Monday, 23 September 2013

Autism Biomarkers – Serotonin: LSD, SSRIs & Cyproheptadine/Periatin

Researchers are always looking for biomarkers of autism as a diagnostic tool; I am more interested in biomarkers as an indicator of might be going wrong and hence, perhaps, an indicator of what to do about it.

Going back more than half a century, just such a biomarker was found.  Increased platelet levels of 5-HT (5-Hydroxytryptophan) were found in 30-40% of the autistic population.  5-HTP increases the production of the neurotransmitter serotonin and so it was suggested that hyperserotonemia may be a factor in autism.

Hyperseratonemia (Serotonin syndrome)

Hyperseratonemia is not treated by reducing the amount of serotonin, rather by using a receptor antagonist that in effect blocks the serotonin effect.

SSRIs and other anti-depressants

Several classes of drugs target the 5-HT system including  anti-depressants, antipsychotics, anxiolytics, antiemetics, and antimigraine drugs, as well as the psychedelic drugs and empathogens.

In you live in the US, you will have heard of Prozac (vitamin P) which is a very widely prescribed anti-depressant.  It is in a class of drug called Selective Serotonin Re-uptake Inhibitors or SSRI.  Many autistic children in the US are prescribed SSRIs like Prozac. In Japan Prozac is illegal.

SSRIs are believed to increase the extracellular level of serotoinin by inhibiting its reuptake.  Excessive use of SSRIs is known to lead to hyperseratonemia.  If you are already prone to hyperserotonemia, like 40% of autistic kids, it would seem that SSRIs could be potentially dangerous drugs.

A good deal of research does exist on the use of SSRIs in autism and it pretty much shows that they do not do much good, (and they certainly can have nasty side effects).  Look at page 6, in the review paper below that included all kinds of drugs trialled in autism.

LSD and other serotonin antagonists

LSD is a banned substance in the US and Europe, but in the time before I was born, it was being used to treat autism.  LSD, among other things, is a serotonin antagonist.  There are indeed several papers published on its use in autism and other conditions.

I was quite surprised to see Ivaar Lovaas, the “father” of Applied Behavioural Analysis (ABA) was merrily giving autistic children LSD at UCLA in the early 1960s.

These old studies are quite interesting and if you want more just click here.

I am not suggesting you take your child to Amsterdam, but if you look on Google you will see that adults with ASD are indeed using LSD therapy.

It now appears that after being banned from use decades ago, medical research with LSD has been restarted.

Fortunately, there are other serotonin antagonists that are available and will not land you in trouble.  The one that attracted my attention is Cyproheptadine or Periactin.

Cyproheptadine in Research

There has been just one study published on autism and Cyproheptadine and that was in 2004.  It is not exactly what we need, since it was being trialed as an adjunct therapy to haloperidol.  Haloperidol is an antipsychotic.

If you live in the US you will be familiar with Risperidone, which is another antipsychotic shown to be effective in autism. In the UK, only specialists such as child psychiatrists can prescribe risperidone for children with autism.  Risperidone can cause side effects like uncontrollable shaking.

So the trial was in effect to see the effect of the antipsychotic + Cyproheptadine vs antipsychotic + placebo.  This is not exactly what we want, but better than nothing.

As you will see in the charts below, the addition of Cyproheptadine did indeed make a marked improvement.  Sadly this research has not been followed up on.


Serotonin and Emotional Response

There was a recent study looking at how the emotional response of adults with autism was affected by lowering serotonin levels, I could not find the full version.


Elevated blood levels of serotonin may or may not be a “red herring” in autism research.  The evidence is far from complete and it is not going to be a magic bullet.  Nonetheless, I suspect lowering serotonin levels may have far more impact than those expensive high EPA Omega 3 pills many parents are feeding to their kids.

The latest research does actually indicate that genetic differences cause the high levels of 5-HT in autism.  100% conclusive research does not exist showing the value of counteracting this genetic difference.  A safe, cheap, serotonin antagonist, Cyproheptadine /Periactin does exist; and it is available OTC in some countries.

Autism gene variant causes hyperserotonemia, serotonin receptor hypersensitivity, social impairment and repetitive behavior


  1. I suppose SSRIs are worst for those with autism and psychiatric disorders in general, I am not sure if ssris make you exhausted or indifferent, which is the cause of violence, since you are indifferent to the consequences of behavior which explains violent behavior in teenagers and suicidal thoughts which is odd that it is an anti-depressant. Of course serotonin itself may not be the culprit because serotonin can be a modulating effect and it depends on receptors. The danger of SSRis is that certain lab studies have shown that removal of the ssri can be make things worse because of the growth of new neurons and the becoming less sensitive to it.

    When you say autism are you meaning broad based including asperger's and other "high functioning disorders" likewise are there misdiagnosis of autism when in effect there are other diseases, I say this as a newbie to this site.

    1. Autism is a very broad term and the more you read the research the more you see that it means very little. Numerous different dysfunctions, many entirely unrelated, can lead to a diagnosis of autism. As a result some interventions that are highly effective in some are ineffective in others, or worse make things worse. Most common drugs prescribed by psychiatrists, like SSRIs, do seem to make things worse.

      Some people with Asperger's clearly benefit from LSD. I do not find this surprising at all.

  2. My daughter (9, ASD) recently started on a very small dose of Remeron, in an effort to increase weight and as a bonus, hopefully improve sleep. It has done both. It also had an immediate unexpected but delightful side effect of improved social skills, more fluent speech and increased amount of conversation. The first day she tried it she made friends with random children in the park, and they had a discussion about how they would design their dream playground.(DD said she would invent and upside down slide, where you start at the bottom and slide up.) It has been amazing for her (so far.)

    1. That is interesting. How small is the very small dose?

  3. Well, the smallest pill is 15mg. We started with 1/4 of that, and currently do 1/2, so 7.5. The initial idea was to titrate up to 15mg eventually. We are staying on 7.5 for now, because it strongly increases appetite for DD, and I can see the potential for that to really get out of hand.

    My DD has always been super slender (she is a tall 9-year old who still weighs less than 50 pounds.) I've always thought that she doesn't really seem to feel hunger. I wonder if this is a sign of some kind of impaired Serotonin pathway/metabolism.

    1. It turns out that Remeron is a highly potent H1 histamine antagonist within the blood brain barrier, like a super benadryl. I think this is what is helping the autism. Very interesting. This is why it stimulanse appetite, this is another effect of histamine.

    2. Thank you for putting that together for me. I thought it was all about the Serotonin and this gives me a whole new angle to investigate. Just another clue in our puzzle.

      BTW, I'm not really sure if this the right place to ask, but I wondered if you have seen Dr. Seneff's discussions about Sulfate deficiency possibly causing ASD's, and if you had any thoughts on her work. I think it is an interesting idea and remembered your posts about Broccoli improving symptoms for some. We tried the powered brand from Australia, and did not see any improvements unfortunately (though I do believe it really helps some.)

    3. Some people take MSM (methylsulfonylmethane) which others call organic sulfur. In fact when you take MSM it raised levels of the antioxidant GSH. There is a better way to do this, by taking the antioxidant NAC.

      So I think sulfur/sulfate is likely a distraction. 80+% of people with autism have oxidative stress. There are many ways to treat this, some involve substances including sulfur. Some are more effective than others.

  4. Just revisiting threads on SSRI's do to this showing up in my feed: low dose sertaline being helpful for younger kids on the spectrum. I will have to get to the whole paper to get more details but wanted to bring it to your attention.

    1. Peter looking through your earlier comment you saying that H1 histamine antagonists can increase appetite as we are having our child on H1 blockers and the demand for food its quite irritating we did not understand this till we read through your post and then researched weight gain ,cravings,and H1 blockers thank for your post .If we reduce the histamine blockers the effect is not as much ,if we continue to give 5ml which is quite small a dosage then we are going to have a bigger problem on hand .Periactin would therefore not likely to be a choice we can trial.
      Unfortunately a very limited diet mainly carbs.

  5. Based on this, I assume that you do not believe 5-HTP would be an appropriate supplement for ASD kids? Is a urine or a blood test an effective or relevant way to measure seratonin? We have been using 50mg 5HTP qd with our son, and it appears to reduce his agitation, although it's hard to tell for sure. 100mg qd of 5HTP was bad for him. We did that for a short time and noticed pronounced loss of energy, strength, interest, and engagement. We stopped it completely for months. But then his anxiety at school grew steadily, which 50mg qd has seemed to ameliorate to some degree.

    1. Matt, what matters is serotonin in the brain and the central nervous system and to measure that you would need to do a lumbar puncture/spinal tap. Having high or low levels in your blood does not tell you anything conclusive. Some serotonin does cross the blood brain barrier, but most serotonin in the brain comes from the brain.

      There are numerous causes of anxiety in autism and people do use this word to mean very different things.

      It may be better to target specific serotonin receptors. The anxiety may of course be unrelated to serotonin. To find out you would just have to try different types of intervention. There is no easy way.

  6. Recently diagnosed Autist at 30, thank you for this excellent reference site. I can anecdotally attest many of your articles, such as the positive effects of psilocin/LSD and my immunity to nicotine. Seriously, thanks for that article on the link between nAChRs, IBS, and autism; that particular mystery was especially aggravating. It also gives me a new foothold for investigation.

    I know you wrote this in 2013 so you might have already addressed this internally but I could have swore LSD is structurally similar to serotonin and is believed to specifically be a 5-HT2A receptor agonist, not antagonist. Of course, there's debate on that as well and I'm looking into it but I'm curious what you think about it.

    My own experience is that microdoses of psychedelics are an effective treatment tool but that conflicts with the theory that autism is linked to increased serotonin levels if LSD/psilocin is actually a 5-HT receptor agonist. On the other hand, if LSD has a lower potency compared to genuine serotonin, then it would functionally serve as an antagonist. But then that leaves me wondering what causes the visual, stimulatory, and mood altering effects.

    I haven't gone through your whole blog yet but if you have any insights you've made in the last 3 years please share or point me in the right direction.


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