Chapter
23
The Science
INTRODUCTION
The Road Back Program
and the development of the program:
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There are basic common denominators of psychotropic
drug side effects.
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How our individual DNA affects drug metabolism.
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The effect of psychotropic medication within the
Hypothalamic-Pituitary-Adrenal Axis and immune
system.
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Utilizing DNA clinical trials, test subject trials
and psychotropic drug clinical trials to formulate
specific nutritional products
to
eliminate, reduce or avert withdrawal side effects,
while not creating drug/supplement interactions.
This research and development complexity has been
transformed into an easy to understand, systematic
program, which allows an individual to taper off their
medication while alleviating a vast percentage of the
debilitating side effects of withdrawal.
The sequence of this program and the application of each
step is the key to success. Your patient will not begin
to reduce a medication until the pre- taper is complete.
The pre-taper is a 7-day process.
Statements of fact:
All psychoactive medications
metabolize through specific pathways.
All psychoactive medications alter the
Hypothalamic Pituitary-Adrenal
Axis to some degree. To some extent, you can
predict the duration before drug-adverse reactions begin
with most psychoactive drugs if the patient’s P450 (CYP)
enzymes have been screened. A poor metabolizer as well
as an extensive metabolizer will eventually reach the
same saturation point; the poor metabolizer much faster,
of course. If one were to look at the basic structure of
the human body, the chemical structure of psychoactive
drugs, and
include how psychoactive
drugs
are metabolized, how foods, vitamins, minerals, DNA,
amino acids, hormones,
glands, proteins, fatty acids and enzymes work,
in relation to psychoactive drugs, you have
The Road Back
science.
The patient has been under some duress and stress before
a diagnosis was given and the prescription was written.
With this in mind the patients JNK gene would have been
overly expressed for some duration. Balancing the JNK
gene activation will lead to a normalization of the
patient in time.
Drug targets for most disorders will be the purinergic
system, the dynorphin opioid neuropeptide system, the
cholinergic system (muscarinic and nicotinic systems),
the melatonin and serotonin system, and the HPA axis. An
additional reason the supplements were selected to be
used in this program; their natural action of helping to
balance the same drug targets.
DNA and Prediction of Drug Adverse Reactions
The following charts detail the P450 enzymes used to
metabolize the most common antidepressants,
anti-psychotics, benzodiazepines and ADHD stimulant
medications. An X in the row denotes that the medication
utilizes that specific pathway. Below each chart, you
will find other routes of metabolism if applicable.
These medications
inhibit metabolism via listed CYP pathways.
Marked medications (*) will also use
other routes for metabolism.
Adapin – ABCB1-P-pg, UGT1A3, UGT1A4
Anafranil – UGT2B10, CYP3A4, UGT1A4, UGT1A4, UGT2B7,
ABCB1-P-gp, CYP3A4
Amitriptyline – 3A4, UGT2B10, UGT1A4, SLC22A1- OCT1,
ABCB1-P-gp, UGT2B7, CYP3A4, CYP2C8, CYP2D6
Celexa – ABCB1-P-gp, CYP3A4
Clomipramine – UGT2B10, CYP3A4, UGT1A4,
UGT2B7, UGT1A4,
UGT1A3
Doxepin – ABCB1-P-gp, UGT1A3, UGT1A4
Desyrel – CYP3A4, ABCB1-P-gp, P-pg Effexor – CYP3A4,
ABCB1-P-gp, P-gp Effexor XR – CYP3A4, ABCB1-P-gp, P-gp
Elavil – UGT1A4, UGT1A3, P-gp
Imipramine – UGT2B10, ABCB1-P-gp, UGT1A4, CYP3A4,
SLC22A2-OCT2, UGT1A3, UGT2B7, SLC22A1-OCT1,
SLC22A3-OCT3, CYP3A4
Luvox – 2B6, P-gp, intestinal 3A, ABCB1-P-gp, CYP2B6,
CYP3A4
Norpramin – SLCC22A1-OCT1, SLC22A2-OCT2, SLC22A3- OCT3,
CYP3A4
Pamelor – CYP3A4, ABCB1-P-gp, CYP2C8
Paxil – 2B6, P-gp, CYP3A4, CYP2B6, ABCB1-P-gp
Paxil CR – CYP3A4, CYP2B6,ABCR1-P-gp
Pristiq – Assorted UGT isoforms
Prozac – 2B6, P-gp, ABCG2-BCRP, SLC22A3-OCT3, CYP3A4,
SLC22A1-OCT1, ABCB1-P-gp
Sarafem – 2B6, P-gp, ABCG2-BCRP, SLC22A3-OCT3, CYP3A4,
SLC22A1-OCT1, ABCB1-P-gp
Serzone -- U
Sinequan – UBCB1-P-gp, UGT1A3, UGT1A4
Tofranil – UGT1A4, UGT1A3, P-gp, Triptil – ABCB1-P-gp
Wellbutrin – 2E1, 2A6, 2B6, CYP2B6
Wellbutrin SR – CYP2B6
Zoloft – UGT2B7, UGT1A4, P-gp, 2B6, CYP2B6, MAO, CYP3A4,
ABCB1-P-gp
Marked medications
(*) will also use other routes for metabolism:
Chlorprom – UGT1A4, UGT1A3, P-gp
Chlorpromanyl – UGT1A4, ABCB1-P-gp
Clozaril – FMO, UGT1A4, UGT1A3, ABCB1-P-gp, FMO3,
ABCG2-BCRP
Geodon – Aldehyde oxidase substrate
Haldol – Glucuronidation, P-gp, UGT2B7, CYP3A4,
CYP3A5, UGT1A9, ABCB1-P-gp
Mellaril – CYP3A4, CES1, P-gp
Ridazine – UGT1A4, ABCB1-P-gp
Risperdal – P-gp, renal extraction, CYP3A4, ABCB1-P-gp,
ABCG2-BCRP
Saphris – Various UGT
Seroquel – Glucuronidation, P-gp, intestinal 3A, epoxide
by quetiapine, CYP3A4, ABG2-BCRP, ABCB1-P-gp
Zyprexa – Glucuronidation, FMO, UGT1A4
Marked medications (*) will also use other routes for
metabolism.
Ativan – UGT2B15, UGT2B7
BuSpar – Intestinal 3A, 3a4
Carbatrol – 3A4, CYP2C8, SLC22A5-OCT2N, UGT2B7, CES1,
CYP2B6, ABCB7-ASAT, SULT1A1, ABCC2-MRP2,
ABCG2- BCRP, SLCO1A2-DATP1A2
Depakene – CYP2B6, UGT1A6, CYP2A6, UGT2B15, UGT2B7,
UGT1A9, ABCB1-P-gp
Depakote – UGT2B7, UGT1A6, UGT1A9, UGT2B15, UGT1A4,
UGT1A3
Dilantin – UGT1A4, UGT1A6, UGT1A9, ABCB1-P-gp, CYP2C9,
CYP2C8, UGT1A1, CYP3A5, UGT2B7, CYP3A4, CYP2B6, UGT2B15
Halcion – CYP3A4, CYP3A5
Klonopin – NAT2, CYP3A4
Lamictal – UGT1A3, UGT2B7, UGT1A4
Librium – CYP3A4
Neurontin – SLC22A4-OCTN1
Valium – CYP3A4, CYP2B6, CYP3A5, UGT2B7
Xanax – Hepatic 3A, CYP3A5, CYP3A4
Marked medications
(*) will also use other routes for metabolism:
Concerta – Glucuronidation, CES1A1. Medate – CES1A1.
Methylin – CES1A1.
Ritalin – Glucuronidation, CES1A1. Ritalin – CES1A1.
Vyvanse – CYP3A4, MAO
How to Use Charts to Decide Sequence of Medication Reduction
If you have two or more medications sharing the same CYP
pathway to metabolize, reduce the medication that uses the
fewest pathways first.
Example:
Ambien used concurrently with Luvox, Paxil, Prozac,
Wellbutrin or Zoloft. Reduce the Ambien first.
If you were to reduce any of the antidepressants listed
first, the Ambien would begin to clear the body faster and
the patient would experience Ambien withdrawal without the
current Ambien dosage being reduced. Ambien would be reduced
by as much as 43% if the antidepressant were reduced first.
(See Ambien product insert.)
The best approach is to always taper the anticonvulsant,
antianxiety, benzodiazepine or sleep medication first and
then tackle the antipsychotic and antidepressant.
If taking two antidepressants concurrently, or taking an
antidepressant and an antipsychotic, selecting which one to
reduce first would also follow the format outlined earlier
in this section. The drug using fewer common CYP pathways
should be reduced first.
If taking two antidepressants or one antidepressant and one
antipsychotic, and the CYP pathways match, evaluate the
current side effects, when each side effect started, when
each medication was introduced, and determine from those
side effects which taper schedule to follow and which drug
to taper first.
From time to time, a person will also be taking a drug as an
inducer of the CYP pathways.
Determine if this “inducer” was prescribed to help offset
the inhibitor drug’s effect or is the
inducer drug
prescribed for other health reasons not related.
You will generally find that those who are also taking the
inducer medication
will be suffering from a wide variety of adverse side
effects. When reducing any medication attached to the same
pathway as an inducer medication, reduce the normal taper
speed by one-half for at least the first 2 months.
You may need to alternate reduction of the inducer drug and
the inhibitor drug every other reduction in order to
maintain a balance.
Other medications must be closely evaluated.
Lipitor, as an example, is an inhibitor of the CYP
2C19, 2D6, and 3A, along with inhibiting the UGT1A3, UGT1A1,
P-gp, and intestinal 3A.
Use drug product inserts to determine metabolism route or
the Physicians’ Desk Reference.
Example 1:
If taking multiple medications and each medication uses the
same metabolic route, each of the medications is competing
for clearance. If one medication is reduced, the other
medications will also be reduced or clear the body faster.
Decide
which medication to taper off first based on:
If patient has used Lexapro for two years and used Risperdal
for 2 months and side effects increased dramatically once
Risperdal was introduced, taper the Risperdal first.
Example 2:
If multiple medications are being taken and all medications
can metabolize through several routes,
the impact will be lessened, and selecting which
medication to taper first would not be pathway dependent.
Avoid all supplements
that compete with the same pathways, and eliminate as
much as possible all foods that compete with the medication
by inducing or inhibiting the metabolism routes of the
medications.
With the advancements of
The Road Back Program,
as described in this book, patients can now taper off
antidepressants, antipsychotics and ADHD medications and
stimulants simultaneously. Reduce the medications as slowly
as possible, as close to 10% reduction as possible, and only
increase the rate of reduction once the patient has shown
tapering success at lower reductions.
Supplements, Herbs and Foods
Supplements, herbs or certain foods can have a direct impact
on the success of the taper.
Datum:
If a person smokes or drinks coffee before starting the pre-
taper, do not suggest they quit. Cigarette smoke induces the
CYP1A2, 2E1,
3A and UGT2B7.
Nicotine inhibits UGT1A1, UGT1A4, UGT2A6, and UGT1A9. If
taking Depakote and starting or stopping smoking, the impact
on the medication will be dramatic.
If a patient starts to smoke or quits smoking while taking
Cymbalta, the drug will be altered by as much as 15%. In
theory, this should apply as well to any other drugs sharing
the same metabolism routes.
Coffee or caffeine inhibits the CYP1A2, 2E1 and the 3A.
A high percentage of these medications metabolize through
these pathways and caffeine usage will dramatically increase
the medication, or if the person were to quit drinking
caffeine, they would begin to go into withdrawal to some
degree because the pathways will begin to metabolize the
medication faster.
The times a person takes medication and when they drink two
cups of coffee can have an impact as well. If the person
drinks two cups of coffee every morning about one hour after
their medication, and they change the time of the morning
they drink the coffee, expect a slight to above average side
effect from the medication.
The person’s current daily routine should not be changed. If
they were on a poor diet before starting this program, do
not change their diet drastically. If they did not exercise
before starting this program, do not advise them to do more
than a casual walk.
Once off all medication for 45 days, a healthy diet can be
implemented, an exercise program that matches their current
physical condition can be started, the patient can stop
smoking, etc.
A trace amount of an herb or supplement
will not create an
adverse reaction or alter the metabolism speed.
DNA Drug Reaction Testing and Taper Prediction
For the past several years, DNA drug reaction testing has
been available to determine the patient’s ability to
metabolize medication through the CYP450 enzymes.
We have conducted over 200 drug reaction tests with the
objective of determining how well drug-adverse reactions
could be predicted, and if there were clinical use of this
DNA data for tapering.
Prediction of a drug-adverse reaction:
The individuals who were slow or poor metabolizers or hyper
metabolizers experienced drug-adverse reactions faster than
normal or intermediate metabolizers.
However,
the normal or intermediate metabolizers still experienced
adverse drug reactions, but after longer usage of the
medication. The
metabolism type of the individual was not indicative of the
severity of adverse reactions or duration. Once the drug
had saturated the CYP enzyme used for metabolism, all the
individuals experienced the same side effect profile
regardless of their metabolism speed noted from the DNA drug
reaction test.
The test results from the DNA drug-reaction test did not
lead to a worthwhile taper guide. It was postulated; if you
were to induce the enzymes or inhibit an enzyme to match a
specific test result and medication, you would be better
able to adjust the metabolism and avoid withdrawal, or
predict the withdrawal sequence. Again, this did not assist
in tapering or eliminating withdrawal side effects in the
slightest. This seems to parallel the results using an
inducer drug to counteract the inhibition of the main drug.
If a DNA drug-reaction test has any use to a physician, it
would be for predicting the dosage of the medication
Coumadin. The initial prescription could be limited to a
narrow band, and the correct therapeutic dosage would be
found in a few weeks, instead of several months.
Nutritional DNA Test
Nutritional DNA testing provided this program substantial
information to work with. We tested the ability of
over 100 subjects to metabolize B vitamins, folate, calcium,
Omega 3, phase II liver detox genes, Interleukin-6, and an
assortment of other genetic differences that ultimately
determine overall health and physical well-being.
The Road Back Program
and all suggested nutritionals used for medication tapering
address the most common genetic variations of the population
at large. Though DNA science is not precise at this date,
enough evidence is available to formulate part of a program
to address the highest percentage of the population.
Hypothalamic-Pituitary-Adrenal Axis (HPA)
Psychoactive medications play havoc with the HPA. While
benzodiazepines usually help with anxiety for a certain time
period, the feedback loop sending incorrect data will
eventually cause cortisol levels to increase, and the result
will be increased anxiety in the morning and mid-afternoon.
Insomnia will usually follow the cortisol level increase.
Other psychoactive medications have their own unique side
effect profile and ultimate effect upon the HPA.
First year medical school textbooks describe the
hypothalamus as: “Hypothalamus/ homeostasis or maintaining
the body’s status quo.” As an example, blood pressure, body
temperature, fluid, the electrolyte balance and body weight
are held in a precise value labeled the “set-point.” The
body’s set-point may change over time,
but from day to day,
the set-point will remain nearly fixed. With the HPA
receiving continual input about the state of the body and
the ability of the HPA to initiate changes, as anything
might sporadically fall out of balance, it is vital for the
HPA to have at hand all necessary nutrients to assist with
the compensation.
When the HPA is out of balance, you will have a problem with
insulin, stress, anxiety, weight gain, thyroid problems,
fatigue, unbalanced sexual hormones and countless other body
difficulties.
The hormone, ACTH, will eventually become out of balance, as
will the other hormones and adrenals.
Psychoactive medication directly alters specific areas
within the HPA. Examine any patient using a psychoactive
medication for more than three months and you will probably
find a problem with hormones, thyroid, adrenals, cortisol
and immune system or other areas within the HPA.
However, it will be equally important to move beyond the
normal view of the HPA. Psychoactive medication side effects
are quite varied and diverse. This is not to rehash data
from medical school, but to tie in the knowledge gained in
the educational process with psychoactive medication.
Some fibers from the optic nerve go directly to a small
nucleus within the hypothalamus (suprachiasmatic nucleus).
This nucleus regulates circadian rhythms, and couples the
rhythms to the light/dark cycles.
The nucleus of the solitary tract will collect sensory data
from the vagus and relay the data to the hypothalamus. This
data will include blood pressure and gut enlargement.
The reticular formation receives a vast supply of inputs
from the spinal cord and relays that data to the
hypothalamus. Part of that data will be skin temperature.
Nuclei, circumventricular organs, are unique in their own
right as they lack a blood-brain barrier. They monitor
substances in the blood and have the ability to monitor
substances normally shielded by the neural tissue. Here you
will find regulation of fluid and electrolyte balance, by
controlling thirst, sodium excretion, blood volume
regulation and vasopressin secretion. Include in this the
area postrema, and you have the detection of blood toxins
and the vomit-inducing center. The OVLT and area postrema
project to the hypothalamus.
The limbic and olfactory systems project to the
hypothalamus. Psychoactive medication side effects, such as
eating problems and reproduction difficulty, will probably
be traced to this area.
Ionic balance and temperature will be subject to the
hypothalamus via the receptors, thermoreceptor and
osmorecepter.
When the hypothalamus
is aware of a problem, it will assert repair
mechanisms. Neural signals to the autonomic system will
attempt to regulate heart rate, vasoconstriction, digestion,
sweating etc., and the endocrine signals to and or through
the pituitary.
The pituitary side effects will include one or all six
hormones, to include
ACTH and the
thyroid-stimulating hormone (TSH). The repair output
attempt, and the psychoactive medication side effect
profile, seem to run near a 50 percent occurrence.
Furthermore, you can directly trace psychoactive medication
side effects to the autonomic nervous system in both the
sympathetic and parasympathetic systems.
The hypothalamus can alter blood pressure; control every
endocrine gland in the body, body temperature, adrenal
levels via ACTH, and metabolism.
The repetition of HPA information in this Chapter has been
intentional. Do not be surprised to find a male patient with
extremely high estrogen levels, a female with high
testosterone or any other problems that can be associated
within the HPA axis.
Taper the medication first, wait 45 days after the last
dosage of the medication, reevaluate the patient, and then
gradually bring all parts of the HPA back into balance. The
nutritionals used with
The Road Back Program were developed to help the body
overcome this imbalance
gradually.
Gradually is italicized because this is where most problems
occur with psychoactive drug-taper programs. Either they do
not address the HPA or the program is really a
detoxification or heavy metal chelating program.
The Road Back Program
utilizes specific nutritionals to address the drug side
effects and to begin the process of balancing the HPA.
Specifics on each nutritional, what each nutritional is
addressing
within the HPA or the body in relation to psychoactive
medications, can
be found in The Road
Back Program patent when published by the U.S. Patent
Office.
Immune System
The immune system and the HPA are in constant communication
and actions within one system will induce response in the
other. The supplements used in this program are designed to
also influence the immune response.
Reducing oxidative stress has been shown to balance
Interleukin-2 (IL-2) as well as Interleukin-6. If you were
to test your bipolar patients IL-2 levels, you will find
they will be too high during the manic phase and IL-6 levels
will have shot up high during the depressive phase. A
schizophrenic will have either too high or too low IL-2
levels and will usually exhibit high IL-6 levels constantly.
The JNK supplement will reduce oxidative stress and lower
IL-2 levels as well as IL-6 levels. The specific cascading
effect is; JNK gene over expression leads to increase of
Interleukin-2 levels which create an imbalance
of Th1 and Th2. CD4 will usually show dysfunction
after prolonged Th1 and Th2 alteration.
Titrating Medication
The Road Back
has tried titrating medication gradually without the use of
nutritionals with limited success. About 50% of the people
could taper off their medication without using these
nutritionals but they still suffered extreme withdrawal side
effects.
Using a gradual titration combined with a basic
detoxification approach had lower than 50% success.
The normal supplements used to remove heavy metal or for a
liver detox produced undesirable results.
A gradual titration with the use of the suggested
nutritionals gives our standard successful results.
The Key to a Successful Taper With
The Road Back Program
Following the pre-taper exactly as described is critical.
The pre-taper is the make or break point for every
successful taper.
Most problems occur when:
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The pre-taper is done too quickly.
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Patient does not stop increasing a nutritional once a
positive change occurs.
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Patient changes the time of day they take medication.
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Patient changes the time of day they take nutritionals.
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Medication is reduced too quickly.
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A new medication is prescribed in addition to existing
medication.
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Patient is switched to a new medication.
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Doctor has patient use additional supplements or
vitamins not
in this program.
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Patient begins taking other supplements.
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Patient makes a major change to their daily routine.
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Patient skips days of taking medication.
Titrating Psychoactive Medication:
Have the patient compound his/her medication whenever
possible. An exact reduction of the medication each week
provides prediction, no guessing, and the highest chance of
success.
In the early days of psychoactive drugs, psychiatry did not
titrate psychoactive drugs up slowly on patients and the
results were catastrophic. Many drugs, other than
psychoactive drugs, must be titrated up as well as down
before complete discontinuing.
There seems to be a medical community consensus that
psychoactive drugs can be reduced quickly, or patients can
abruptly be taken off one psychoactive drug and prescribed
another psychoactive drug without an adverse consequence.
This is not the case. Even switching a patient from a
tablet form of a psychoactive drug to the liquid form of the
same psychoactive drug can cause extreme adverse drug
reactions.
Dr. Donald E. McAlpine, psychiatrists at the Mayo Clinic
states: “It’s important to taper off slowly, extending the taper over several
weeks under your physician’s direction. When you stop too
quickly, you may experience so-called discontinuation
symptoms, which can masquerade as relapse.”
The discontinuation process and side effects therein can be
confusing to both the patient and physician. Which side
effect is coming from the medication, or is it a return of
the original symptom?
With a full pre-taper completed before reducing the
medication, rest assured the side effect starting during the
taper is due to one of the following:
The patient changed something.
The reduction of the medication is too large.
A change made by the patient can be the most difficult to
find. It might be something the patient does not feel is a
change.
Years ago, I had a person nearly halfway off Paxil. This
person experienced no withdrawal side effects tapering the
Paxil to that point. When trying to taper off Paxil in the
past, the individual had extreme withdrawal side effects
after the first reduction attempt and would then need to
return to a full dosage.
With no valid explanation, this person began to suffer
withdrawal side effect symptoms similar to those earlier.
Two weeks passed and I could not find anything the person
had changed. Finally, it was mentioned to me by the
individual he or she had started an all-protein diet and
began the diet 3 days before the side effects started.
For this person doing this diet was not a change. He or she
would go on this all-protein diet every six months.
I give you this example to point out that the change
a patient makes may not be so obvious. You may need to dig.
If a patient is keeping a complete Daily Journal these
changes can be spotted more quickly and trouble tapering can
be avoided.
Use the Suggested Supplements
If you want the standard results with
The Road Back Program,
use the exact supplements suggested. Read through Chapter 3,
“Nutritionals” Used on
The Road Back Program for a list of all supplements,
basic description of each and where they are available.
Most, if not all of the manufacturers of these supplements
offer a healthcare provider distributor program, if you wish
to carry them in your practice.
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