#404 ‒ Mental health beyond neurotransmitters: the role of hormones in psychiatry, why symptom reduction isn't enough, and the future of psychedelic therapies | Linus Abrams, M.D.

“But I think enough that they'll understand, because I think we have to understand serotonin if we're going to talk about the endocrine system and how estradiol and serotonin factor in this life. So I want to make sure we get everybody up to a certain level of understanding, and I think the drugs help us do that. Sure. Well, on a foundational level, psychotropics”

“off of estradiol. And similarly, for both sexes, that men who needed testosterone, weren't getting it, were being told it wasn't safe, similarly had an erosion of their function across multiple domains.”

“within that framework. In other words, is there actual estradiol in a synapse or is it removed from that given its size and it's regulating it? It's regulating upstream of the actual synaptic contents between, you know, where the actual neurotransmitters live.”

“of psychopathology or emotional variability in response to change in estradiol levels, it's more the actual change and fluctuations and oscillations of those levels themselves.”

“Absolutely. Can you say anything about this in men? Because, again, I think this is counterintuitive, but I don't think men are particularly less susceptible to this, both testosterone and estradiol. Yeah, well, let's start. Let me just say men get their estradiol from testosterone, from the aromatization of testosterone.”

“of testosterone. So, testosterone is a pro-drug for estradiol, as well as, of course, being a primary drug for all the obvious reasons. But as a primary hormone, testosterone modulates, there's a lot of system redundancy.”

“that might be worth your reiterating. Yeah. I think what's always misleading when you look at a laboratory report is the number for estradiol is so much bigger than the number for testosterone in women. Right. But that's because testosterone is reported in picograms per mil per deciliter.”

“Testosterone is reported in nanograms per deciliter. Estradiol is reported in picograms per deciliter. So you have to normalize those because they're off by a factor of a thousand. And when you do that, you realize that a woman's testosterone level is about 10 times higher than her estradiol level, although it's about one-tenth the level of a man.”

“And with estradiol levels and progesterone at their peaks, these women are, you know, women in general at the end of pregnancy are primed to be in wonderful moods.”

“change can occur in that critical window. And I find that of interest because, of course, estradiol creates a lot of neuroplasticity because it acts through BDNF and NMD and glutamate.”

“optimal estradiol levels, for example. And giving, administering a psychedelic medication can also alter neuroplasticity, is intended really to alter neuroplasticity in the studies of psychedelics for the most part.”

“And that's how it works for that drug. Now, there are also probably familiar to many of the audience a newer class called SNRIs, serotonin and norepinephrine reuptake inhibitors, and that gives a certain balance because raising serotonin can decrease dopamine.”

“So when you think about then the differences between a drug that gets formally labeled an SSRI versus a drug that gets formally labeled an SNRI, it's really just a continuum. Because it's basically saying like, I mean, I'm being a little bit cheeky, but if on a”

“and a four out of 10 on norepinephrine, at some point we just say, oh, well, we're going to start classifying you as an SNRI. That's true. I think it's underappreciated. You know, there are certain more pure SSRIs. So it sounds like Prozac was a very pure SSRI.”

“So when would an SNRI, which, again, you always think the newer the drug, the better it is, but when would you turn to an SSRI over an SNRI?”

“SNRIs stabilize mood? Well, irritability is such a huge category. And a lot of people with depression have a lot of irritability.”

“No. No. You were all SSRI or SNRI? Yeah. Okay. Yeah. Or bupropion. Okay. Which is Welbutrin for the listener. So each of those therapies in monotherapy had not been successful. And then even when you layered on presumably not a bipolar dose of lithium, but...”

“Well, I would say just empirically, men who take Clomiphene tend to be dissatisfied. Even though their numbers are high in the periphery. Yes. Yeah. That's been our experience.”

“Absolutely. Yeah. Yeah. So, okay. I wondered if that was your experience. Let's mention the primary reason why Clomiphene is typically prescribed as well as HCG. No, the rationale. Okay, so there's, I think there's three rationales for Clomiphene and Enclomiphene.”

“Yes, which of course comes with it. Yeah. So that's a huge part of it. I think even when you consider HCG, which I think is a superior drug to Clomiphene and Enclomiphene because it's administered peripherally, it acts peripherally and it doesn't have a central block.”

“It's very expensive. It's inconvenient. It's got all those problems. Clomid's cheap. It's oral. And by the way, a lot of people don't know this. It's not regulated. So testosterone and HCG are schedule four. Clomid and Clomiphene are not regulated.”

“Clomid and Clomiphene are not regulated. For now. Yeah. So any, you don't have to go and see a doctor formally to do it. It can be kind of a jack-in-the-box online thing that can give it to you.”

“Not to say that it's not effective for a lot of depression. It was actually a sort of the first SSRI fluoxetine was a... Which is Prozac? Yes. Exactly. Generic Prozac developed by Eli Lilly in a targeted way to block the serotonin reuptake pump.”

“Now, there are certain more pure SSRIs. So it sounds like Prozac was a very pure SSRI. Perhaps. Generic Lexapro, Escitalopram might be the best example. Got it. From my understanding right now, of a pure SSRI.”

“Not necessarily, but the side effect profile tends to be better. So remember, when fluoxetine came out, the first SSRI, really the first of the next generation of anti-anxiety antidepressants to call them dual-intended targets.”

“And they're just not well understood. It's not like, hey, if we're going to give you Prozac, we sort of know that most people respond at this dose. Some people need it to be at this dose.”

“instead of a mood stabilizer like lamotrigine. I see. Because lamotrigine, sorry to interrupt. Lamotrigine can be very effective about treating depression.”

“and lamotrigine, for example, can be very effective at treating depression with monotherapy for many patients.”

“So I started her on lamotrigine, and that was a road to restitution of her life's narrative. She didn't know what was happening to her entire adult life.”

“Lamotrigine can be very effective about treating depression. People think of bipolar drugs as treating the elevated moods, but lithium and lamotrigine, for example, can be very effective at treating depression with monotherapy for many patients.”

“I think it changes sodium channels. Okay. And do we know why lithium works? I don't believe so. Okay. So lithium monotherapy or Lamictalin monotherapy is not just given to manage the mania, but you're saying it can also improve the depression.”

“in combination therapies with antidepressants and mood stabilizers and let's say lithium, which is a so-called augmentation strategy. But this was not bipolar. Not bipolar. Not depression.”

“class of drug. Presumably during your training, we were dealing with MAOIs, we were dealing with tricyclics, we were dealing with drugs that actually still probably have great efficacy, provided the indication is understood.”

“existing medications on the market, the tricyclic antidepressants, had typically much more severe side effects. And were dangerous in overdose, so they were potentially lethal in overdose.”

“called xuranolone, which is now in a pill form. It used to be brexanolone, which was an intravenous infusion given in an ambulatory center where a woman had to stay there for a protracted period of time.”

“And then even when you layered on presumably not a bipolar dose of lithium, but... Or an atypical antipsychotic, because those are also indicated for treatment resistant depression. Drugs like Rexulti, there are a number of them that are used now. Abilify, Rexulti, Brexpiprazole, Aripiprazole, Zyprexa, Olanzapine.”

“No. No. You were all SSRI or SNRI? Yeah. Okay. Yeah. Or bupropion. Okay. And which is Wellbutrin for the listener. So each of those therapies in monotherapy had not been successful. And then even when you layered on presumably not a bipolar dose of lithium, but...”

“I can drink four cups of coffee and I don't feel anything. So the doses of these agents that I require to feel anything are much higher than other people.”

“And the major ones are Venlafaxine and Desvenlafaxine, Cymbalta, and Pristiq. And those can be very effective and potentially less likely to cause the cognitive dulling or affective blunting that people sometimes get with SSRIs”

“Because it boosts metabolism and energy. And when you say T3 for the listener, can you differentiate between the FDA-approved T3 cytomel, which is very short-acting, versus the compounded formulations that are more time-released?”

“And the two most common ways to do that are giving HCG, which is giving effectively luteinizing hormone, telling the body to make testosterone. And then the other would be using drugs like clomid or clomiphene or enclomiphene,”

“This is what estrogen is doing. This is why we're replacing it. I have to. If you're giving a patient levothyroxin or Cytomel, this is why, and this is what's going to do. So when the patient, when you suspect that, hey, a big part of what's going on here is hyper-arousal.”

“So what had you tried before? I tried a series... I tried a series of monotherapies with antidepressants in combination therapies with antidepressants and mood stabilizers and, let's say, lithium, which is a so-called augmentation strategy.”

“So I want to make sure we get everybody up to a certain level of understanding, and I think the drugs help us do that. Sure. Well, on a foundational level, psychotropics historically have worked at the level of intervening on neurotransmitter modulation, and particularly the monoamines, serotonin, dopamine, and norepinephrine.”

“Not all SSRIs are pure SSRIs. For example, Sertraline, generic Zoloft, also blocks dopamine. It's also a mild dopamine reuptake inhibitor.”