Dopamine and Serotonin Agonists Given in tandem remit Multiple Medical Conditions: Are These Neurotransmitters the Primal Regulators? A paradigm-shifting hypothesis
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Are the Monoamines dopamine and Serotonin Neurotransmitters the Primary
Regulators? A paradigm-shifting hypothesis
The serotonin (5HT) agonist, fenfluramine (FEN), and the dopamine (DA)
agonist, phentermine (PHEN) when given in tandem have an extremely wide
therapeutic effect. Combined FEN/PHEN administration has far superior
anorectic effects when compared to either of these substituted
amphetamines taken alone. Furthermore, not only is there a superior
weight loss result, but also tachyphylaxis does not develop(1).
FEN/PHEN abolishes not only alcohol and alcohol craving(2,3) but also
resolves all psychoneuroses in nineteen severely depressed alcoholics,
seven of them cocaine co-addicted(4). Over the last 39 months,
582 patients with affective and/or obsessive/compulsive disorders (OCD)
with (166) or without (416) alcohol or substance addiction have enjoyed
relief of depression, obsession and craving. More than 300 alcoholics
and 100 cocaine-addicted individuals had experienced craving relief, very
nearly always in less than 2 hours if craving at the time of the first
These monoamines, acting reciprocally, act clinically as TH1 and TH2
modulators(5). Dopamine is almost certainly a TH1-type agonist and an
inhibitor of TH2 while 5HT is a TH2-like agonist and a TH1
Patients suffering from immediate and delayed hypersensitivity disorders
(IHD, DHD) enjoyed a similar relief and also had a resolution of their
immune disorders. At least thirty-nine asthmatics, more than twelve of
them refractory to traditional treatment, savored resolution of symptoms.
Their previously prescribed sympathomimetics, antihistamine and
corticosteroids became redundant. Persistence of allergic rhinitis,
urticaria, or asthma is an indication to increase DA in the FEN/PHEN
protocol. The response is universal.
A forty-three year old registered nurse with not only refractory asthma
but also idiopathic and shellfish anaphylaxis had a resolution of her
asthma despite the cessation of multiple medications,had no reaction when
she ate shellfish and reduced her markedly elevated histamine levels to
Response to TH2-driven conditions also respond. More than 20 efractory
psoriasis patients,Two out of three with Crohn's disease(2/3),
individuals with cutaneous lupus and Sjogren's enjoyed a total or near
total resolution. Both IHD and autoimmune patients were able to
discontinue all other medications.
A patient suffering from amyotrophic lateral sclerosis lost his extensive
fasciculations and severe fibromyalgia-like pain within 60 minutes of
initiation of therapy and continues without them two months later. The
only patient with multiple sclerosis, previously experiencing
exacerbations every three to four months, commented that not only had she
had no attacks in the eighteen months she has been taking FEN/PHEN but
the amount of physical exertion she was capable of doing during the
recent blizzard couldn't have been done by her 18 months before therapy.
The response rate in all these conditions has been greater than 75%.
Three HIV+ patients have had clinically significant improvement. All
three showed impressive psychological and physical improvement when
treated with FEN/PHEN. In two of these cases, CD4+ counts increased with
FEN/PHEN (170 to 480, 480 to 900). They had relief of severe depression
and cocaine craving. The third patient, suffering from advanced AIDS,
had a CD+ count of five. He suffered from oral and esophageal thrush,
wasting, depression, anxiety, abdominal pain with diarrhea, anorexia and
Treatment with FEN/PHEN was initially directed toward relief of his
affective disorders. This goal was realized after three days of
treatment. By the fifth day, his thrush and all the other symptoms had
resolved. Appetite returned with a 2.5 kg. Weight gain for the six weeks
he continued the protocol. Abdominal pain and his chronic diarrhea
resolved. Unfortunately, he expired two weeks after his AIDS physician
stopped FEN/PHEN therapy.
Many patients report a marked decrease in viral illnesses and that an
increase in the DA agonist dose results in a marked decrease of symptoms.
Patients with frequent or chronic candidiasis have found relief.
There is increasing belief that a balance of TH1 and TH2 promotes health
and homeostasis eerily similar to Hippocrates balance of the humors or
Yin/Yang(8-11). Serotonin, in relative excess, presumably triggers
immediate hypersensitivity disorders. Immediate hypersensitivity
patients, not fully responding to the initial FEN/PHEN, will go into
remission with a DA increase. Excessive TH1, caused by dopamine relative
excess causes organ-specific autoimmunity(12). Conversely, those with
psoriasis or Crohn's respond to when the TH1 antagonist FEN dose is
Dopamine and 5-HT deficiencies are not only found in HIV but also in
chronic stress(13) and during alcohol withdrawal(14,15). These monoamine
deficiencies have been considered the etiology of stress-induced
behavioral and immunological pathology(13,16). The HIV and murine stress
immobilization induce excessive TNF-alpha and interferon-gamma
production and start a cascade resulting in DA and 5-HT deficiency(17).
TH1 cytokines increase indoleamine 2,3 dioxygenase (IDO)(18). This
enzyme shunts tryptophan towards the kynurenic pathway thereby decreasing
5HT production. Marked increases in kynurenate and quinolinate(19) and
deficiencies of tryptophan, 5-hydroxytryptophan and 5-HT result(17).
Excessive quinolinic acid being a dopaminergic cell neurotoxin, DA
production and DA levels decrease.
A similar tyrosine depletion secondary to an increase in tyrosine
aminotransferase activity occurs with chronic stress(20). A similar
mechanism may be occurring in HIV.
Clinicians have been utilizing this monoamine immunomodulating effect
unknowingly. Pentoxifylline, a methylxanthine, is a DA and 5HT
agonist(21) and is effective against both endotoxic shock(22) and HIV in
vitro replication(23). Methylxanthines and cannabis, both effective
against asthma(24), are DA and 5-HT agonists(25,26). Bromocriptine, a DA
agonist, combined with cyclosporine, a 5-HT agonist(27), increases murine
and human cardiac transplant survival(28,29). Finally, fluoxetine and
other SSRI's, the "panaceamycins" of the 90's, promote 5-HT and DA(30).
It is likely that thalidomide, with its wide therapuetic range, is also a
combined monoamine agonist.
FEN/PHEN's ability to reverse psychiatric, craving, and immediate and
delayed hypersensitivity disorders suggests that DA and 5HT, both only
one precursor away from amino acids may be not only Selye's "first
mediators of stress," but also the primary regulatory neurotransmitters
formed coincident or shortly after life began. The hypothesis is that all
other controlling mechanisms are derived from the DA-HT interaction with
multiple intricate mediators developing along the way.
Further studies, especially if done expeditiously, are eagerly awaited by
the author who, as a internist in general medicine, is neither
practically nor ethically able to proceed with these mandatory studies.
However,unpublished murine studies by Bart Hoebel at Princeton and Hans
Fisher at Rutgers confirm the addiction hypothesis. In the works are
alcohol and cocaine studies at the Kansas City VA, a Persian Gulf illness
and fibromyalgia study at the U. of Wisc. and an asthma study at Mass
1. Weintraub, M. 1992. Long-term weight control study: conclusions. Clin.
Pharmacol. Ther. 51:642.
2. Hitzig, P. 1993. Combined dopamine and serotonin agonists: a
synergistic approach to alcoholism and other addictive behaviors. Md.
Med. J. 42:153.
3. Rothman, R. B., T. Gendron, and P. Hitzig. 1994. Combined use of
fenfluramine and phentermine in the treatment of cocaine addiction: a
pilot case series. J. Subst. Abuse Treat. 11:273.
4. Hitzig, P. 1994. Combined serotonin and dopamine indirect agonists
correct alcohol associated craving and alcohol-associated neuroses. J.
Subst. Abuse Treat. 11:489.
5. Devoino, L., G. Idova, M. Cheido, E. Alperina, and N. Morozova. 1986.
Monoamines as immunomodulators: importance of suppressors and helpers of
the bone marrow. Methods Find. Exp. Clin. Pharmacol. 8:175.
6. Arzt, E., M. Costas, S. Finkielman, and V. E. Nahmod. 1991. Serotonin
inhibition of tumor necrosis factor-alpha synthesis by human monocytes.
Life Sci. 48:2557.
7. Borgundvaag, B., J. E. Kudlow, S. G. Mueller, and S. R. George. 1992.
Dopamine receptor activation inhibits estrogen-stimulated transforming
growth factor-alpha gene expression and growth in anterior pituitary, but
not in uterus. Endocrinology 130:3453.
8. Hernandez-Pando, R. and G. A. Rook. 1994. The role of TNF-alpha in
T-cell-mediated inflammation depends on the Th1/Th2 cytokine balance.
9. Lacour, M. 1994. Acute infections in atopic dermatitis: a clue for a
pathogenic role of a Th1/Th2 imbalance? Dermatology. 188:255.
10. Rook, G. A., R. Hernandez-Pando, and S. L. Lightman. 1994. Hormones,
peripherally activated prohormones and regulation of the Th1/Th2 balance.
Immunol. Today 15:301.
11. Romagnani, S. 1992. Human TH1 and TH2 subsets: regulation of
differentiation and role in protection and immunopathology. Int. Arch.
Allergy Immunol. 98:279.
12. Romagnani, S. 1994. Lymphokine production by human T cells in disease
states. Annu. Rev. Immunol. 12:227.
13. Anisman, H. and R. M. Zacharko. 1986. Behavioral and neurochemical
consequences associated with stressors. Ann. N. Y. Acad. Sci. 467:205.
14. Nemeth, S. 1978. A three hours study of the response of plasma
corticosterone and of three liver enzymes in rats subjected to stress in
late afternoon or during the morning hours. Endokrinologie. 72:223.
15. Nardoni, A., V. Di Piazza, V. Moretti, R. Copetti, and G. Trinco.
[Is serotonin implicated in the pathogenesis of the alcohol abstinence
syndrome?]. Minerva. Med. 80:281.
16. Edwards, E., W. Kornrich, P. V. Houtten, and F. A. Henn. 1992.
Presynaptic serotonin mechanisms in rats subjected to inescapable shock.
17. Brown, R. R., Y. Ozaki, S. P. Datta, E. C. Borden, P. M. Sondel, and
D. G. Malone. 1991. Implications of interferon-induced tryptophan
catabolism in cancer, auto-immune diseases and AIDS. In Kynurenine and
R. Schwarcz, ed. Plenum Press, New York, p. 425.
18. Nemeth, S. 1977. Inhibitory effect of immobilization stress on
depression of liver tyrosine aminotransferase and tryptophan pyrrolase by
glucose feeding in rats. Endocrinol. Exp. 11:43.
19. Heyes, M. P., B. J. Brew, K. Saito, B. J. Quearry, R. W. Price, K.
Lee, R. B. Bhalla, M. Der, and S. P. Markey. 1992. Inter-relationships
between quinolinic acid, neuroactive kynurenines, neopterin and beta
2-microglobulin in cerebrospinal fluid and serum of HIV-1-infected
patients. J. Neuroimmunol. 40:71.
20. Nemeth, S. 1977. The effect of stress on the activity of hepatic
tryptophan pyrrolase, of tyrosine aminotransferase in various organs and
on the level of tryptophan in the liver and plasma of rats. Physiol.
21. Cardinali, D. P. 1978. Effect of pentoxifylline and aminophylline on
biogenic amine metabolism of the rat brain. Eur. J. Pharmacol. 47:239.
22. Zabel, P., M. M. Schonharting, U. F. Schade, and M. Schlaak. 1991.
Effects of pentoxifylline in endotoxinemia in human volunteers. Prog.
Clin. Biol. Res. 367:207.
23. Paul, W. E. 1994. A turning point in AIDS research. Vital Speeches of
the Day September:710.
24. Tashkin, D. P., B. J. Shapiro, Y. E. Lee, and C. E. Harper. 1975.
Effects of smoked marijuana in experimentally induced asthma. Am. Rev.
Respir. Dis. 112:377.
25. Curzon, G. and J. C. Fernando. 1976. Effect of aminophylline on
tryptophan and other aromatic amino acids in plasma, brain and other
tissues and on brain 5-hydroxytryptamine metabolism. Br. J. Pharmacol.
26. Murphy, L. L., R. W. Steger, M. S. Smith, and A. Bartke. 1990.
Effects of delta-9-tetrahydrocannabinol, cannabinol and cannabidiol,
alone and in combinations, on luteinizing hormone and prolactin release
and on hypothalamic neurotransmitters in the male rat.
27. Fernandes, J. B., U. P. Naik, M. S. Markell, and E. Kornecki. 1993.
Comparative investigation of the effects of the immunosuppressants
cyclosporine A, cyclosporine G, and FK-506 on platelet activation. Cell
Mol. Biol. Res. 39:265.
28. Carrier, M., J. Wild, L. C. Pelletier, and J. G. Copeland. 1990.
Bromocriptine as an adjuvant to cyclosporine immunosuppression after
heart transplantation. Ann. Thorac. Surg. 49:129.
29. Di Stefano, R., M. Carmellini, A. Carobbi, F. Vaglini, M. Petrini, F.
Ricci, F. Mosca, and G. Malvaldi. 1990. Bromocriptine plus suboptimal
cyclosporine treatment abrogates acute rejection of rat cardiac
allografts. Transplant. Proc. 22:2015.
30. Benloucif, S. and M. P. Galloway. 1991. Facilitation of dopamine
release in vivo by serotonin agonists: studies with microdialysis. Eur.
J. Pharmacol. 200:1.
31. Sternberg, E. M., G. P. Chrousos, R. L. Wilder, and P. W. Gold. 1992.
The stress response and the regulation of inflammatory disease. Ann.
Intern. Med. 117:854.
32. Chrousos, G. P. and P. W. Gold. 1992. The concepts of stress and
stress system disorders. Overview of physical and behavioral homeostasis.
NOTE OF EXPLANATION
In this advanced era clinicians are unable to pass through all the
hurdles imposed by IRB's, cannot do double-blind studies. Journals,
oriented towards the laboratory, demand placebo controlled work. Despite
a wealth of clinical data, the author has been unable to have his
material printed. In the late nineteenth century, Baron von Humboldt
once commented, and I paraphrase that revolutionary ideas go through
three stages. In the beginning these ideas are ignored, next they are
ridiculed, and, finally, the experts say they knew it all along.
Fortunately, I have been fortunate to have strong allies. Dr. Richard
Rothman, a research psychiatrist at NIDA, for three years carried the
FEN/PHEN crusade forward. Despite murine confirmatory work, the
byzantine politics of NIDA was stronger.
I suppose it should be a signal honor that Dr. Alan Leschner, the chief
at NIDA, executed the alcohol and cocaine studies. Despite wide-spread
use of the self-same drugs for obesity, he was able to say with a
straight face that the toxicity of these medications out in the
marketplace for thirty years was in question. Whether he is involved in
the alternative work being done at NIDA, Hopkins, and Guilford
Pharmaceuticals is not known. Fortunately, Jan Campbell, Rothman, and I
are collaborating in the VA Kansas City.
Dr. Dan Malone, his interest whetted by my claim that FEN/PHEN treated
fibromyalgia, and his scepticism vanishing when he reproduced the
findings, has been pushing for a fibromyalgia study. That multi-center
study should start in the very near future.
Dr. Bernard Hitzig, a second cousin once removed and a Harvard research
pulmonologist, has had an informal approval from Mass. General's
pulmonary division. Now, when we get the money........
I would appreciate any potential researcher or clinician acknowledge the
fact that the basic concepts have been covered by patents and FEN/PHEN is
Sorry for the length. I would have preferred NEJM, Nature, SCIENCE,
JAMA, or Lancet but they are not interested in clinical findings anymore.
copyright 1996, all rights reserved, Pietr Hitzig
9515 Deereco Road, Ste. 810
Voice: (410) 560-5733
E-mail fen_phen at internetmci.com
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