Patent Application: US-25035505-A

Abstract:
the present invention relates to a kit and an intravenously administrable preparation , both with a signal transmitter precursor , an enhancer of precursor uptake , and an inhibitor of neurotransmitter reuptake or signal transmitter catabolism . the kit also contains an appropriate swab for obtaining oral cells suitable for allelic analysis . the intravenous formulation contains similar materials and , in some cases , ethanol . either the kit composition or the intravenous formulation may be used as guided by a subjects allelic analysis . collections of particular alleles , especially those relating to neural system are comprehensible in terms of likelihood of success in the administration of an intraveinous formulation or ingestion of components of the subject kit .

Description:
the following information forms an important basis of the invention . in an embodiment of the invention , each gene studied will be specified , and the survey will pinpoint the primary presenting problem which will dictate the type of neutraceutical to be employed . it is anticipated the diagnosis and treatment unit will consist of four parts : four swabs , one scale , a bottle of the rds neutraceutical , and a selection of herbal or other remedies to ameliorate the specific rds behavior which is the focus of attention . the above references do not limit in any shape or form the type of swab , envelope , survey type , or type of bottles , or caplets , capsules , liquid , gums , powder , bars or any configuration , size standard to the art . in an important embodiment , the present invention concerns a method for diagnosing and detecting compulsive disorder susceptibility of an individual . the method comprises initially obtaining a dna sample of said individual and then determining the presence or absence of particular human d2 receptor gene alleles in said sample . detection of said alleles in the sample are indicative of predilection to compulsive disorder . a most preferred embodiment is to detect predisposition to impulsive , addictive , and compulsive disorders such as , but not limited to , alcoholism , obesity , smoking , polysubstanceabuse and drug addiction , particularly because said alleles have been found to be present in a majority of individuals clinically diagnosed with these compulsive disorders . the human d2 receptor gene a1 , bi , and ˜ haplotype i alleles are most preferably detected in said sample . a preferred embodiment includes a four component unit or kit comprising of a . the gene test , b . an inventory scale , c . the smart formula , d . the synergene herbal formula . also , in one form of the embodiment , the kit would contain the forms as illustrated in tables 1 through 3 . after thousands of years of speculation about the nature of alcoholism and other impulsive , addictive , compulsive behaviors , and half a century of intensifying research into their causes , a consensus is beginning to emerge that is agreed to by most scientists in the field : craving for abusable substances is a malfunction of the reward centers of the brain involving the neurotransmitters the enzymes that control them and that certain other repetitive behaviors are due to imbalances of neurotransmitter systems . as yet , this information has not led to dependable methods of prevention or cure . in the area of addiction , abstinence is still the only sure way to combat addiction to alcohol or drugs . but we now have adjuncts that make treatment easier . tests are under development that will enable us more accurately to identify individuals at risk . the goal is to diagnose individuals “ at risk ” for rds behaviors sufficiently early to prevent the impulsive , addictive , or compulsive behavior from becoming established and to diagnose them accurately enough to help in the removal of the treatment retarding “ denial ” phenomenon . an additional goal is to provide more targeted treatment in tertiary probands either for alcoholism with bromocryptine as a function of one &# 39 ; s genome ( lawford et al ., 1995 ) or for carbohydrate binging with chromium response as a function of one &# 39 ; s genome ( blum et al ., 1999 ). the important point to make here is that as we make progress with regard to understanding the human genome , and as we continue to identify genetic links to polymorphisms for many disease states the more refined treatment approaches will be derived from such knowledge . in fact we believe , a new scientific term will emerge in this new millennium — pharmacogenomics . this area of endeavor will help define the role of our genome in terms of individual differences with regard to a number of drug responses including pharmacokinetics and pharmatherapeutics . the relationships among a wide range of impulsive , addictive , compulsive behaviors — from alcoholism to drug addiction to food abnormalities to attention deficit disorder — are now beginning to be understood , and the door to effective therapies is beginning to open wide . the first definitive insight grew out of the discovery that addiction - free behavior is facilitated by an adequate supply of neurotransmitters ; the availability of enzymes to regulate the supply of such brain chemicals and maintain balance among them ; and the presence of receptors to give neurotransmitters access to the neurons that determine feelings of well - being . a malfunction in any of these areas may trigger a biogenic behavioral disorder . the second definitive insight was that these various rds disorders involve complex interactions of neurotransmitters . in alcoholism , for example , we may see the progressive involvement of serotonin , opioid peptides , gaba , dopamine , and — in some instances — norepinephrine . each in its turn initiates or promotes changes in the brain &# 39 ; s biochemistry . the third definitive insight grew out of the discovery of an association between a severe form of alcoholism and defects in the d 2 gene in the reward area of the brain and other dopaminergic genes ( i . e . the dopamine transporter gene and the dopamine β - hydroxylase gene ). this genetic defect leads to such behavioral disorders , as severe alcoholism , polysubstance abuse / dependence , attention deficit disorder , and carbohydrate binging , severe gambling , nicotine abuse among other behavioral abnormalities . the fourth definitive insight was that these physiological conditions constitute a somatopsychological syndrome : sequential changes in brain chemistry that cause or trigger changes in feelings , beliefs , and behaviors . just as emotional and mental disturbances can lead to physical illness as in psychosomatic medical theory , so somatic deficiencies or imbalances can cause emotional and mental disturbances including compulsive diseases , anxiety , hostility , depression , or anti - social attitudes . if a genetic defect is the original cause of the behavioral anomaly , somatopsychological responses may be the mind &# 39 ; s way of coping with or adapting to the problem in the gene . the recent scientific literature continues to support this definitive insight ( see meta analyses by uhl et al ., 1993 ; blum et al ., 1995 ; and , noble , 1998 ). the initial work opening the way to an understanding of common causes underlying compulsive behaviors was carried out by the present inventor and associates in 1990 . a variant of the d 2 gene was shown to be associated with a severe form of alcoholism . this sparked numerous studies of similar associations of gene variants with a wide spectrum of related compulsive disorders . as previously discussed , numerous studies found significantly high prevalence of the d 2 variant gene in subjects with adhd , tourette &# 39 ; s disorder , conduct disorder , and posttraumatic stress disorder ( ptsd ). one striking example was that 59 percent of vietnam veterans with ptsd carried the d 2 gene variant , compared with only 5 percent of those who did not . these results suggest that not only do drug abuse , adhd , tourette &# 39 ; s disorder , conduct disorder , and ptsd have a common genetic origin , but that the d 2 gene is one of the primary causative factors . given the widespread prevalence of adhd in children and the frequent association of adhd with substance use disorder and a wide range of other behavioral disorders , it seems reasonable to suggest that childhood adhd may be a predisposing cause in these other anomalies or at least a pre - existing condition . gittleman ( 1985 ), for example , found a significant correlation between adhd and adult substance use disorder . studies by comings ( 1991 ) showed an intimate relationship between tourette &# 39 ; s disorder and adhd . in his various studies , 50 percent to 80 percent of persons with tourette &# 39 ; s disorder had adhd , and 20 percent to 60 percent of their relatives , who themselves had tourette &# 39 ; s disorder , also had adhd . while the exact identity of the genes causing adhd and tourette &# 39 ; s disorder are still unknown , mutations of genes affecting dopamine function have been strongly implicated . certainly , the d 2 gene appears to be one of the primary genes involved . one of its variants seems to lower the number of d 2 receptors , thereby affecting dopamine function , and perhaps playing the role of risk factor for adhd , tourette &# 39 ; s disorder , conduct disorder , anti - social personality disorder , food binging , smoking behavior , posttraumatic stress disorder , pathological gambling , and polysubstance dependence , including severe alcoholism . while other genes playing a role in these interrelated disorders are still to be identified , the concept of a “ reward deficiency syndrome ” ( rds ), first proposed by kb , unites addictive , impulsive , and compulsive behaviors and may explain for the first time the way in which simple genetic anomalies give rise to complex aberrant behavior . as milam ( 1992 ) pointed out in his landmark paper , “ the alcoholism revolution ”, which may serve the addiction field best by providing a blueprint for action : “ - - - meanwhile , the ugly battle for control will continue in the political arena . the public has heard the hostile allegations ( fingeratte 1988 ) that nobody understands alcoholism , that alcoholism does not exist , that it is merely willful misbehavior , that since treatment does not work anyway , only the briefest and least expensive should be funded . “ . . . every word they say chagrins us ” . . . because all of these criticisms are true of the bankrupt psychogenic approach to alcoholism ; none , however , is true of the biogenic approach .” in a more modern approach to treat or prevent the onset of rds behaviors , we know that premorbid behaviors to substance use disorder , including nicotine dependence , food addiction , violence , sexual deviancy , acting out in a variety of uncontrollable type behaviors , potentially could be treated with behavioral therapy , along with amino acid therapies , pharmaceuticals , electrical therapies , acupuncture type therapies , subluxation correction , biofeedback therapies , which all work on the neurophysiological mechanisms controlled by our brain . this novel approach will short circuit the genetic roots to this premorbid trait and reduce rds behaviors . it is the hope of the inventor that , through rigorous scientific exploration in both animals and humans , still unsolved mysteries about our “ addictive brains ” will become less mysterious . however , at this juncture we believe that great progress already has been made and it is time to move from the bench to the clinic and begin to apply our present knowledge base . in this regard we are working , in different ways , toward the development of standard diagnosis and treatment of “ reward deficiency syndrome ”. the inventor is hopeful that he will find an optimal amino - acid composition which will constitute the core of the short - term intravenous bolus therapy similar to what has been proposed in this provisional application . the inventor is convinced that treatment of rds associated behaviors should consist of : physiological and psychological diagnosis ( based on genetic testing , brain electrophysiological mapping and psychometric testing ); re - balancing the neurotransmitters ( through pharmacotherapies and amino acid based therapies ); neurotransmitter activation ( through biofeedback , cranial electrostimulation , acupuncture / auriculotherapy and perhaps chiropractic induced subluxation ); and , traditional therapies ( including psychotherapy , self - help groups , structured aftercare programs , etc .). they also are convinced the treatment of rds behaviors in the future will include the development of a wide variety of treatment settings which include development of community outpatient clinics , day hospitals , inpatient treatment programs , etc . these treatment programs will have programs geared for all the subtypes of behavioral problems under one - roof similar to the a one - stop shopping network . all of the rds behaviors will be treated together in one location ( alcoholism , substance use disorder , smoking , eating disorders - carbohydrate bingers , pathological gambling , sex addiction , violent offenders , and attention deficit hyperactivity disorder ). it is the goal of the inventors to continue the search for solutions to the world &# 39 ; s oldest dilemia our addictive brains and we believe through sound scientific exploration as described herein , we will as humans begin to learn how to ease oue “ legacy of pain ”. in alcohol and the addictive brain ( 1991 ) blum ( in collabration with payne ) stated : “ in the remainder of this century and the early decades of the century to come , i think that we will see neurobiology , neuropharmacology , biogenetics , psychiatry , and medicine moving forward in close coordination to reduce the devastating behavioral and social costs of faulty brain function . my vision of the future is a world in which the chemical and electrical functions of the brain are understood ; the problem of chemical imbalances as they affect behavior has been solved ; the role of genetic anomalies in defective brain chemistry is understood ; pharmaceutical and nutritional intervention as an adjunct to twelve - step programs and professional treatment is precise and effective ; and the technique of defective - gene replacement has been perfected , enabling us to break ( or repair ) the genetic chain of inherited addiction . in this world , each individual will be able to enjoy the inborn legacy of reward and pleasure without having the need for addictive substances , without having to pay the price of addiction and pain . currently , due to poorly distributed knowledge regarding the etiology of the variety of rds behaviors , all the treatment categories listed above are treated separately . we the inventors , believe that with the knowledge base described in this patent application the rationale of developing standard protocols for the treatment of all rds behaviors ( intravenous amino - acid bolus short - term therapy ) in integrated groups is clear and clearly will be cost effective . this should give all of us involved in the diagnosis and treatment of impulsive , addictive , compulsive disorders hope for the future . moreover , it is important to realize that awarding of this invention is important because the commercialization of this knowledge will positively benefit millions here in america and around the globe . for example , in the united states alone there are 18 million alcoholics , 28 million children of alcoholics , 6 million cocaine adicts , 14 . 9 million people who abuse other substances , 25 million people addicted to nicotine , 54 million who are at least 20 pounds overweight , 3 . 5 million school - aged children with adhd or tourette &# 39 ; s syndrome , and about 3 . 7 million compulsive gamblers . the inventors believe that using amino - acid bolus intravenous therpy on a short term and repeated basis coupled with genotyping humans for the alleles of the drd2 gene as well as other genes ( described in blum &# 39 ; s pct application ) related to psychological disorders in the present invention is indeed the first steps toward rational treatment for a devastating problem in society . the invention first provides intravenous compositions for the treatment of rds behaviors in a subject . in certain aspects this composition comprises the following : a composition comprising of an intravenous amount of any polar or non - polar substance known to inhibit the enzymatic - destruction of an opiate / peptidyl opiate or opioid . the intravenous solution must contain an opiate destruction - inhibiting amount of at least one substance which inhibits the enzymatic destruction of a neuropeptidyl opiate , the substance being either amino acids , peptides , and structural analogues or derivatives thereof and zinc / zinc complexes . a composition comprising of an intravenous amount of any polar or non - polar substance known to act as a neurotransmitter synthesis - promoting amount of at least one neurotransmitter precursor , the neurotransmitter precursor being either a dopamine precursor such as l - tyr , l - phe and l - dopa , a serotonin precursor such as 1 - trp and 5 - hydroxytrytophan , or a gamma amino butryic acid ( gaba ) precursor such as l - glutamine , l - glutamic acid , and l - glutamate . a composition comprising of an intravenous tryptophan concentration enhancing amount of the mineral chromium . the chromium utilized includes but is not limited to chromium piccolinate or chromium nicotinate or polynicotinate salts or other chelates . a composition comprising of an intravenous polar or non - polar compound known to cause the release of neuronal opiate peptides / peptidyl opiates / opioid peptides such as enkephaline . the enkephaline releaser being , but not limited to , a peptide , and preferably a d - amino acid containing peptide . a composition comprising of an intravenous polar or non - polar compound known to promote the synthesis and enhance the functional activity of serotonin , opioid peptides , and catecholamines ( dopamine and norepinephrine ) selected from the group rhodiola or huperzine , but not limited to these substances . a composition comprising of a intravenous compound known to promote neuronal dopamine release in the nucleus accumbens , selected from the group consisting of ethanol and calcium , but not limited to these substances . the type of enkephalinase inhibitors , the neurotransmitter precursor , chromium compound , enkephalinase releaser and neurotransmitter synthesis promoting substance and enhancer of neurotransmitter functional activity alone or combined ( combining at least one composition a - e ), in addition to the compounds specifically listed above , are further described herein in this application and are encompassed by this invention . in certain preferred aspects of the invention , the composition is preferably used in the treatment of sud and other preferred embodiments such as smoking behavior , carbohydrate bingeing and even adhd , attentional processing and / or memory , and stress . as used herein “ derivative ” may refer to a chemically modified compound , and “ anolog ” refers to a different compound that has similar properties or structure to the compound it is being compared . in certain aspects of the invention , these intravenous compositions which have never been used before as short - term bolus therapy , may be used in the treatment of all rds related behaviors previously disclosed in blum &# 39 ; s published pct application of apr . 29 , 1998 which has been nationalized in numerous countries on oct . 29 , 1999 and nov . 29 , 1999 . rds behaviors are those behaviors related to a chemical imbalance which manifests itself as one or more behavioral disorders related to an individual &# 39 ; s feeling of well - being with anxiety , sud , smoking , body mass index , obesity , carbohydrate binging , pathological gambling , sexual deviancy , axis ii diagnosis , schizoid avoidant behavioral cluster , add / adhd , conduct disorder , tourettes syndrome , family history of sud , and obesity as well others previously defined as well as other non - rds disorders as defined herein . the inventor believes that various psychological disorders are linked by a common biological substrate , a “ hard - wired ” system in the brain that provides pleasure in the process of rewarding certain behavior . the inventors propose in this invention that an inborn chemical inbalance that alters the intracellular signaling in the nucleus accumbens or other limbic reward regions could supplant an individual &# 39 ; s feeling of well - being with anxiety , anger or a craving for a substance ( i . e . alcohol ) that can alleviate the negative emotions . this chemical inbalance manifests itself as one or more behavioral disorders for which the term “ reward deficiency syndrome ” has been coined ( blum et al . 1996a ). while a major aspect of this invention involves the use of an intravenous amino - acid based bolus composition for the short - term treatment of rds behaviors as well as other non - rds behaviors , disorders or diseases , certain aspects of this invention does involve the coupling of intravenous administration with gene testing . the gene testing aspect has already been applied for via a previous pct application ( apr . 29 , 1998 ). in order to be complete it is important to realize that in rds , genetic defects in the reward pathways is best understood as a polygenic disorder , and genetic testing would require the testing of multiple genes . the earlier pct identified the correlation between predisposition to rds and alleles of a number of genes including but not limited to the dopaminergic genes drd1 , drd2 , drd3 , drd4 , drd5 , dopamine transporter gene ( dat1 ), serotonin genes htt , htra , htrdb , htra , htrc , htia , 5ht2r , tryptophan 2 , 3 - hydroxylase ( tdo2 ); norepinephrine genes , dbh , adraa , adrac , nt , catecholamine metabolizing genes , maoa , comt , gaba genes , gabraa , gabrab , canabinoid receptor gene , cnr ; nicotinic cholinergic , chrna ; nmda receptor gene , nmdar ; enkephalin genes . penk , androgen receptor gene , ar ; interfereron gamma gene , infg , cda ; presenilin , ps , crf gene , crf ; obesity genes , ob , leptin recteor gene ; catechol - 0 methyl - transferase ( comt ) gene ; the neuronal nitric oxide gene synthase gene ( nnos1a ); apolipo protein - d ( apo - d ) and , uncoupling protein ( ucpi and ucp2 ) among others . enkephalins and endorphins are opiate - like substances which have been found to be endogenous in various animal species and man , whereby the general term endorphins includes but is not limited to beta - endorphin , methionine - enkephalin , leucine - enkephalin and dynorphins . these substances are peptides or polypeptides which are normally found in the brain and in the periphery as well . as pointed out in u . s . pat . no . 4 , 439 , 452 , it has been observed that both enkephalins and endorphins have an ability to act as a biologically active pain killer when administered by even intracerebral injections . however , the major drawbacks of utilizing the endogenous substances directly for therapeutic purposes , including intravenous therapy to treat rds or non - rds disorders , are their extremely labile nature and poor penetration into the brain via oral administration and their ability to induce addiction . it is known that the destruction of the endognous enkephalins and or endorphines is due to the actions of certain enzymes which resemble carboxypeptidase or endopeptidase ( catelepsin ), respectively . these and other enzymes which inactivate enkephalins and endorphins are known collectively as enkephalins and endorphinases . an enkephalinase inhibitor is a substance which inhibits a class of enzymes known as enkephalinases and endophinases known to destroy these neuropeptides in both animals and humans . aqueous compositions of the present invention comprise an effective amount of the various compounds disclosed to treat rds related disorders , including substance use disorder , obesity , adhd , tourettes syndrome , pms , smoking , any other related behavior described herein , dissolve or dispersed in a pharmaceutically or pharmacologically acceptable carrier or aqueous medium . the phrases “ pharmaceutically or pharmacologically acceptable ” refer to molecular entities and compositions that do not produce an adverse , allergic or other untoward reaction when administered to an animal , or a human , as appropriate . a preferred chromium salt , in addition to those previously mentioned , is chromium niacin - glycerate . clyclodextrin maybe added to composition in the kits of the present invention . this clyclodextrin could aide in the absorption of many of the various components in the composition . the kits also preferably contain a reward deficiency syndrome related scale . this scale allows the patient to gage the degree of his rds problems . each of the several embodiments of the invention hereinafter to be described not only reduces intake of alcohol , cocaine , heroin , nicotine , glucose but reduces all known rds behaviors . the following examples of compositions is provided to best describe the invention herein : the invention includes the intravenous administration of a new class of anti - craving compositions provided by substances which inhibit the breakdown of endogenous substances such as enkephalins and endorphins . specifically , d - phenylalanine , dl - phenylalanine , d - leucine , dl - leucine , and hydocinnamic acid , each in an intravenous solution in sufficient concentration to bring about enkephalinase inhibition which would significantly lower alcohol intake in animals and humans . the anti - alcohol desire effect has been observed in animals genetically prone to choose alcohol over water , but this effect has never been observed via the intravenous route . the inventors believe that the intravenous route would be advantageous since the dose needed would be much less than what is required by the oral dose . in a series of experiments the exact dose will be determined in both humans and animals to at least reduce alcohol or drug intake . in this invention only and not in limitation , the term enkephalin inhibitors includes d - phenylalnine ( dpa ), dl - pa , hydrocinnamic acid and d - amino acids such as d - leucine . it is anticipated that other enkephalinase inhibitors ( depending on ability to place the substance into a safe and effective intravenous solution ) selected from a group consisting of certain protein synthesis inhibitors ( bacitracin , bestatin , and puromycin ); and peptide amino acids ( mono free form amino acids in the d - form ; thiol benzyl amino acids ( 2 -[ mercapto - 3 - phenyl - propanoyl ]- l - leucine ; carboxyalkyl methyl esters , n -[( r , s )- 2 carbethoxy - 3 - phenyl propanol ]- l - leucine ; as well as a number of other structurally unrelated compounds such as secobarbital , pyrophosphate , o - phenanthroline , phosphamidon , z - leucine - nhoh , and z - glycine - nhoh . the potencies will be determined by trial and error , but a starting point for the various enkephalinase inhibitors in vitro range from 10 nm to nm amounts and , therefore , the anticipated human dosage range is from milligrams to micrograms per kilogram based on a 80 kilogram man . it is understood that the daily , recommended dosage is to be sufficient to alter the activity of enkephalinase and / or opioid receptor function so as to reduce the craving for euporiants such as alcohol , cocaine , heroin , marijuana , nicotine , glucose as well as behavioral acts including but not limited to pathological gambling and sexual deviancy . it is further anticipated that the broad range of dosage will be provided in the final application due to both pharmacogenetic and pharmacogenomic elements . it is also important for this invention , that these substances alone , in equal dosages are less efficatious enkephalinase or endorphinase inhibitors in reducing craving but should be synergistic when used in combination with said inhibitors and other precursor amino - acids and even when combined with intravenous ethanol solutions . for example , without testing , it is anticipated , that the range of the daily dosage of d - amino acid like d - leucine is between 15 - 5000 mg but a more definitive amount will be determined . the intravenous solution could be expanded to include any substance which inhibits enkephalinases , endorphinases and or dynorphinases . it is also anticipated that intravenous solutions could also contain the dl - forms as well . the inventor believes that the substrate for rds behaviors is mediated by regions in the brain &# 39 ; s “ pleasure center ” or “ reward centers ” which are high in a number of neurotransmitters including dopamine . these regions include the dopamine - containing nucleus accumbens , and its projection to limbic structures and frontal cortex . it has been observed that if dopamine projections to limbic and cortical areas are lessioned the self - administration of psychoactive drugs which release dopamine ( e . g . alcohol , cocaine , heroin , nicotine etc ) by animals are greatly reduced . moreover , selective dopamine receptor antagonists , like haloperidol , atenuate or block alcohol and cocaine self - administration in animals . similarly , in humans , pretreatment with dopamine receptor antagonits will block stimulant - induced “ euphoria ”. additionally , dopamine receptor agonists ( e . g . bromocryptine , apomorphine etc ) have rewarding actions . these and other studies suggest that the lack of “ reward ” as observed in rds subjects is due to a deficiency of certain neurotransmitters involved in the mediation of dopamine release and function . a second step in the invention is to induce restoration and balance within the limbic structures of important neurotransmitters . this is accomplished by utilizing the brain &# 39 ; s own natural biochemical mechanisms involved in the synthesis of individual chemical messengers such as serotonin , gamma - amino - butryic acid ( gaba ) and the catecholamines ( dopamine , norepinephrine and epinephrine ). in understanding the chemistry involved , these neurotransmitters of the monoamine type are derived via enzymatic actions concerned with known precursor amino acids . catecholamine are compounds which passes two adjacent hydroxyl ( oh ) groups on a benzene ring . in the body , such substances are synthesized from the aromatic amino acid l - tyrosine , which is hydroxylated to l - 3 , 4 - dihydoxyphenylalanine ( l - dopa ) by the enzyme tyrosine hydroxylase . l - trosine is actively taken up into noradrenergic nerve terminals . l - phenylalanine is a precursor of l - tyrosine . in the cytoplasm , l - dopa is decarboxylated to dopamine by l - aromatic amino acid decarboxylase , an enzyme which requires pyridoxal phosphate ( vitamin b6 ) as a cofactor . the dopamine is actively taken up into granular storage vesicles in which the dopamine is hydroxylated to form norepinephrine by the enzyme dopamine - beta - hydroxylase . it is known that dopamine is the precursor of norepinephrine and epinephrine , and each of these three neurotransmitters have distinct functions in the central nervous system and at some ganlia in the autonomic nervous system . dopamine is stored in storage granules where the catecholamine is complexed with chromogranins , divalent metal ions and atp . dopamine is believed to be released into the syneptic cleft by exocytosis . as with norepinephrine , this is a calcium dependent process and occurs in response to action potentials reaching nerve terminals or to drugs . the following drugs / substances can induce a dopamine release — they include : alcohol , cocaine , amphetamine , methyamphetamine , amantadine , morphine , heroin , phentermine , nicotine , marijauna , glucose to name a few . the use of these precursors may be supplemented at appropriate stages of treatment of an rds subject following the short - term bolus intravenous therapy . these include dopaminergic releasers , blockers , agonists or antagonists or agents affecting the reuptake or degradation of dopamine , norepinephrine or epinephrine . however , it should be understood that the entire range of dopaminergic activity including synthesis , and release is regulated to some degree by certain opioid peptides ( e . g . enkephalins and endorphins ). centrally administered opioid peptides produce elevations in levels of catecholamines in blood plasma in animals and humans ( clouet ann n . y . acad . sci ., 398 ; 130 - 139 , 1982 ). in fact , blockade of presynaptic dopaminergic receptors results in an enhancement of b - endorphin release , showing a unique reciprocal relationship . serotonin ( 5 - ht ) is a cns neurotransmitter . it is also found in the enterochromaffin system of the intestine , and in blood platelets . this neurochemical is biosynthesized by first hydroxylating the precursor amino acid l - tryptophan to obtain 5 - hdroxytryptophan and then decarboxylating the latter to obtain serotonin . the hydroxylation ( the rate limiting step ) is performed by the enxyme tryptophan hydroxylase , while the decarboxylation is accomplished by the ubiquitous enzyme l - aromatic acid decarboxylase . this enzyme requires pyridoxal phosphate as acofactor . unlike tyrosine hydroxylase , tryptophan hydroxylase , under normal physiological conditions , is not saturated , therefore , the enzyme is not working to full capacity and thus tryptophan hydroxylase activity is significantly affected by 1 - tryptophan . the amount of available free tryptophan is dependent on a number of factors including the concentration of circulating l - tryptophan in the plasma at the rate of its uptake in the brain and presynaptic terminals . we contemplate using l - tryptophan or 5 - hdroxytryptophan , to restore the serotonergic system disrupted by either genes or other environmental elements . there is come controversy concerning the usefulness of another amino acid precursor , 5 - hydroxytryptophan , which is about 20 times more potent than l - tryptophan . the rate of entry of l - tryptophan into the brain depends upon the ratio of free - bound tryptophan in the plasma , and this ratio is influenced by the concentration in the blood of neutral amino acids , insulin , glucose levels , and pharmaceutic agents , which compete for plasma protein binding sites , as well as for the tryptophan - uptake sites . also 5 - hdroxytryptophan is taken up by neurons other than just serotoninergic neurons ; therefore the increases in serotonin synthesis are not selectively limited to serotoninergic neurons . since the inventors plan to utilize the intravenous compositions via an fda approved drug drug , and since in the united states physicians are allowed to subscribe or utilize l - tryptophan , the preferred embodiment is the l - tryptophan precursor rather than the l - 5 - hydroxytryptophan amino - acid . serotonin can be released into the synaptic cleft by the process of exocytosis in response to action potentials and to certain drugs / substances . facilitation of serotonin release is accomplished with cocaine , alcohol , amphetamine . metamphetamine , fenfluramine , chlorimipramine and others . gaba is an inhibitory neurotransmitter which controls the release of dopamine ( gessa et al . 4th world congress on biological psychiatry 459 no . 620 : 10 1985 ). the main synthetic pathway to gamma - aminobutyric acid is via decarboxylation of l - glutamic acid by glutamic acid decarboxylase ( gad ). like other amino acid decarboxylases , this enzyme needs pyridoxal phosphate or vitamin b6 . gad is found exclusively in the cytoplasm of synaptic gaba nerve terminals . the basic control of gaba synthesis is gad , which is the rate limiting step . saturation concentrations of l - glutamic acid are present in the presynaptic neurons : thus , increased substrate concentrations do not normally affect the rate of gaba synthesis . therefore , the exogenous administration of l - glutamic acid may not significantly increase gaba levels , unless the l - glutamic levels are abnormally low . however , it has been shown that a 10 day administration of 1 - glutamine (@ 500 ng / kg per day ) with the drinking water to adult albino rats resulted in significant increase in the content of glutamate , gaba and taurine in the brain . glutamine is an active intermediate in transport of ammonia from brain and therefore may greatly affect metabolism of different amino acid acids in nervous tissue . after deamination , glutamine may become a precursor of glutamate and , accordingly , gaba . ( thawki et al . j . neurochem . 41 : 611 - 617 , 1983 ). changes in affinity of gaba receptors for gaba , the benzodiazepine - binding sites for benzodiazepines and / or barbiturate binding site for barbiturates is regulated by a protein “ gaba - modulin ”. no reports have indicated that the use of gaba precursors can postively affect rds behaviors in the short - term . however , the inventors believe , that since in a number of rds behaviors there is a significant association of stress and / or anxiety the addition of l - glutamine may act to increase gaba , which in turn could stimulate the benzodiazepine - ionophor complex and reduce anxiety through this mechanism , even on a short time period for initial interaction via the intravenous route . it will also be recognized that while this invention is directed to the use of a substance which inhibits the destruction of endogenous neuropeptidyl opiates ( as described in example 1 ), especially in combination with dopamine , serotonin and / or gaba precursors , it may also be beneficial to add certain soluble neurotransmitter agonists , blockers , antagonists , releasers , or degradation inhibitors into one intravenous solution if desired or if proven to effect the efficacy of the base composition . there are other substances which could also effect the activity of neurotransmitters and brain cell dynamics which can be contemplated as well in this invention . for example , calcium is a required substance for proper neurotransmitter release and function . zinc is essential for protein synthesis and can inhibit enzymes involved in the destruction of endogenous opiates . thiamine promotes the synthesis of niacinamide and enhances oxidative metabolism of brain cells . riboflavin is a cofactor which acts as a hydrogen acceptor and promotes the conversion of tryptophan to niacinamide . niacinamide is an essential part of the enzyme system concerned with the efficient use of oxygen by neurons and promotes brain cell respiration . pantothenic acid is a vital substance involved in cellular metabolism . it is believed that the combination of riboflavin , niacinamide , and pantothenic acid reduce irritability , restlessness and fatigue . cyanocobalamine is a cofactor / coenzyme for both chemical synthesis and neuronal electrical activity . ascorbic acid is involved in the metabolism of phenylalanine and tyrosine and can reduce drug - induced withdrawal reactions . follic acid promotes oxidation in the blood as a hematopoietic agent . d - ribose is a cardiac protector and may play a role in memory . an example of the precursor amino - acids in treating rds behaviors as an intravenous composition is as follows : in an intravenous solution these amino - acid precursors could be given alone or in any combination with any of the other precursor amino - acid at the specified dosage range . l - phenylalanine - 1500 mg l - tyrosine - 900 mg l - tryptophan - 500 mg l - glutamine - 300 mg pyridoxal phosphate 20 mg note . while the foregoing doses are preferred , it is contemplated that the quantities of each ingredient may be varied by an order of magnitude ( 10 % to 1000 %). because of the interactions of the various neurotransmitters , an increase in the amount of one ingredient may facilitate the reduction of another ingredient . also , other substances of similar activity , as noted above in the text of this invention , may be substituted for those of the example . in this composition the inventors are including a tryptophan concentration enhancing amount of all salts and chelates of chromium ( e . g . picolinate , nicotinate , ablion chelate etc .). body cells need chromium to keep insulin working properly as well as a host of other important biological actions . scientists agree , that insulin directs the movement of digested food into the body &# 39 ; s cells and affects how that food is used . when insulin doesn &# 39 ; t act as intended , blood glucose and fat aren &# 39 ; t stored and used properly . this malfunction leads to obesity , heart disease , or diabetes . our diets contain little chromium , and what chromium we do eat is often in a form that is difficult for the body to absorb . therefore , chromium must be combined with a substance that will allow this substance to enter the bloodstream . a number of forms include picolinate , polynicotinate as well as ablion chelate . dozens of studies have proven that chromium , in the form of chromium picolinate , helps control blood fat , blood glucose , body fat , food cravings , and age - related bone weakening or osteoporosis , lowers blood pressure and reduces both total and ldl cholesterol , and induce higher levels of hdl cholesterol . dietary chromium is an essential nutrient whose value in human nutrition has been conclusively documented . interest in chromium stems from the view that because chromium is an essential trace mineral and a cofacactor to insulin , it could play a role in glucose , lipid , and amino acid metabolism by it &# 39 ; s potentiating effects on insulin action . supporting this argument is the observation that chromium deficiency results in impaired glucose tolerance , insulin resistance , elevated blood glucose levels , and symptoms of type ii diabetes ; in addition , adequate amounts of physiogically active forms of chromium can reduce insulin requirements in humans ( kaats et al . 1996 ). the national academy of sciences has classified chromium as an essential trace mineral and recommends daily intakes of 50 to 200 micrograms . however , the most reliable studies report that among americans ( which is similar for other countries ) is suboptimal — only 40 % of the minimum for women and 60 % for men . there are more than 25 human studies documenting the beneficial effects of supplemental chromium on subjects living at home including improvements in glucose , insulin , and lipid levels : impaired glucose tolerance ; adults with elevated cholesterol levels ; insulin and hypoglycemic patients ( mertz , 1992 ). to increase the bioavailability of chromium , several studies have suggested using picolinate acid , a naturally occurring metabolic derivative of tryptophan . picolinate acid appears to combine with trace metal ions in the intestines and blood which facilitates the collection and use of essential trace metals ( evans & amp ; brown , 1992 ). we are in this invention , only interested in the intravenous use of chromium . we will explore the absorption of unsalted chromium compared to various salts and chelated forms in terms of absorption and potency using typical studies involving glucose sensitivity and tolerance as a measure of biological activity . because deposition of body fat appears in part by insulin , improvements in insulin utilization should lead to reductions in fat deposition . enhancing the effects of insulin can also have positive effects on muscle tissue because insulin directs amino acids into muscle cells ; once amino acids enter the muscle cells , they are assembled into proteins through insulin &# 39 ; s effect on the cell &# 39 ; s genetic material , that is , dna and ribonucleic acid . this effect of chromium is important for this invention , since by doing so it reduces required amounts of the amino acid tryptophan ( wurtman , 1982 ). by enhancing tryptophan , this will lead to an enhanced synthesis of serotonin . the newly synthesized serotonin , will stimulate dopamine release via an indirect action on enkephalinergic neurons resulting in gaba inhibition , and through this mechanism enhance dopamine release at the nucleus accumbens . this would therefore benefit rds behaviors , including substance use disorder , carbohydrate binging , pathological gambling , sexual deviancy , adhd among other known and defined rds behavioral subtypes . moreover , chromium can potentially facilitate the maintenance or addition of fat - free mass ( ffm ). it has been suggested that if chromium can lower insulin resistance it can improve body composition , as insulin resistance or deficiency results in impaired entry of glucose and amino acids into muscle cells , and increased catabolism of muscle protein as well as insulin deficiency &# 39 ; s potential to accelerate lipid disposition ( kaats et al . 1996 ). other references indicate that insulin resistance may help stabilize body fat in the obese patient , albeit at an obese level , acting much like a “ set point ” to prevent further weight gain ( eckel , 1992 ). in general , although animal studies have supported this contention ( liarn et al , 1993 ), one human study found positive changes in body composition with chromium supplements ( hasten et al . 1992 ), another reported positive , although not statistically significant changes in body composition ( hallmark et al . 1993 ), and a third failed to find any positive changes in body composition with chromium supplementation ( clancey et al . 1994 ). the controversial nature of the literature reveals that most human studies used small numbers of subjects , and patients often followed exercise or conditioning programs that could increase the need for chromium at amounts higher than amounts provided in these studies . previous work observing concurrent chromium supplementation and exercise training has been restricted to effects on body weight and composition , with conflicting results ( clancy et al , 1994 ; evans et al 1989 ; evans et al , 1993 ; hallmark et al . 1996 ; hasten et al . 1992 ). chromium picolinate is the most heavily used , studied and promoted compound , but in vitro work suggests that chromium nicotinate may be also viable in the area of weight loss and changes in body composition . in this regard , very recent work by grant et al . ( 1997 ), suggests that the nicotinate salt may be even more important than the picolinate salt . while there still is controversy regarding the effects of chromium salts ( picolinate and nicotinate ) on body composition and weight loss in general , recent work seems to support the positive change in body composition in humans . considering the work of lawford , et al . ( 1995 ), showing a selective positive effect of bromocryptine , a d 2 agonist , in reducing relapse rates in alcoholics as a function of dopamine d 2 receptor genotype , one of us ( kb ) embarked on a similar phamacogenomic study with crp ( see below ). recently , there was concern over the demonstration that , at concentrations thousands of times higher than physiological levels , trivalent chromium can break chromosomes in cell culture . it is the inventor &# 39 ; s position that this finding is not relevant to nutritional supplementation . in this regard , a prediction that crp will accumulate in tissues to dangerous levels during long - term supplementation is based on an inappropriate pharmacokinetic model and is at odds with data from long - term rat feeding studies . furthermore , clastgenicity is not equivalent to either mutagenicity or carcinogenicity and studies in animals reveal that any effects observed with regard to clastogenicity of trivalent chromium is only relevant to cell culture studies , not to living animals or humans . moreover , the therapeutic - toxic - dose ratio for trivalent chromium is 1 : 10 , 000 and the environmental protection agency in the united states has established a “ reference dose ” for nutritional chromium that is 350 times higher than the upper end of the nutritional range . considering the wide margin of safety for trivalent chromium , as well as its picolinate salt , we believe large scale , worldwide use of crp is justified as an important dietary supplement to assist in reducing obesity . thus , it can be seen that effects of chromium supplementation on different subject populations ( obese and lean ) were variable with respect to changes in body composition regardless of dose . given the comparable study designs for most studies , the results taken together suggest that a subset of responders in each study may account for the observed variability among studies . in order to resolve the issue of non - responders , the inventor decided to test the hypothesis that typing the obese patients by genotyping the drd2 gene prior to treatment with crp would result in a differential treatment outcome . this was based on previous research which indicated that the drd2 taqa1 allele associated with obesity in general ; the bmi ; carbohydrate binging ; co - morbid substance use disorder ; and contributed to the overall variance of percent body fat in the present population at the high rate of 45 . 9 percent ( blum et al . unpublished ). one of us ( kb ) predicted carriers of the drd2 a2 allele would retain the positive metabolic effects of p , but in contrast the drd2 a1 carriers , because there is a proclivity to increased carbohydrate binging , would possibly mask the metabolic effects of crp on weight loss and change in body fat attenuating any positive effects . one prophetic example as described earlier ( see page 48 ): the inventor genotyped 130 obese subjects for the dopamine d 2 receptor gene ( drd2 ) utilizing standard pcr techniques . the subjects were assessed for scale weight and for percent body fat using dual energy x - ray absorptiometry ( dexa r ). the subjects were divided into matched placebo and chromium picolinate ( crp ) groups ( 400 ug . per day ). the sample was separated into two independent groups ; those with either an a1 / a1 or a1 / a2 allele and those with only the a2 / a2 allelic pattern . each of these groups was tested separately for differences between placebo and treatment means for a variety of measures of weight change . these measures consisted of calculations of the percent of fat weight change ; the change in fat weight ; the change in body weight ; the change in free mass , the percent change of fat weight ; the body composition index ; and the body weight change in kilograms . t - analysis revealed that carriers of the drd2 a2 allele were more responsive to the effects of crp than were the drd2 a1 allele carriers . the measures of the change in fat weight ( p & lt ; 0 . 041 ), change in body weight ( p & lt ; 0 . 017 ), the percent change in weight ( p & lt ; 0 . 044 ), and the body weight change in kilograms ( p & lt ; 0 . 012 ) were all significant , whereas no significance was found for any parameter for those subjects possessing a drd2 a1 allele . these results suggest that the dopaminergic system , specifically the density of the d 2 receptors , confers a significant differential therapeutic effect of crp in terms of weight loss and change in body fat . moreover , we propose for the first time that mixed effects now observed with crp administration in terms of body composition , may be resolved by typing the patient via drd2 genotyping prior to treatment with chromium salts . the point here is that , depending on a number of important factors , genetic make - up as well as absorption results obtained with any chromium supplement are equivocal . it is the intent of this invention to resolve this controversy by administering the chromium via the intravenous route either alone ( 25 - 10 , 000 ug ), or in combination with composition b as specified above . l - phenylalanine - 1500 mg l - tyrosine - 900 mg l - tryptophan - 500 mg l - glutamine - 300 mg pyridoxal phosphate 20 mg chromium ( picolinate , or 400 ug nicotinate ) note : while the foregoing doses are preferred , it is contemplated that the quantities of each ingredient may be varied by an order of magnitude ( 10 % to 1000 %). because of the interactions of the various neurotransmitters , an increase in the amount of one ingredient may facilitate the reduction of another ingredient . also , other substances of similar activity , as noted above in the text of this invention , may be substituted for those of the example . in this composition the prime element is the use of an enkephalinase releasing substance which is known to release neuronal endorphins or enkephalins , said substance being selected from the group consisting of polypeptides or amino - acids . the inventor believes that an important embodiment is the inclusion of a opioidergic releasing agent . therefore , a further enhancement of the intravenous composition , is to combine an enkephalinase inhibitor with an enkephalin releasing agent . the rationale for this is that by doing so we could significantly enhance the effect of enkephalin on its respective opiate receptor sites ( e . g . delta or mu ). to accomplish this aim , we would prefer to use the peptide tyr - arg ( kyotorphin ), or its stable analog , tyr - d - arg , which has been shown to be analgesic and to enhance intracellular calcium in synaptosomes in rat brain slices . these substances appear to be putative methionine - enkephalin releases acting by an unknown mechanism ( udeda et al . biochem . biophy . res . comum . 137 : 897 , 1986 ). to provide both enkephalinase inhibition as well as enhanced neuronal enkephalinase release the substance kyotorphin may be used as a daily dosage range of 15 micrograms - 15 milograms orally . in our experiments to come , the inventors will provide the best dose for the intravenous composition preferred . ( takagi et al . eur . j . pharm . 55 : 109 , 1979 ). the more stable analog tyr - d - arg , at a daily dosage range could be substituted as an enkephalin releaser and it to will be studied in terms of it &# 39 ; s appropriate effective and safe intravenous dose ( tajima et al . chem . pharm , bull . 28 : 1935 , 1980 ); ueda , et al . biochem . biophys . res . commun ., 137 : 897 - 902 , 1986 ). thus , an enkephalin releaser may be combined with an enkephalinase inhibitor to achieve a high degree of enkephalinergic activity at the synapse to further augment the release of neuronal dopamime . this will act as a form of bolus short term “ replacement therapy ” and produce a surprising long - term reduction in aberrant craving behavior for a number of addictions . l - phenylalanine - 1500 mg l - tyrosine - 900 mg l - tryptophan - 500 mg l - glutamine - 300 mg pyridoxal phosphate 20 mg chromium ( picolinate , or 400 ug nicotinate ) tyr - d - arg 15 ug note : while the foregoing doses are preferred , it is contemplated that the quantities of each ingredient may be varied by an order of magnitude ( 10 % to 1000 %). because of the interactions of the various neurotransmitters , an increase in the amount of one ingredient may facilitate the reduction of another ingredient . also , other substances of similar activity , as noted above in the text of this invention , may be substituted for those of the example . a composition comprising of an intravenous polar or non - polar compound known to promote the synthesis and enhance the functional activity of serotonin , opioid peptides , and catecholamines ( dopamine and norepinephrine ) selected from the group rhodiola or huperzine , but not limited to these substances . rhodiola rosea , or golden root , is a perennial herbaceous plant of the orpine ( crasssulaceae ) family , growing in the polar arctic and alpine regions . in the altai mountains , in eastern siberia , tien - sdhein and in the far east , the cultivation of rhodiola rosea has been successfully mastered . the rhizomes contain phenolic compounds , among them the most important are p - oxyphenylethanol ( tyrasol ) and its glycoside salidoside determining the biological activity of the rhodiola preparations ( saratikav et al . 1968 ). rhodiola possess stimulative and adatogenic characteristics . it is thought that this compound improves the ability to perform physical work ; reduce fatigue ; shorten the recovery period after prolonged muscular workloads ; and normalize cardiovascular activity . during intensive muscular work , rhodiola prevents loss of phosphates in brain and muscles by optimization of the processes of oxidative phosphorylation , stabilizing the muscular activity of lipids ; improving the indicators of metabolism ( activation of aminacyl - t - rna - synthetase ) in the skeletal muscles , increase of the rna content , and increasing the blood supply to the muscles , especially to the brain . rhodiola can increase attention span , memory ; improve mental work and enhance performed work . the area of the brain involved in this activity is the thalamocortical and posterior hypothalamus ( marina et al . 1973 ). various other actions have been noted for rhodiola and include ; prevent development of hyper - and hypoglycemia , leukocytosis and leukopenia , erythrocytosis and erythropenia , hypoxia ; reduce stress and bring about a cardio - protective action . the stress - regulative effect of rhodiola involves it &# 39 ; s normalizing effect on the hypophyso - adrenal and opioidergic system . it has also been found that rhodiola increases the anti - tumor resistance of the organism . it significantly inhibits the growth of experimental tumors , decreases the frequency of their metastasises ; prolongs the life expectancy of animals with recidivistic tumors , and decreases the outcome of spontaneous tumors ( dementyeva and yaremnko , 1983 ). there is some evidence that this compound also reduces neurosis and fights exhaustion ( saratikov , 1977 ). salidosid ( an extract of rhodiola ) [ sal ], at 30 mg / kg prevented disulfuram - induced decrease of ne in the brain of animals . sal influences brain ne by virtue of it &# 39 ; s ability to inhibit the activity of comt and mao . sal does not decrease the permeability of the blood brain barrier ( bbb ) for precursors of the catecholamines and serotonin , and this property makes it useful for the intravenous composition to treat rds behaviors . administration of rhodosine ( which contains sal , aglycone p - tyrosol and rosavin ) at 2 mg / kg increases the brain concentration of dopa , dopamine , and serotonin in the cortex and a decrease of the level of ne in the caudate nucleus in the brain of the intact mice , 30 min after subcutaneous injection . others have shown that sal did not alter the levels of epinephrine and dopa : at a dose of 30 mg / kg , it decreased the content of ne by 26 % and of 5 - ht by 15 %; at a dose of 100 mg / kg , it decreased the concentration of ne , dopamine and serotonin by 20 , 28 , and 23 % respectively . studies involving the administration of l - dopa ( 50 mg / kg ) and 5 - htp ( 100 mg / kg ) to mice showed that sal ( 30 mg / kg ) increases the rise in exogenous dopa and serotonin in animals by 26 and 13 %, respectively , compared to saline - dopa - 5 - ht - controls . these data indicate that the preparation increased the permeability of the blood - brain barrier for the catecholamine precursor . moreover , from the research of petrov ( 1981 ) indicates that sal decreases mao activity and inhibits comt activity thereby , slowing the inactivity of catecholamines by o - methylation and oxidative deamination . moreover , studies have shown that sal does not alter the activity of 5 - htp decarboxylase . consequently , it does not influence the synthesis of serotonin from 5 - htp , but may slow the biotransformation of the amine , by slightly inhibiting mao . evidently the increase in the rise of serotonin in the brain in studies involving the combined administration of 5 - htp and sal is governed by the capacity of the latter to increase the permeability of the blood brain barrier for 5 - htp . the effects of rhodiola in rats was studied using several methods of active avoidance with negative and positive reinforcement ( petrov et al . 1986 ). using the maze - method with negative reinforcement , it has been found that rhodiola extract in a single dose of 0 . 10 ml per rat improves learning and retention after 24 hours . in terms of the bolus therapy , it is of interest that significant improvements of the long - term memory is also established in memory tests after 10 day treatment with the same dose of the extract . other work on the positive effects of rhodiola on learning and memory has been noted ( lazarova et al . 1986 ). huperzine is a compound belonging to a class known as acetlycholinesterase inhibitors . it has been shown to inhibit the enzyme that is responsible for the breakdown of acetylcholine , an important neurotransmitter , or brain chemical , which is critical in not only memory and / or learning but is critical in peripheral nervous system as well . this could have a beneficial effect in the disorder known as myastenia gravis . huperzine is a naturally occurring compound that was originally isolated from the club moss huperzine serrata . it has been used in chinese folk medicine and more recently in limited clinical trials conducted in china as a treatment for age - related memory disorders . results suggest that it improves learning and memory in certain patients . however , these suggested results have not been substantiated by clinical trials . this natural substance is contemplated for use with the composition of matter claimed in this patent application ( provisional ) to affect attentional processing . in humans the recommended oral dose to enhance memory is 150 micrograms daily ( the therapeutic range is 1 . 5 to 1 , 500 mcg daily ). we will determine the best intravenous dose via experimentation alone and in combination with the claimed compositions . huperzine a , a novel potent , reversible , and selective acetylcholinesterase ( ache ) inhibitor has been expected to be superior to other ache inhibitors now known for the treatment of memory deficits in patients with alzheimer &# 39 ; s disease . the compound has been studied by a number of investigators including zhi and associates ( 1995 ) with very positive results . in fact huperzine a is superior in activity to cognex r , the first drug licensed in the usa for alzheimer &# 39 ; s disease . the drug also blocked glutamate - induced cellular death of neurons . the duration of action of huperzine a at 3 hours is superior to cognex r ( 2 hours ) and physostigmine ( 30 min .). in behavioral studies of learning and memory enhancement in animals , the difference between amounts of the extract effective for memory and learning and the non - toxic - effect dose was 30 - 100 fold . these data strongly suggest that huperzine a can be useful in treating alzheimer &# 39 ; s disease with minimal side effects . toxicology and efficacy studies of huperzine a show it to be non - toxic even when administered at 50 - 100 times the human therapeutic dose . the extract is active for six hours at a dose of 2 micrograms / kg with no remarkable side effects . l - phenylalanine - 1500 mg l - tyrosine - 900 mg l - tryptophan - 500 mg l - glutamine - 300 mg pyridoxal phosphate 20 mg chromium ( picolinate , or 400 ug nicotinate ) tyr - d - arg 15 ug rhodiola rosea 25 mg and / or huperzine a 10 ug note : while the foregoing doses are preferred , it is contemplated that the quantities of each ingredient may be varied by an order of magnitude ( 10 % to 1000 %). because of the interactions of the various neurotransmitters , an increase in the amount of one ingredient may facilitate the reduction of another ingredient . also , other substances of similar activity , as noted above in the text of this invention , may be substituted for those of the example . in one such example the inventors propose the combination of utilizing compositions a - e , with the patented method of treating alcohol dependence by bonin ( u . s . pat . no . 5 , 418 , 225 incorporated by reference into the present invention ) issued in 1995 . the bonin invention relates to a treatment for alcohol dependence involving intravenous infusion of an alcohol solution . in the present invention , the inventors propose to expand the use to all rds behaviors . the rational here is that bonin never appreciated the fact that alcohol like other substances of abuse such as nicotine , heroin , cocaine , marijauna , glucose to name a few , all release neuronal dopamine at the “ reward site ” in the brain . it is anticipated then that by using alcohol to induce dopamine release , the subject would overcome potential genetic deficits as outlined in this application and induce , for example , proliferation of dopamine d2 receptors , thereby reducing generalized craving behavior as seen in most rds subjects . therefore , this short - term approach may even be useful in adhd , tourettes , pathological gambling and even sexual deviancy . it is the intent of the inventor to determine the potential optimal and wide spread utility of this intravenous approach as first proposed by bonin ( specific for alcohol dependence ). the inventor will also determine the best composition ( a - e ) described herein to combine with the ethanol solution . the bonin invention is a method of treating alcohol dependence in which an ethanol solution is infused intravenously into a patient . typically , for the new patient , the treatment is continued for ten days , with a steady decrease in the amount of ethanol infused each day . it is preferred that about 40 - 50 ml of ethanol be initially administered in two separate aliquots , and that the volume of ethanol be decreased by about 2 to 4 ml per day for the first three days . on the fourth day , the volume of ethanol is decreased by about 20 ml and this volume is given in only one aliquot . from the fourth through the tenth day , the volume is again decreased by about 2 ml per day so that on the final day , preferably only about 4 ml of ethanol is infused in one aliquot . the preferred concentration of ethanol in solution is about 10 to 20 % by volume . however , the concentration and the total volume of solution infused can vary considerably ( 5 % to 25 %), depending primarily on the tolerance and weight of the patient . one suitable alcohol solution which is available in prepackaged form is manufactured by kendall - mcgraw laboratories , inc . and contains 5 % dextrose and 10 % ethanol in distilled water . according to the bonin patent , it has been found that after the initial treatment program , the patients who suffer recidivism ( this can be checked against genotyping the individual for multiple polymorphisms such as the drd2a1 allele — see tables presented herein ), can often be effectively retreated by a six day course of alcohol infusion , rather than the full ten day treatment program . with this shorter program , the same volume of ethanol , i . e . about 40 to 50 ml , is initially administered , and it is then decreased following the same schedule described above for the ten day treatment . on the final day treatment , preferably about 12 ml of ethanol infused . preferred solution includes the 5 % dextrose and 10 % ethanol solution , begins with 220 ml of solution twice daily on the first day . at least about two and one - half hours rest or waiting period should be given between successive infusions . following the above - described treatment on the first day , the preferred treatment schedule , using the aforementioned 10 % ethanol solution , is as follows : day two : 200 ml , twice daily ; day three : 180 ml , twice daily ; day four : 160 ml , once daily ; day five : 140 ml , once daily ; day six : 120 ml , once daily ; day seven : 100 ml , once daily ; day eight : 80 ml , once daily ; day nine : 60 ml , once daily ; day ten : 40 ml . once daily . recidivists can often be effectively re - treated . preferably , if using the preferred 10 % ethanol solution , 220 ml is administered twice on the first day . the amount of solution infused is then reduced as follows : day two : 200 ml , twice daily ; day three : 180 ml , twice daily ; day four : 160 ml , once daily ; day five : 140 ml , once daily ; day six : 120 ml , once daily . if the shorter treatment program is not effective , a longer re - treatment program can be used . further , the volume of solution , the rate of infusion , and the concentration can all be varied with the shorter program in the same manner , and subject to the same concentrations , in which they are varied in the longer ten day program . in terms of expanded use , the inventors point out that bonin was very specific in its specified use — alcohol dependence and alcohol craving . this is stated in the preamble of the claims and throughout the text . in fact bonin ;&# 39 ; s proposed mechanism is strictly directed to alcoholism . he states : “ a proposed explanation for the effectiveness of this treatment is that alcohol addiction is the result of an immune response to ethanol antigen . the intestine is lined by a great number of macrophage . phagocytization of an antigen by macrophage is usually the first step in the immune response . thus , when alcohol is introduced intravenously , it does not pass through the macrophage - rich intestine , and the immune response is substantially ameliorated . at the same time , however , this alcohol is available in the blood stream to satisfy the needs of the central nervous system and abate the usual [ alcohol induced ] withdrawal symptoms . because the amount of alcohol administered in gradually decreased , the patient is desensitized to the alcohol antigen , which caused the allergic - type reactions . ultimately , the patient becomes immunologically non - reactive to alcohol , and the craving for it diminishes .” therefore , if bonin is correct the use of intravenous alcohol alone would have no effect on other substances of abuse and addiction i . e cocaine , heroin , nicotine , glucose , marijauna as well as other rds behaviors ( adhd , pathological gambling , sexual deviancy etc .). the inventor expects to find a surprising and unexpected effect of ethanol infusions to reduce cravings for other drugs of abuse ; this would be indeed a patentable advance . this coupled with the outlined amino - acid , herbal and mineral combinations would also provide a novel step in the treatment of rds behaviors with short - term bolus intravenous therapy . l - phenylalanine - 1500 mg l - tyrosine - 900 mg l - tryptophan - 500 mg l - glutamine - 300 mg pyridoxal phosphate 20 mg chromium ( picolinate 400 ug or nicotinate ) tyr - d - arg 15 ug rhodiola rosea 25 mg and / or huperzine a 10 ug ethanol 10 % note : while the foregoing doses are preferred , it is contemplated that the quantities of each ingredient may be varied by an order of magnitude ( 10 % to 1000 %). because of the interactions of the various neurotransmitters , an increase in the amount of one ingredient may facilitate the reduction of another ingredient . also , other substances of similar activity , as noted above in the text of this invention , may be substituted for those of the example . it is important the inventors will carry out certain pharmaconetic studies and mass spectrophotometry on the resultant compositions , especially as it relates to the biochemical interactions , if any , with ethanol and the amino - acids , herbals and minerals contained in the final preferred compositions . it should be understood that the forgoing terms , expressions are exemplary only and not limiting , and that the scope of protection is defined only by the claims which follow and includes all equivalents of the subject matter of the claims . the following references as well as those cited elsewhere herein are incorporated by reference herein in pertinent part to supplement this disclosure . the & amp ; mgr opiate receptor as a candidate gene for pain : polymorphisms , variations in expression , nociception , and opiate responses . molecular neurobiology branch , intramural research program , national institute on drug abuse , national institutes of health , baltimore , md . 21224 , usa . there are differences between human individuals and between mouse strains in levels of & amp ; mgr ; opiate receptor (& amp ; mgr ; or ) expression , responses to painful stimuli , and responses to opiate drugs . one of the best candidates for contributing to these differences is variation at the & amp ; mgr ; or gene locus . support for this idea comes from analyses of the human and murine & amp ; mgr ; or genes , assessments of individual differences in human & amp ; mgr ; or expression add further support . studies with mice , including knockout - tranegenle , quahtltativo trait locus , and strain - comparison studies , also strongly support the possibility that & amp ; mgr ; or gene alleles would be strong candidates for contributing to individual differences in human nocleeption and opiate drug responses . this paper reviews current analyses of the murine and human & amp ; mgr ; or genes , their important variants , and correlations between these variants and opiate influences on pain dopamine transporter : transmnembrane phenylalanine mutations can selectively influence dopamine uptake and cocaine analog recognition . lin z , wang w , kopajtic t , revay r s , uhi g r molecular neurobiology branch , national instltute on drug abuse , intramural research program , national institutes of health , baltimore , md . cocaine blocks the normal role of the dopamine traris ˜ porter ( dat ) in terminating doparriine signaling through molecular interactions that are only partially understood . cocaine analog structure - activity studies have suggested roles for both cationic and aromatic interactions among dat , dopemine , and cocaine . we hypothesized that phenylalanine residues lying in putative dat tranemombrane ( tm ) domains wore good candidates to contribute to aromatic and / or cationic interactions among dat , dopamine , and cocaine . to test this idea we characterized the influences of alanine substitution for each of 29 phenylalanine residues lying in or near a putative dat tm domain . cells express 22 mutartts at near wild - type levels , manifest by dat immunohistochemistry and binding of the radiolabeled cocaine analog [( 3 ) h ](−)- 2 - beta - carbomethoxy - 3 - beta -( 4 . fluoroph5nyl ) tropane © ft ), seven mutants fail to express at normal levels . four mutations selectively reduce cocaine analog affinities . alanine substitutions at phe ( 76 ), phe ( 98 ), phe ( 390 ), and phe ( 381 ) located ln tm domains 1 and 2 , the fourth extracelkilar loop near tm 4 and in tm 7 , displayed normal affinities for dopan ˜ lne but 3 - to 8 - fold reductions in affinities for cft . one tm 3 mutation , f ( 155 ) a , selectively decreased dopamine affinity to less than 3 % of wild - type levels while reducing cpt affinity less than 3 - told . in a current dat structural model , each of the residues at which alanine substitution selectivefy reduces cocaine analog or dopamine affinities faces a central transporter cavity , whereas mutations that influence expression levels are more likely to lie at potential helixlhellx interfaces . specific , overlapping sets of phenylalenine residues contribute selectively to dat recognition of dopermlne and cocaine . choilnergic axon terminals in the ventral tegrnental area target a subpopulauon of neurons expressing low levels of the dopamlne transporter . garzon m , vaughan r a , uhl g r , kuhar m j , plcl ˜ el v m department of neurology and neuroscience , cornell university medical college , new york , n . y . ioo2i , usa . mgarzon - mell . med . comell . edu chohnerglc activation of dopen - lnerglc neurons in the ventral tegmental area ( vta ) is thought to play a major role in ˜ ognltive functions and reward . these dopamlnergic neurons differentially project to cortical and limbic forebrain regions , wheretheir . terminsls differ in levels of expression of the plasmalemmal dopamlne transporter ( dat ). this transporter selectively identifies dopaminergic neurons , whereas itie vesicular acetyictioline transporter ( yacht ) is present only in the neurons that store arid release acetyicholine . we examined immunogold labeling for dat and immunoperoxidase localization of vacht antipeptlde antisera in single sections of the rat vta to determine whether dopaminefgic someta and dendrites in this region differ in their levels of expression of dat and / or input from cholinergic terminals . vacht immunoreactivity was prominently localized to membranes ˜ f small synaptic vesiclee in unmyelinated axons and axon terminals . vacht - immunoreactive terminals formed almost exclusively asyrnnietnc synapses with dendrites . of 159 dendrites that were identified as cholinergic targets , 36 % contained plasmalemmul dat , and 65 % were without detectable dat immunoresetivity . the dat - immunoreactive dendrites postsynaptic to vacht - labeled terminals contained less than half the density of gold particles as seen in other dendrites receiving input only from unlabeled terminals . these results suggest selective targeting of cholinergic afferents in the vta to non - dopaminergic neurons and a subpopulation of dopaminergic neurons that have a limited capacity for plasmalemmal reuptake of dopamine , a characteristic of those that project to the frontal cortex . visceral chemical nociception in mice lacking mu - opioid receptors : effects of morphine , snc80 and u - 50a88 . sara i , li x f , funada m , kinsey s , uhi g r molecular neurobiology branch , intramural research program , national inetituta on drug abuse , national institutes of health , baltimore , md . 21224 , usa . writhing responses to intraperitoneal acetic acid administration and their modulation by mu -, kappa - and delta - oploid receptor agonists were compared in wild - typo and mu - opioid receptor knockout mice , unpretreated homozygous knockout mice displayed less writhing than wildtype mlce . u - 50 , 488 [ trans - 3 , 4 - dlchloro - n - methyl - n - f2 -( 1 - pyrolldlnyl ) cyclohexyij - b ˜ nze neacetamide ]) reduced writhing responses in wild - type and khockouts . morphine and snc80 (( 4 )- 4 -[ 9 .- alpha - r )- alpha -( 2s , 5ro - 4 - ellyl - 2 ˜- dimethyl - i - piperazinyl )- 3 - methoxybenzylj - n , ndiethylbenzsmide ] were effective in wild - type mice but ineffective in knockouts . mu - opioid receptors appear to play important roles in responses to this visceral nociceptlve stimulus and rt ˜ modulation by mu - and delta - oploid receptor agonists . absence of q - protsin activation by mu - opioid receptor agonists in the spinal cord of mu - opioid receptor knockout mice . narita m , mlzoguchl h , narita m , sora i , uhl g r , teeng l f 1 . the ability of mu - opioid receptor agonists to activate g - proteins in the spinal cord of muopicici receptor knockout mice was examined by monitoring the binding to membranes of the non - hydrolyzable analogue of gtp , guanoslne -˜ ae - o -( 3 - t35 $ 1thio ) triphosphate ( t36s1gtpgammas ). 2 . in the receptor binding study , soatchard analysis of [ 3h ][ daa2 , nhph4 , gly - oflenkephaiin ([ 3h ] damgo ; mu - opioid receptor ligand ) binding revealed that the heterozygous mu - knockout mice displayed approximately 40 % reduction in the number of mu - receptors as compared to the wild - type mice , the homozygous mu - knockout mlc . e showed no detectable mu - binding sites . 3 . the newly isolated mu - opioid peptides endomorphln - 1 and - 2 , the synthetic selective mu - opiold receptor agonist damgo and the prototype of mu - oploid receptor agonist morphine each produced concentration - dependent increases in [ 35s ] grpgammas binding in wild - type mice . this stimulation was reduced by 55 - 70 % of the wild - type level in heterozygous , and virtually eliminated in homozygous knockout mica . 4 no differences in the [ 35s ] gtpgammas binding stimulated b - ae specific deftal -([ d - pen2 , 5 ] enkephalin ), delta2 -( ed - ale2ldeltorphin ii ) or kappal -( u50 , a ˜ 8t - 1 ) oploid receptor egonlets were noted in mice of any of the three genotypes . 5 . the data clearly indicate that mu - opioid receptor gene products play a key role in g - prdtein actru ˜ ation by endomorphins , damgo and morphine in the mouse spinal cord , fl .˜ y support the idea that mu - op . oid receptor densities could be rate - limiting steps in the g - proteln activation by muoplold receptor agoniats in the spinal cord . these thus indicate a limited phyelologlcal mureeeptdr reserve . furthermore , little change in deital -, delta2 - orkappal - oplold receptor - gprotein complex appears to accompany mu - opioid receptor gene deletions in this region . charactenzation of mechanical withdrawal responses and effects of mu -, delta - and kappoploid agonists in normal and mu - opioid receptor knockout mace . fuchs p n . raze c , sara i . uhi g , rain s n oepartment of neurosurgery , johns hopkins school of medicine , 600 north wolfe stre4 meyer 5 - 109 , baltimore , md . 21257 , usa . fuch o uta . edu clinical and expenmental observations suggest that opiates can exert different influences on the perception of stimuli from distinct sensory modalities . thermally - induced nociception is classically responsive to opiate ugonists . mu - opioid receptor - deficient transgenic mice are more sensitive to thermal noclceptlve stimuli a ,˜ d morphine faile to attenuate the nocloeptive responses to thermal stimuli in these animals . to enhance our understanding of opiate influences on mechanical sensitmty , we have examined withdrawal responses to a sequence of ascending forces of mechanical stimuli in mice with normal ( wild type ), half - normal ( heterozygous ) and absent ( honiozygous ) mu - opioid receptor levels . we report data from mice examined without drug pretreatment or following pretreatment with morphine , the selective kappa - oplold agonist , u5048811 , end the selective delta - opio ; d agonist , dpope . saline pretreated mice of e8ch genotype displayed similar , mnonotonlcally increasing frequency of withdrawal responses to the graded stimuli . subcut . aneously administered morphine produced a dose - 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