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A New Kind of Serotonin Med

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There’s a new crop of psych meds that work through serotonin receptors, but not in the way you’d expect. They range from antipsychotics like lumateperone (Caplyta) to novel therapies for depression and anxiety like psilocybin and MDMA, as well as a few familiar meds like mirtazapine, trazodone, and quetiapine. Learn how the 5HT-2A receptor strings together their effects in some paradoxical ways.

Published on: 4/27/20

Duration: 28 minutes, 49 seconds

Article Referenced:Nuplazid: Novel Mechanism, Modest Benefits,” The Carlat Psychiatry Report, April 2020

Rough Transcript: Think you know serotonin? Think again. There’s a new crop of serotonin medications that don’t act like the old SSRIs. Today we’ll take you on the magical mystery tour of serotonin 5HT2A.

Welcome to the Carlat Psychiatry Podcast, keeping psychiatry honest since 2003. I’m Chris Aiken, the editor in chief of The Carlat Psychiatry Report.

KN: And I’m Kellie Newsome, a psychiatric NP and a dedicated reader of every issue.

“I think I have a serotonin deficiency.” Patients have been saying this since the 1990’s, and the idea comes more from marketing than science. Although Selective Serotonin Reuptake Inhibitors treat depression and anxiety, it’s far from clear how they work. They do increase serotonin in the synaptic cleft initially, but it takes 2-4 weeks for their benefits to kick in. By that time, a cascade of other changes have taken place in the brain that may be responsible for their antidepressive effects: increased dopamine and norepinephrine transmission, and elevated BDNF.

As a neurotransmitter, serotonin’s effects depend on where in the brain – or the body – it is and which receptor it binds to. There are 16 serotonin receptors, and they’re grouped into 7 families. Today we’re going to focus on the 5-HT2A receptor because it’s the target of several new medications for depression and psychosis. Those are Pimavanserin (Nuplazid, released in X for Parkinson’s disease psychosis), lumateperone (Caplyta), an antipsychotic that was just FDA approved for schizophrenia, and psilocybin (Magic mushrooms), which was recently fast-tracked by the FDA for depression.

The first two of those treat psychosis by blocking this 5HT2A receptor. Pimavenserin is an inverse agonist at 5HT2A, which means it activates the receptor but causes it act in a way that’s opposite of how an agonist would make it act. Lumateperone – Caplyta – is a neutral antagonist, which means it doesn’t have any direct effects on the receptor, but stands in the way so that nothing else can affect it. The third medication – psilocybin – is an agonist at 5HT2A, and it’s this agonist effect that is thought responsible for it’s antidepressant effect as well as its notorious side effects – hallucination, dissociation, and panic.

That’s right, activating serotonin can cause psychosis and panic, at least if it’s the 5HT2A that gets activated.  This is pretty new territory, so let’s start with an overview of 5HT2A.

Serotonin was first identified in the 1940’s by Maurice Rapport who discovered that it works as a vasoconstrictor in the serum, i.e. it was a tonic that increased the vascular tone. He put those two words together – “serum” and “tonic” – and came up with the name Serotonin. It’s official chemical name is 5-HT, which is short for 5-hydroxytryptamine. So when you see the word “5-HT” just think “serotonin.”  In fact Serotonin is a great name so let’s just stick with that.

Fast forward to 1957 and the Serotonin 2A receptor was discovered, though it wasn’t officially called this until 1979. The receptor was genetically cloned in 1990, so we know its size and shape. It comes from a family of three – Serotonin 2A, 2B, and 2C are the receptors in the Serotonin-2 family, and like a nuclear family they share a family resemblance – 50% of their DNA coding is identical.

For 2B, think of the heart. It is regulates cardiac structure and is responsible vasoconstriction that serotonin was first known for in the blood vessels.   You don’t overstimulate this 2B – too much 2B agonism can cause valvular heart disease. That’s a well known side effect of LSD, which is an agonist at 2A and 2B.

2C, think suicide. Victims of suicide have an abnormally high number of 5-HT2C receptors in the prefrontal cortex. Too much activation of this receptor causes depression and anxiety. Some patients are more vulnerable to that effect than others, and it might explain why SSRIs arely cause anxiety and even suicidal ideation when they are first started.  That effect dampens down over time, as the 2C receptors down-regulate over the first month of SSRI treatment.

In the mid 90’s we learned through animal studies that blockade of 5HT2A treats depression, anxiety and psychosis. That’s right, blocking the receptor improves mental health.

Clinical Use
So far, it sounds like boosting serotonin levels is not a good idea – too much serotonin agonist activity causes anxiety, psychosis, suicidality, and valvular heart disease at least in the 5HT family. So why has the FDA fast-tracked a serotonin 2A agonist – psilocybin – for depression? We hope to shed some light on that through this podcast, but here’s a hint. 

People are unique, and receptors are complex – they produce a myriad of possible effects depending on what else is going on in the brain. So saying that activation of Serotonin 2A causes depression is a bit like saying that minor chords make people sad. Yes, they are used more often in the blues, but when used in the right combination those minor chords can create uplifting, even transcendent states, and that’s where this musical analogy becomes reality – because activation of serotonin 2A seems to treat depression by creating self transcendent states.

To recap, here’s what we know about serotonin 2A:

Activating 2A – through agonists – can cause psychosis, dissociation, and panic. LSD and psilocybin – also known as magic mushrooms – are the best known agonists.  But 2A activation can also cause xxx. That’s why psilocybin and LSD were prescription medications in the 1950’s and early 1960’s, when they were used to enhance the psychotherapy experience. 

Blocking serotonin 2A can treat psychosis and depression. This is important to understand the two new antipsychotics pimavanserin (Nuplazid) and lumateperone (Caplyta), because they are the first antipsychotics with very little D2 Dopamine activity. Clozapine and quetiapine might also fit in this category of relatively low D2 blockade and higher Serotonin 2A blockade. It’s for that reason that all of the antipsychotics I’ve just mentioned have minimal extrapyramidal side effects, like muscle stiffness and akathisia – and why they are a better fit for patient’s with parkinson’s disease where Pimavanserin is FDA approved.

But this blockade of serotonin 2A may also prove helpful in depression. This month’s Carlat Report gave a full run-down of Pimavanserin which has a positive controlled trial in major depression. The new antipsychotic lumateperone (Caplyta) is being explored for bipolar depression, and of course quetiapine / seroquel is already FDA approved there. Risperidone, Olanzapine, Ziprazidone, and aripiprazole also block serotonin 2A, and both of these treat depression, though they have stronger D2 effects.

KN: Wait a minute, risperidone treat depression?

CA:  Yes, it augments antidepressants in unipolar depression. It’s not known to work in bipolar depression. In 2015 Xinyu Zhou’s group did a network meta-analysis of the atypical antipsychotics in depression – I’ll read you from his paper “risperidone appeared to be the most beneficial in balancing efficacy, tolerability, and quality of life.” That’ s interesting because it’s not FDA approved in depression, but he found that only risperidone and aripiprazole improved quality of life, and that risperidone was the best tolerated of the various atypicals used in depression. The caveat here is that this was based on only 3 randomized controlled trials. The typical dose was 1-2mg though they went as low as 0.25mg and as high as 3mg.

Other serotonin 2A blockers are already soundly grouped in the antidepressant category. Those are Mirtazipine, trazodone & nefazodone, maprotiline (Tetracyclic antidepressant). There’s also Cyproheptadine – an antihistamine that also blocks the serotonin2 family of receptors. Cyproheptadine has a two small study in depression, as well as small studies for nightmares, sexual dysfunction, akathisia, and anorexia, but it causes a lot of fatigue and weight gain so isn’t often used in psychiatric practice. 

Further afield is Yokukansan, an herbal medicine used in China and Japan for anxiety and depression that blocks serotonin 2A.

KN: Do any of those antidepressants that block 2A treat psychosis?

CA: Mirtazapine may – it has a few controlled trials in schizophrenia where it improved both positive and negative symptoms. Mirtazapine and trazodone have also been used to treat akathisia.


There are thought to be 3 routes to psychosis:

  • Too much dopamine at D2
  • Too much serotonin at 2A
  • Too much glutamate

And each of these has its own distinct flavor of psychosis.

Serotonergic hallucinations are seen with psychedelic drugs like LSD, mescaline, and psilocybin (, MDMA, DOI (dimethoxy-4-iodoamphetamine)). They tend to be visual and dream-like in nature, and the person usually has some awareness that they are hallucinations and are not real.  Dopaminergic hallucinations tend to be more life-like and crisp – people usually believe they are real. 

Now, it’s rare to see these in pure form, because there’s often an overlap of mechanisms. LSD affects serotonin and dopamine, and Ketamine causes psychosis through serotonin 2A and glutamate, and for people with schizophrenia it looks like all 3 mechanisms are contributory: serotonin, dopamine, and glutamate.

But activation of serotonin 2A does not simply cause psychosis.  Here’s where the picture gets more nuanced.  It can cause mystical, out of body experiences. 2A is implicated in our sense of self and personal meaning.  When people take psilocybin or LSD they can have intense spiritual experiences – and they ascribe deep personal relevance to otherwise meaningless objects and events. A bookshelf they are sitting next to can feel like it contains all the wisdom that the world has to offer, and a bowl of grapes can tell you something deeply personal about the finite nature of existence.  We see a similar phenomenon in schizophrenia – ideas of reference – where the patient feels they are getting personal messages from the TV or media.  

Sleep Paralysis

KN:  The way you describe them reminds me of sleep paralysis. Are these dream-like hallucinations of serotonin 2A related to real dreams.  

CA:  It’s been speculated that they are.  Sleep paralysis happens when people partially wake up before the paralysis of their muscles – that helpful paralysis that keeps us from acting out our dreams wears off.  The result is dreaming while awake. Typically the patient has intense visual hallucinations like of aliens or ghosts – its often frightening – and indeed the serotonergic hallucinations of psychedelics are also frightening. Serotonin is involved in waking and arousal. The orexin neurons excite serotonin-producing neurons that in turn promote cortical arousal.

KN: Isn’t that how these new sleep medicines like suvorexant (Belsomra) and the one that’s about to be released – Lemborexant (Dayvigo). They induce sleep by blocking orexin – which keeps us awake and alert. 

CA:  Yes and that’s more relevant to sleep paralysis than serotonin 2A.  The research on serotonin 2A and sleep paralysis is in the speculative stages – but you should know this. Sleep paralysis can happen on its own – it happens with stress or in association with mental illnesses – but mainly it’s a sign of narcolepsy, as is extreme fatigue and sudden sleep attacks or cataplexy. We covered the orexin antagonists in a recent issue and sleep paralysis is a rare side effect of them.  They also are contraindicated in narcolepsy, which is caused by a deficiency of orexin neurons.  But back to Serotonin 2A

Default mode network

I said that 2A is involved in the sense of self, which is why out of body experiences, dissociation, depersonalization and – on a good day – self-transcendence can happen when it’s activated.  The reason has to do with the default mode network, which is a network of several brain pathways that are involved in self consciousness, social awareness, and – on a bad day – depressive rumination.  It’s sometimes said that people with depression are painfully self aware, and the default mode is why. We featured it in our 2018 summer issue where we interviewed Edward Watkins, who developed a version of CBT to treat depressive rumination.

One part of the default mode – the Temporoparietal junction (TPJ)  has lots of serotonin 2A receptors. Activation of 2A in that area appears to turn down the default mode. The result is that we are less self conscious, and more self transcendent.  In the studies on psilocybin it’s this quality – self transcdence – that is linked to its antidepressant effects.  These are remarkable studies.  A single dose of psilocybin lead to full resolution of treatment resistant depression in a small study – and the effects lasted several years.  The patients who entered self-transcendent states were the ones who recovered.  Similar experiences have been reported on ketamine, which also turns down the default mode.  Just as ketamine’s antidepressant effects are short lived, so are it’s effects on the default mode network – which only last about 10 days.

Anxiety and PTSD

KN:  You said “on a good day” this can lead to self transcendence, but these psychedelic drugs can also cause panic and anxiety.

CA: Yes 5HT2A is involved in anxiety, particularly in conditioned fear responses, and 5HT2A medications are being explored for PTSD – most notably MDMA, a 5HT agonist.  To put it simply, activation of the serotonin 2A system tells us if something is personally meaningful, but “meaningful” can be good and bad it also tells us if something is personally dangerous.

Anmials with with a deficiency of 5-HT2A receptors lack normal fear reactions, and people who have higher serotonin activity tend to have more fearful personalities

During stress, serotonin 2A is upregulated.  This has been shown in animals under various stressful conditions – electric shock, isolation, forced swim, immobilization, defeat scenario.  Each of those translates to stressors that our patients may experience: physical pain, isolation, overwork, captivity, abuse and bullying. This upregulation of 2A tells the brain that danger is present.


KN:  But wait – you said that MDMA is being studied as a treatment for PTSD – but it’s a serotonin 2A agonist, so wouldn’t it raise anxiety?

CA:  This is a paradox that we don’t fully understand.  It seems 2A is involved in conditioning fear responses – telling us what is dangerous – as well as in deconditioning them – unlearning the fear. What behaviorists call fear extinction.  The best explanation for this is that it allows near memories – new conditioned tracks in the brain – to replace the stuck, fearful ones of PTSD.

MDMA was used as a treatment for psychiatric disorders in the 1970s and early 1980s. Some psychotherapists suggested that its so-called ‘empathogenic’ effects supported its use in counseling sessions (Greer and Strassman, 1985; Grinspoon and Bakalar, 1986; Greer and Tolbert, 1998). Other clinicians used MDMA as an adjunct to ‘insight oriented’ psychotherapy (Shulgin, 1986). Following its scheduling in the mid-1980s, there was over a decade in which there was a near-hiatus on clinical studies with MDMA (Parrott, 2007).  MDMA-assisted psychotherapy for the treatment of PTSD has recently progressed to phase 3 clinical trials and received breakthrough therapy designation by the FDA, at least in part, because of durable remission rates approaching 70%.

KN:  We end then with 2 mysteries.  Activation of serotonin 2A can cause anxiety, but it may treat ptsd.  And… Antagonism of serotonin 2A treats depression, but so does the opposite – activation of this receptor.  All this tells me that we’ll need to watch carefully – and with an open mind – as these serotonin 2A agonists and antagonists enter clinical practice.

KN: Join us next week where Peter Yellowlees will share his top telepsychiatry tips for these pandemic times. Dr. Yellowlees is the coauthor of the APA textbook on telepsychiatry.

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  1. Diane Inda says:

    Wonderfully thought provoking!

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