potential secondary effect that's not related to a direct action of lithium on the organism, but rather related to it destroying something that causes destruction of the organism, right?

Rif: Yeah. Yeah. I think it's related to the apoptosis, the reduction of apoptosis and consequently the reduction of cell division.