Strange as
it may sound, but if you have ASD a strong cup of coffee and a cigarette may
actually do you some good. Following on
from my earlier post about Serotonin, showing that LSD was seen as an effective
therapy in the 1960s, you might be wondering where my blog is taking us. I just follow the science, wherever it takes
us.
First of all
what is the Cholinergeric system.
Cholinergic system (a summary from Wikipedia)
Cholinergic typically refers
to acetylcholine
in the neurological sense. The parasympathetic nervous
system, which uses acetylcholine almost exclusively to send its
messages, is said to be almost entirely cholinergic. Neuromuscular junctions,
preganglionic neurons of the sympathetic nervous system,
the basal forebrain, and brain
stem complexes are also cholinergic
In neuroscience and related fields, the term cholinergic is used in the
following related contexts:
- A substance (or ligand) is cholinergic if it is capable
of producing, altering, or releasing acetylcholine
("indirect-acting") or mimicking its behaviour at one or more of
the body's acetylcholine receptor types
("direct-acting").
- A receptor is cholinergic if it uses
acetylcholine as its neurotransmitter.[2]
- A synapse is
cholinergic if it uses acetylcholine as its neurotransmitter.
Acetylcholine is one of many neurotransmitters in the autonomic nervous system
(ANS). It acts on both the peripheral nervous system
(PNS) and central nervous system (CNS)
and is the only neurotransmitter used in the motor division of the somatic nervous system.
In the
central nervous system, acetylcholine and the associated neurons form a neurotransmitter system, the cholinergic
system, which tends to cause anti-excitatory actions.
Damage to the cholinergic (acetylcholine-producing) system in the brain has
been shown to be plausibly associated with the memory deficits associated with Alzheimer's disease.
Synthesis and degradation
Receptors
Nicotinic
Muscarinic
Muscarinic
receptors are metabotropic, and affect
neurons over a longer time frame. They are stimulated by muscarine
and acetylcholine, and blocked by atropine.
Muscarinic receptors are found in both the central nervous system and the
peripheral nervous system, in heart, lungs, upper GI tract and sweat glands.
Extracts from the plant Deadly night shade included
this compound (atropine), and the blocking of the muscarinic AChRs increases
pupil size as used for attractiveness in many European cultures in the past
--- end of wikipedia ---
The Research Showing Abnormality in
ASD
The
following study was carried out in the UK in 2002 on post mortem brain tissue
from “Brain banks” in the US. It is
extensively referred to in the later research.
An earlier paper on the same
subject:-
CONCLUSIONS: These neurochemical abnormalities
implicate the cholinergic system in developmental disorders such as autism and
suggest the potential for intervention based on cholinergic receptor
modulation.
If the low
level of cortical nicotinic receptors is consistently observed and clinically
relevant, therapeutic strategies could include receptor agonists, such as
nicotine, which has already been applied in Tourette’s disorder with
amelioration of symptoms. Such treatment could also be disease modifying.
Other
studies on autistic brain samples have shown diminished acetylcholine and nicotinic receptor
activity.
Implications 10 years on remain the
same
A recent study by neuroscientists at Ohio
State University, concludes that neuronal nicotinic
acetylcholine receptor (nAChR) alterations are biomarkers for ASD and that
specific nAChRs subtypes are likely to be useful therapeutic targets for the
treatment of core deficits. They claim a case can be
made for the use of α7 nAChRs to reduce neuroinflammation in the brain in those ASD
individuals with such clinical pathology. The ultimate hope is that these
agents, when administered early in development, by their presumed ability to
modulate a number of different neurotransmitter systems and associated
signaling pathways, could help correct core deficits associated with ASD.
Interventions
Just by
spending 5 minutes on Wikipedia, you can find logical interventions that could
have been tested since 2002. Some have
indeed been tested, others have not.
Here below is a copy-paste from Wikipedia, with interesting drugs
highlighted.
Reversibel acetylcholinesterase inhibitor (often abbreviated AChEI)
Compounds which function as reversible competitive or noncompetitive
inhibitors of
cholinesterase are those most likely to have therapeutic uses. These include:
Natural
Compounds
ACh
receptor agonists/antagonists
Acetylcholine receptor agonists
and antagonists can either have an effect directly on the receptors or exert
their effects indirectly, e.g., by affecting the enzyme acetylcholinesterase, which degrades the receptor ligand.
Agonists increase the level of receptor activation, antagonists reduce it.
Drugs
acting on the cholinergic system
Blocking, hindering or mimicking
the action of acetylcholine has many uses in medicine. Drugs acting on the
acetylcholine system are either agonists to the receptors, stimulating the
system, or antagonists, inhibiting it.
ACh and its
receptors
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Direct
acting
These are drugs that mimic
acetylcholine on the receptor. In low doses, they stimulate the receptors, in
high doses they numb them due to depolarisation
block.
------- end
of Wikipedia ---------
Evidence based approach
The web is
full of commentators telling you to only pay attention to evidence-based
treatments. This sound great in principle,
but it assumes there are copious amounts of well-constructed clinical
trials. Moreover, is assumes that there
is just one type of autism, or that clinical trials are sophisticatedly
constructed to test individual sub-types, one at a time (which they are not).
So, in reality,
the evidence is generally poor quality and so applying a pure evidence-based
approach will leave you exactly back where you started.
I have
gathered together what I think is a remarkable amount of evidence from multiple
imperfect trials and anecdotal case studies.
Use Of Donepzil
Following on two earlier trials, Chez et Al carried out a double-blind
study of Donepezil hydrochloride, an acetylcholinesterase inhibitor to confirm those findings.
The
trial concluded:-
Expressive and receptive
speech gains, as well as decreases in severity of overall autistic behavior,
were documented after 6-weeks for the treatment group. These improvements were
statistically significant when compared to placebo, and were clinically
meaningful as assessed over time. Donepezil hydrochloride appears to improve
expressive and receptive language as well as overall autistic features, consistent
with the hypothesis of acetylcholinergic enhancement
Here is a
more recent case study from India
A woman consulted psychiatric Out-Patient Department (OPD) for
her 5-year and 2-month-old son presenting with typical autistic symptoms like
social, behavioural, and communicational ineptitudeness. Subsequent treatment
with Donepezil resulted in marked improvement in the aforementioned
symptomatology. Recent studies in autistic child have shown diminished acetylcholine
and nicotinic receptor activity, thus an acetylcholinergic enhancer, Donepezil,
likely accounts for improvement in autistic symptoms. Evidently, the case
report consolidates Donepezil role as a potentially useful agent in the
treatment of cognitive and behavioural symptoms
observed in this disorder.
Mecamylamine
There was a
recent trial of Mecamylamine, with mixed results, but the researcher is already
planning a follow trial of a similar drug called varenicline, that was
previously suggested by other researchers.
RESULTS:
Eighteen participants (10 mecamylamine,
8 placebo) completed the study. All doses were well tolerated; the only side
effect of note was constipation (50% compared with 25% of placebo group). Three
children had clinically nonsignificant electrocardiographic QT prolongation.
Both groups showed modest to moderate improvement, but differences between
groups were negligible. On the primary outcome measure, the Ohio Autism
Clinical Impressions Scale, 90% of the active treatment group showed
improvement at some point (but only 40% sustained it), compared with 62% on placebo.
Of the four in active treatment that sustained improvement, three had a maximum
dose of 0.13-0.15 mg/kg/day, while those who regressed had doses ≥0.18
mg/kg/day. Graphed means suggested better outcome with lower mg/kg and longer
medication duration. Four
parents spontaneously reported reduced hyperactivity and irritability and
better verbalization and continued mecamylamine at their own expense.
CONCLUSION:
Mecamylamine appeared to be safe, but
not very effective in autism. The suggestion of better results at lower doses
and longer exposure warrants consideration for future trials. The next step would be
exploration of a more specific α4β2 nAChR agonist, such as varenicline.
Varenicline is a drug developed to help people to stop
smoking. It is widely used and looks set
to be trialed in autism
Galantamine
Galantamine was successfully trialed and I am
surprised we do not hear more about it.
In fact, it was developed in the Soviet Union in the 1950s and is now
used for Alzheimer's. It is
based on snowdrop flowers. It is
available as a drug and as a supplement, depending on where you live.
RESULTS:
Patients showed a significant reduction
in parent-rated irritability and social withdrawal on the ABC as well as
significant improvements in emotional lability and inattention on the Conners'
Parent Rating Scale--Revised. Similarly, clinician ratings showed reductions in
the anger subscale of the Children's Psychiatric Rating Scale. Eight of 13 participants
were rated as responders on the basis of their improvement scores on the
Clinical Global Impressions scale. Overall, galantamine was well-tolerated,
with no significant adverse effects apart from headaches in one patient.
CONCLUSION:
In this open trial, galantamine was
well-tolerated and appeared to be beneficial for the treatment of interfering
behaviors in children with autism, particularly aggression, behavioral
dyscontrol, and inattention. Further controlled trials are warranted
The missing evidence
You will
have noticed caffeine and nicotine in the title of this post. You may have noted that back in 2001/2 the
original researchers suggested the logical next step was to trial nicotine
patches.
All I can
find is one case report in ADHD, which to me is just ASD-lite.
If you look
in internet forums you will see that DAN doctors in the US are using nicotine patches. You will also find people giving small doses
of caffeine.
Having reviewed
“the evidence” I think it is entirely logical to trial SMALL doses of nicotine and
caffeine. The research indeed tells us
that only SMALL does may have the desired effect.
One report I
read was a DAN Doctor giving her own child a quarter of 7mg nicotine
patch. By my research, that equals the nicotine
of a single cigarette.
You will
also see older kids with HFA (high functioning autism) writing on the web how they
feel it easier to (pretend to) be more NT (neuro-typical) after drinking coffee and/or smoking. (Maybe they
just look more NT, or maybe there is some truth in it). They do not talk about alcohol.
The other “obvious” thing
that has not been trialed is acetylcholine or choline itself. It is known to be deficient in autism. It is sometimes included in multivitamin
pills in small amounts. Choline is widely available as a supplement. It is also used for its nootropic
properties and there are claims it
reduces neuroinflammation. It is used in
depression, memory loss, Alzheimer’s and schizophrenia It also lower cholesterol. Most
surprisingly, choline is prescribed to control asthma, a comorbidity of ASD.
Choline is
used by people trying to boost their brainpower by combining it with other nootropic
drugs. Their favourite drug
appear to be Piracetam, which is the same drug used for ASD in Ukraine and subject
of a clinical trial in Iran, that I wrote about recently.
It is
remarkable how many drugs I am writing about are either (ab)used by body builders
or now IQ builders.
Conclusion
This post
has really surprised me. Firstly, there
more drugs that look like they actually do work in autism (Donepezil and Galantamine). There is an interesting phase 4 trial underway using Donepzil + Choline. Phase 4 is the final phase.
Nicotine may set alarm bells ringing, but if you check
it out, you will see that very small amounts are apparently harmless. Thanks to smokers, there exists a perfect
transdermal delivery system. Just why
nobody trials it in autism (Glaxo produce Nicorette patches) is inexplicable.
Small amounts of coffee are given to even young children
in many strong coffee drinking countries (like the Balkans). Coca Cola and even
Ice Tea are caffeine-rich.
Choline is probably the simplest, cheapest and safest
intervention; but that does not mean it
is will be effective. Nobody has made a
controlled trial with it, probably because there is no money in it.
For a change in my posts, it looks like there is something for everyone.
