Rather
like negotiating with North Korea, today’s post does rather meander. It does in
the end up with some interesting options for some people.
Korea - the centre of Ginseng research
There
has been quite a lot of coverage in this blog about agonists of GABAB receptors,
like Baclofen and Arbaclofen. Some people with an autism diagnosis do indeed
seem to benefit, ranging from some with Fragile-X to others with Asperger’s.
Russian-developed GABAB agonists like Phenibut and Pantogam are
widely used by adults self-treating their behavioural/emotional disturbances.
Some
Aspies have commented in this blog that far from helping, Baclofen made them
feel worse; perhaps the opposite therapy might help? (the Goldilocks scenario,
from the previous post)
The
paper below shows how a GABAB antagonist (the opposite of
Baclofen) might benefit some with autism.
GABAB receptors are
G-protein-coupled receptors that mediate inhibitory synaptic actions through a
series of downstream target proteins. It is increasingly appreciated that the
GABAB receptor forms part of larger signaling complexes, which
enable the receptor to mediate multiple different effects within neurons. Here
we report that GABAB receptors can physically associate with the
potassium-chloride cotransporter protein, KCC2, which sets the driving force
for the chloride-permeable ionotropic GABAA receptor in mature
neurons. Using biochemical, molecular, and functional studies in rodent
hippocampus, we show that activation
of GABAB receptors results in a decrease in KCC2 function,
which is associated with a reduction in the protein at the cell surface. These
findings reveal a novel "crosstalk" between the GABA receptor
systems, which can be recruited under conditions of high GABA release and which
could be important for the regulation of inhibitory synaptic transmission.
SIGNIFICANCE STATEMENT Synaptic
inhibition in the brain is mediated by ionotropic GABAA receptors
(GABAARs) and metabotropic GABAB receptors (GABABRs).
To fully appreciate the function and regulation of these neurotransmitter
receptors, we must understand their interactions with other proteins. We describe a novel association
between the GABABR and the potassium-chloride cotransporter protein,
KCC2. This association is significant because KCC2 sets the
intracellular chloride concentration found in mature neurons and thereby
establishes the driving force for the chloride-permeable GABAAR. We demonstrate that GABABR
activation can regulate KCC2 at the cell surface in a manner that alters
intracellular chloride and the reversal potential for the GABAAR.
Our data therefore support an additional mechanism by which GABABRs
are able to modulate fast synaptic inhibition.
In
bumetanide-responsive autism, neurons remain immature because the “GABA switch“
never flipped and so NKCC1 is overexpressed and KCC2 is underexpressed,
chloride levels remain high and the neurotransmitter GABA works backwards
(excitatory, rather than inhibitory).
Bumetanide
partially counters the over-abundance of NKCC1 transporters that carry chloride
into neurons, but is a partial solution.
The
above research suggests that blocking GABAB receptors might increase
the flow of chloride ions exiting through KCC2.
All
very complicated sounding, but in effect it means that a GABAB antagonist
might boost the effect of bumetanide.
Which GABAB
antagonist?
This
was Ling’s question.
Saclofen is a competitive antagonist for the
GABAB receptor. This drug is an analogue of the GABAB
agonist baclofen.
Phaclofen/phosphonobaclofen, is a
selective antagonist for the GABAB receptor.
Since
these “–aclofens” are not accessible we are left with a choice of homotaurine (developed
to treat Alzheimer’s) or Ginsenosides
from Korean/Panax ginseng.
Both homotaurine and Ginsenosides have various other
effects beyond GABAB.
Since Ling is in Scandinavia, homotaurine is an
option. It seems to be banned in the US, though it is approved in Canada and
sold in Europe.
Ginseng is very widely used, indeed it is the most
widely consumed herbal nutritional product in the world, with sales of $400
million in 2012.
I was
surprised that there actually is research in both humans and animal models
using Ginseng in autism and indeed ADHD.
N-Acetyl
homotaurine, a derivative of homotaurine,
is a registered drug called Acamprostate. It is used to treat alcohol
dependence. It affects both NMDA and GABA receptors. Acamprostate has been
shown to benefit Fragile-X, as has bumetanide. A drug that affects GABAB will
inevitably also affect NMDA receptors.
This
was covered in this post from 2015.
which
highlighted this paper:
Homotaurine has been reported as
a GABA
antagonist as well as a GABA agonist. In vitro studies have found
that homotaurine is a GABAA
partial agonist as well as a GABAB
receptor partial agonist with low efficacy, becoming an antagonist and a displacing full agonist of GABA or baclofen at
this receptor.[15] In a study in rats, homotaurine reversed the
catatonia
induced by baclofen (the prototypical GABAB
agonist),[16]
and was able to produce analgesia via the GABAB
receptor, an effect that was abolished when CGP 35348, a GABAB
receptor antagonist was applied.[17][18]
One
study in rats showed that homotaurine suppressed ethanol-stimulated dopamine
release, as well as ethanol intake and preference in rats in a way similar to the N-acetyl derivative of homotaurine, acamprosate.[20]
Acamprosate was approved by the FDA in 2004 to treat alcohol dependence.[3]
Fragile X syndrome (FXS) is an inherited form
of developmental disability and a single gene cause of autism. As a disorder
with increasingly understood pathophysiology, FXS is a model form of
developmental disability for targeted drug development efforts. Preclinical
animal model findings have focused targeted drug treatment development in FXS
on an imbalance between excessive glutamate and deficient gamma-aminobutyric
acid (GABA) neurotransmission.
Acamprosate
was generally safe and well tolerated and was associated with a significant
improvement in social behavior and a reduction in inattention/hyperactivity. The increase
in BDNF that occurred with treatment may be a useful pharmacodynamic marker in
future acamprosate studies. Given these findings, a double-blind,
placebo-controlled study of acamprosate in youth with FXS is warranted.
Back to
Ginseng
Background
Autism spectrum disorder (ASD) is
heterogeneous neurodevelopmental disorders that primarily display social and
communication impairments and restricted/repetitive behaviors. ASD prevalence
has increased in recent years, yet very limited therapeutic targets and
treatments are available to counteract the incapacitating disorder. Korean Red
Ginseng (KRG) is a popular herbal plant in South Korea known for its wide range
of therapeutic effects and nutritional benefits and has recently been gaining
great scientific attention, particularly for its positive effects in the
central nervous system.
Objectives
Thus, in this study, we
investigated the therapeutic potential of KRG in alleviating the
neurobehavioral deficits found in the valproic acid (VPA)-exposed mice models
of ASD.
Design
Starting at 21 days old,
VPA-exposed mice were given daily oral administrations of KRG solution (100 or
200 mg/kg) until the termination of all experiments. From P28, mice behaviors
were assessed in terms of social interaction capacity, locomotor activity,
repetitive behaviors, short-term spatial working memory, motor coordination, and
seizure susceptibility.
Results
VPA-exposed mice showed
sociability and social novelty preference deficits, hyperactivity, increased
repetitive behavior, impaired spatial working memory, slightly affected motor
coordination, and high seizure susceptibility. Remarkably, long-term KRG
treatment in both dosages normalized all the ASD-related behaviors in
VPA-exposed mice, except motor coordination ability.
Conclusion
As a food and herbal supplement
with various known benefits, KRG demonstrated its therapeutic potential in
rescuing abnormal behaviors related to autism caused by prenatal environmental
exposure to VPA.
In
the trial below the dose appears very low at 250mg. In the more encouraging
study in ADHD the dose was 1000mg twice a day.
Autism is a pervasive developmental disorder,
with impairments in reciprocal social interaction and verbal and nonverbal
communication. There is often the need of psychopharmacological intervention in
addition to psychobehavioral therapies, but benefits are limited by adverse
side effects. For that reason, Panax ginseng, which is comparable with
Piracetam, a substance effective in the treatment of autism, was investigated
for possible improvement of autistic symptoms. There was some improvement, which suggests some benefits of
Panax ginseng, at least as an add-on therapy.
Three male outpatients (age range 18.4–22.2
years; mean=21.3 years; SD =4.1 years) meeting ICD-10 criteria for autistic
disorder participated in our observation. IQs ranged from 54 to 82 (68 +/− 14),
which were obtained from the Wechsler Intelligence Scale. At least two child
and adolescent psychiatrists independently diagnosed the subjects for autistic
disorder. All subjects had no additional medical or neurological illnesses.
They had been treated with either methylphenidate, or neuroleptics before entry
into the study, without any positive effect (nonresponder). One patient’s
language consisted of monosyllabic utterances, second patient’s
language consisted of single words(10-word vocabulary),and the third patient spoke in
sentences. Parents and mentors’ (i.e., the person who takes care of the patient
in daily life, and supports the patient’s educational efforts) rated
instruments included weekly ratings by means of the Aberrant Behavior and Symptom
Checklist. Clinician ratings consisted of the Global Assessment Scale,
Psychiatric Rating Scale (CPRS), and Clinical Global Improvement. Panax ginseng
(oral administration of tablets containing 250-mg alcoholic Panax ginseng berry extract, pure encapsulations)
was administered for 4 weeks (dosage: 250 mg daily). Patients were free of medication for at
least 4 weeks before the beginning of the study. During that time, there were
no changes in the symptoms of the patients. Subjects continued to receive
educational and behavioral interventions, which were not altered substantially
in any of the patients during their participation in the study. The means of
parent and mentor ratings were averaged over the 4-week treatment period. Clinician
and mentor ratings were made at the beginning of the treatment period and then
weekly up to the end of the treatment. Ratings were compared by paired t-test.
RESULTS
Panax
ginseng slightly improved the ratings on the ABC factors: irritability (before
treatment, 13.2 +/− 5.9; after treatment, 11.3 +/− 6.2; p =.41), hyperactivity
(before treatment, 20.6+/−12.4;
after,18.4+/− 9.4; p = .33), inadequate eye contact (before treatment,
8.6 +/− 5.4; after, 7.5 +/− 3.2; p .35), and inappropriate speech (before
treatment, 6.1+/−2.2;after, 4.3 +/− 3.6; p = .41). The symptom checklist scores
revealed a slight increase in drowsiness (before treatment, 1.6 +/− 2.2; after,
2.9+/−4.2; p =.31) and decreased activity (before treatment, 2.5 +/− 3.3;
after, 4.4 +/− 3.1; p = 0.40). None of the clinician ratings showed significant
improvement. This may result from different impressions of clinical visits and
daily life observations of caregivers. Panax ginseng has some moderate sedative
effect with effects especially on daily life, a fact that also makes it
effective in the treatment of attention deficit/hyperactive disorders. None of
the subjects appeared to have headaches or stomach aches, although report of
such side effects was limited by the expressive language and social skills of
these subjects. Medication was continued after the observation period. We did
not see any significant changes in symptoms.
DISCUSSION
Although this was a very small study (n = 3),
which revealed very modest therapeutic effect of Panax ginseng in the
management of autistic patients in some of the subjects (which might be due to
the small sample size), it may be mentioned that its role in the management of
these symptoms in patients with autistic disorder may be limited, especially
because of its risk for estrogen-associated problems in females
(Papapetropoulos, 07). Since
there does not seem to be any significant improvement caused by Panaxginseng,
its effect as an add-on therapy remains completely open and requires further
investigation. Before
knowing its efficacy for adults, Panax ginseng should not be recommended for
treating children suffering from autism.
Ginseng for
ADHD?
Objective: There is evidence that Korean red ginseng
(KRG) can reduce the production of the adrenal corticosteroids, cortisol, and
dehydroepiandrosterone (DHEA), and thus may be a viable treatment for
attention-deficit/hyperactivity disorder (ADHD). The present randomized
double-blind placebo-controlled clinical trial tested the effect of KRG on
children with ADHD symptoms.
Methods: Subjects 6–15 years, who satisfied the
inclusion criteria and had ADHD symptoms, were randomized into a KRG group (n=33)
or a control group (n=37). The KRG group received one pouch of KRG (1g KRG extract/pouch) twice a
day, and the control group received one pouch of placebo twice a day. At
the 8 week point, the primary outcomes were the Diagnostic and Statistical
Manual of Mental Disorders (DSM-IV) criteria for inattention and
hyperactivity scale scores, which were measured at baseline and 8 weeks after
starting treatment. Secondary outcomes were quantitative electroencephalography
theta/beta ratio (QEEG TBR) (measured at baseline and week 8) and salivary
cortisol and DHEA levels (measured at baseline and at 4 and 8 weeks).
Results: The baseline characteristics of the KRG and
control groups were not statistically different. The mean ages of the KRG and
control groups were 10.94±2.26 and 10.86±2.41, respectively. The KRG group had significantly
decreased inattention/hyperactivity scores compared with the control group at
week 8 (least squared means of the differences in inattention adjusted for
baseline scores: −2.25 vs. −1.24, p=0.048; hyperactivity: −1.53 vs.
−0.61, p=0.047). The KRG group had significantly decreased QEEG TBR
compared with the control group (least squared means of the differences: −0.94
vs. −0.14, p=0.001). However, neither the KRG group nor the
control group exhibited significant differences in salivary cortisol or DHEA
levels at week 8 compared with the baseline levels. No serious adverse events
were reported in either group.
Conclusions: These results suggest that KRG extract
may be an effective and safe alternative treatment for children with
inattention and hyperactivity/ impulsivity symptoms. Further studies to
investigate the efficacy and safety of KRG are warranted.
Although medications to treat psychiatric
disorders for children and adolescents have been widely researched and several
are on the market, natural products may also be effective in these patients
while inducing fewer significant adverse effects. The present randomized
controlled trial was performed to assess whether KRG, a well-known traditional
medicine plant that is used particularly frequently in Eastern Asia, can
improve the adrenal function and inattention/hyperactivity symptoms of
chronically stressed children with ADHD symptoms. KRG extract significantly improved the inattention and
hyperactivity of the subjects and had a good safety profile. However, the KRG
extract did not have significant effects on cortisol or DHEA levels
Clinical
Significance
To our
knowledge, this is the first randomized controlled trial to investigate the
efficacy and safety of Korean red ginseng extract for children with ADHD. The
stimulant medications for ADHD have demonstrated not only clinical efficacy, but
also significant adverse events such as poor growth, tics, and psychosis. Although KRG extract did not
affect the salivary cortisol or DHEA, it significantly improved ADHD symptoms
and QEEG TBR. And the safety profile of KRG extract was good. The results imply that KRG
extract is a possible effective alternative medication for ADHD children.
OBJECTIVE:
A combination herbal product
containing American ginseng extract, Panax quinquefolium, (200 mg) and Ginkgo biloba extract (50 mg) (AD-FX; CV
Technologies, Edmonton, Alta.) was tested for its ability to improve the
symptoms of attention-deficit hyperactivity disorder (ADHD).
DESIGN:
Open study.
PATIENTS:
36 children ranging in age from 3
to 17 years who fit the diagnostic criteria for ADHD.
INTERVENTIONS:
AD-FX capsules were taken twice a
day on an empty stomach for 4 weeks. Patients were instructed not to change any
other medications during the study.
OUTCOME MEASURES:
At the beginning of the study,
after 2 weeks, and then at the end of the 4-week trial, parents completed the
Conners' Parent Rating Scale--revised, long version, a questionnaire that
assesses a broad range of problem behaviours (and was used as an indication of
ADHD symptom severity).
RESULTS:
After 2 weeks of treatment, the
proportion of the subjects exhibiting improvement (i.e., decrease in T-score of
at least 5 points) ranged from 31% for the anxious-shy attribute to 67% for the
psychosomatic attribute. After
4 weeks of treatment, the proportion of subjects exhibiting improvement ranged
from 44% for the social problems attribute to 74% for the Conners' ADHD index
and the DSM-IV hyperactive-impulsive attribute. Five (14%) of 36
subjects reported adverse events, only 2 of which were considered related to
the study medication.
CONCLUSIONS:
These preliminary results suggest AD-FX treatment may improve symptoms of
ADHD and should encourage further research on the use of ginseng and Ginkgo
biloba extracts to treat ADHD symptoms.
Interactions of ginsenosides with ligand-bindings of GABA(A) and GABA(B) receptors.
Abstract
1. Total saponin fraction
decreased the affinity of specific [3H]muscimol binding without changes in
Bmax. Ginsenoside Rb1 Rb2, Rc, Re, Rf and Rg1 inhibited the specific
[3H]muscimol binding to the high-affinity site. 2. Total saponin fraction
increased the affinity of specific [3H]flunitrazepam binding. Ginsenoside Re
and Rf enhanced specific [3H]flunitrazepam binding.
3. Total saponin fraction
decreased the affinity of specific [35S]TBPS binding without changes in Bmax.
Ginsenosides did not affect specific or non-specific [35S]TBPS binding.
4. Total saponin fraction
decreased the affinity of specific [3H]baclofen binding without changes in
Bmax. Ginsenoside Rc inhibited
specific [3H]baclofen binding.
very detailed paper
Also (Ling) note that there is an effect on ERbeta
A ginseng-derived oestrogen receptor
beta (ERbeta) agonist, Rb1 ginsenoside,
attenuates capillary morphogenesis.
Ginseng
extracts contain a variety of active ingredients and have been shown to promote
or inhibit angiogenesis, depending on the presence of different ginsenosides
that exert opposing effects on blood vessel growth. Leung et al. in this
issue of the British
Journal of Pharmacology report that Rb1, a ginsenoside that
constitutes only 0.37–0.5% of ginseng extracts (depending on manufacturing and
processing methods), blocks tube-like network formation by endothelial cells in vitro. At the
molecular level, Rb1 binds to the oestrogen receptors and stimulates the
transcription of pigment epithelium-derived factor that, in turn, inhibits
matrix-driven capillary morphogenesis.
Ginseng, the root of Panax ginseng and
related species, has been a key component of traditional medicine in the Far
East for over a thousand years. The genus name Panax means ‘cure
all' in Greek; it, thus, comes as no surprise that ginseng has been described
as beneficial in many different ailments (Huang, 1999; Kiefer and Pantuso, 2003; Ng, 2006). Perhaps the most studied biological
actions of ginseng extracts and constituents are those relating to its
inhibitory effects on solid tumour growth (Yun, 2001). The main active ingredients in
ginseng-based herbal preparations are thought to be the ginsenosides,
comprising 3–6% of ginseng extracts (Huang, 1999).
Reviewed here is the existing evidence for
the effects of ginseng extracts and isolated ginsenosides relevant to cognition
in humans. Clinical studies in healthy volunteers and in patients with
neurological disease or deficit, evidence from preclinical models of cognition,
and pharmacokinetic data are considered. Conditions under which disease
modification may indirectly benefit cognition but may not translate to
cognitive benefits in healthy subjects are discussed. The number of chronic
studies of ginseng effects in healthy individuals is limited, and the results
from acute studies are inconsistent, making overall assessment of ginseng's
efficacy as a cognitive enhancer premature. However, mechanistic results are
encouraging; in particular, the ginsenosides Rg3 , Rh1 , Rh2 , Rb1 , Rd, Rg2 ,
and Rb3 , along with the aglycones protopanaxadiol and protopanaxatriol,
warrant further attention. Compound K has a promising pharmacokinetic profile
and can affect neurotransmission and neuroprotection. Properly conducted trials
using standardized tests in healthy individuals reflecting the target
population for ginseng supplementation are required to address inconsistencies
in results from acute studies. The evidence summarized here suggests ginseng
has potential, but unproven, benefits on cognition.
Ginseng is the most widely consumed herbal
nutritional product in the world. According to the most recent data available, ginseng
had a total world export value in 2010 of over US$350 million, which was expected
to rise to more than US$400 million in 2012
The survey had 54 respondents and 4 (8.5%) used
Ginseng.
Conclusion
There
is a long list of substances shown to have a benefit in some autism. Today we
can add the Asian type of Ginseng and also Acamprosate (at least for Fragile-X).
It
would be interesting to see the effect of Phaclofen and Saclofen which may be more selective for GABAB
receptors.
Ginseng has so many effects there is no way to know
which is the one that benefited autism and ADHD in today’s highlighted posts.
We also have the problem with natural substances
that there is natural variation and that supplement companies are known to
cheat with ingredients. Ginseng roots are not cheap and apparently ginseng is
known to get adulterated. Drug companies
are usually much more reliable.
If anyone tries out homotaurine or ginseng, let us all
know the result.
Homotaurine was originally developed as an
Alzheimer’s drug, but did not work well enough, its developer then tried to
sell it as a supplement called Vivimind, but it was rejected by the FDA. It is
sold in Canada and Europe.
For our Aspie readers, here is a link for them:-
