Acute Phenylalanine/tyrosine Depletion Research Articles

Pharmacological Treatments for Cocaine Craving: What Is the Way Forward? A Systematic Review.

cocaine craving is a core feature of cocaine use disorder and remains a critical challenge for abstinence and relapse prevention. This review summarizes the anti-craving efficacy of pharmacotherapies tested for cocaine use disorder, in the context of randomized-controlled clinical trials. we assessed the databases of the U.S. National Library of Medicine, Google Scholar, and PsycINFO, without date restrictions up to August 2022, to identify relevant studies. we included double-blinded randomized-controlled trials investigating pharmacotherapies for cocaine craving and/or cocaine use disorder whose outcomes included cocaine craving. Two authors screened studies' titles and abstracts for inclusion, and both read all the included studies. We systematically gathered information on the following aspects of each study: title; author(s); year of publication; sample size; mean age; sample characteristics; study set-ting; whether participants were treatment-seeking; study design; craving measures; study interventions; drop-out rates; and other relevant outcomes. Overall, we appraised 130 clinical trials, including 8137 participants. We further considered the drugs from the studies that scored equal to or greater than six points in the quality assessment. There was a correlation between craving and cocaine use outcomes (self-reports, timeline follow-back or urinary benzoylecgonine) in the vast majority of studies. In the short-term treatment, acute phenylalanine-tyrosine depletion, clonidine, fenfluramine, meta-chlorophenylpiperazine (m-CPP) and mecamylamine presented promising effects. In the long term, amphetamine, biperiden, carbamazepine, lisdexamfetamine, lorcaserin, methamphetamine, mirtazapine, pioglitazone, progesterone, guanfacine, levodopa, nefazodone presented promising anti-craving effects. Unfortunately, the highly tested medications were not successful in most of the trials, as follows: propranolol in the short term; amantadine, aripiprazole, bromocriptine, citicoline, ketamine, modafinil, olanzapine, topiramate in the long term. The remaining 52 medications had no positive anti-craving outcomes. Our review was limited by high heterogeneity of craving assessments across the studies and by a great range of pharmacotherapies. Further, the majority of the studies considered abstinence and retention in treatment as the main outcomes, whereas craving was a secondary outcome and some of the studies evaluated patients with cocaine use disorder with comorbidities such as opioid or alcohol use disorder, schizophrenia, bipolar disorder or attention deficit hyperactivity. Lastly, most of the studies also included non-pharmacological treatments, such as counseling or psychotherapy. There is a direct association between craving and cocaine use, underscoring craving as an important treatment target for promoting abstinence among persons with cocaine use disorder. Clonidine, fenfluramine and m-CPP showed to be promising medications for cocaine craving in the short-term treatment, and amphetamine, biperiden, carbamazepine, lisdexamfetamine, lorcaserin, methamphetamine, mirtazapine, pioglitazone, progesterone, guanfacine, levodopa, nefazodone in the long-term treatment.

Dopamine depletion effects on cognitive flexibility as modulated by tDCS of the dlPFC

BackgroundRecent evidence suggests that transcranial direct current stimulation (tDCS) may interact with the dopaminergic system to affect cognitive flexibility.Objective/hypotheses: We examined whether putative reduction of dopamine levels through the acute phenylalanine/tyrosine depletion (APTD) procedure and excitatory anodal tDCS of the dorsolateral prefrontal cortex (dlPFC) are causally related to cognitive flexibility as measured by task switching and reversal learning. MethodA double-blind, sham-controlled, randomised trial was conducted to test the effects of combining anodal tDCS and depletion of catecholaminergic precursor tyrosine on cognitive flexibility. ResultsAnodal tDCS and tyrosine depletion had a significant effect on task switching, but not reversal learning. Whilst perseverative errors were significantly improved by anodal tDCS, the APTD impaired reaction times. Importantly, the combination of APTD and anodal tDCS resulted in cognitive performance which did not statistically differ to that of the control condition. ConclusionsOur results suggest that the effects of tDCS on cognitive flexibility are modulated by dopaminergic tone.

Effects of serotonin depletion and dopamine depletion on bimodal divided attention

Objectives: This study aimed to explore the effects of acute phenylalanine tyrosine depletion (APTD) and acute tryptophan depletion (ATD) on bimodal divided attention. A balanced amino acid mixture (BAL) served as control condition.Methods: Fifty-three healthy adults (final analyzed sample was N = 49, age: M = 23.8 years) were randomly assigned to APTD, ATD or BAL in a double-blind, between-subject approach. Divided attention was assessed after 4 h. Blood samples were taken before and 6 h after challenge intake.Results: Amino acid concentrations following challenge intake significantly decreased (all P ≤ 0.01). There was a significant difference in the mean reaction time (RT) towards auditory stimuli, but not towards visual stimuli between the groups. Post-hoc comparison of mean RTs (auditory stimuli) showed a significant difference between ATD (RT = 604.0 ms, SD = 56.9 ms) and APTD (RT = 556.4 ms, SD = 54.2 ms; P = 0.037), but no RT difference between ATD and BAL or APTD and BAL (RT = 573.6 ms, SD = 45.7 ms).Conclusions: The results indicate a possible dissociation between the effects of a diminished brain 5-HT and DA synthesis on the performance in a bimodal divided attention task. The difference was exclusively observed within the RT towards auditory signals.

Dopamine and light: effects on facial emotion recognition.

Bright light can affect mood states and social behaviours. Here, we tested potential interacting effects of light and dopamine on facial emotion recognition. Participants were 32 women with subsyndromal seasonal affective disorder tested in either a bright (3000 lux) or dim light (10 lux) environment. Each participant completed two test days, one following the ingestion of a phenylalanine/tyrosine-deficient mixture and one with a nutritionally balanced control mixture, both administered double blind in a randomised order. Approximately four hours post-ingestion participants completed a self-report measure of mood followed by a facial emotion recognition task. All testing took place between November and March when seasonal symptoms would be present. Following acute phenylalanine/tyrosine depletion (APTD), compared to the nutritionally balanced control mixture, participants in the dim light condition were more accurate at recognising sad faces, less likely to misclassify them, and faster at responding to them, effects that were independent of changes in mood. Effects of APTD on responses to sad faces in the bright light group were less consistent. There were no APTD effects on responses to other emotions, with one exception: a significant light × mixture interaction was seen for the reaction time to fear, but the pattern of effect was not predicted a priori or seen on other measures. Together, the results suggest that the processing of sad emotional stimuli might be greater when dopamine transmission is low. Bright light exposure, used for the treatment of both seasonal and non-seasonal mood disorders, might produce some of its benefits by preventing this effect.

Dopamine and light: dissecting effects on mood and motivational states in women with subsyndromal seasonal affective disorder

Despite evidence that bright light can improve mood, the neurobiology remains poorly understood. Some evidence implicates the catecholamines. In the present study, we measured the effects of transiently decreasing dopamine (DA) synthesis on mood and motivational states in healthy women with mild seasonal mood changes who were tested in either bright or dim light. On 2 test days, participants slept overnight in a light-controlled room. On the morning of each session, half of the participants awoke to gradual increases of bright light, up to 3000 lux, and half to dim light (10 lux). For all participants, DA was reduced on 1 of the test days using the acute phenylalanine/tyrosine depletion (APTD) method; on the other day, they ingested a nutritionally balanced control mixture (BAL). Beginning 4 hours postingestion, participants completed subjective mood questionnaires, psychological tests and a progressive ratio breakpoint task during which they worked for successive units of $5. Thirty-two women participated in our study. The APTD lowered mood, agreeableness, energy and the willingness to work for monetary reward. The effects on energy and motivation were independent of light, while the effects on mood and agreeableness were seen in the dim condition only, being prevented by bright light. Acute phenylalanine/tyrosine depletion might affect systems other than DA. The sample size was small. These results suggest that increased DA function may be responsible for some of the beneficial effects of light, while adding to the evidence that the neurobiology of mood and motivational states can be dissociated.

Appropriate amino acid mixtures for tryptophan depletion and tyrosine/phenylalanine depletion and the safety of long-term amino acid depletion in humans

AbbreviationsATD Acute tryptophan depletionAPTD Acute tyrosine/phenylalanine depletionGMP GlycomacropeptideTrp TryptophanTyr TyrosinePhe PhenylalanineDOPA dihydroxyphenylalanineDear Editor,In a recent review in this journal, Badawy ( 2013) discussedthe appropriate composition of amino acid mixtures for acutetryptophan depletion (ATD) and acute phenylalanine/tyrosinedepletion(APTD)studiesandsuggestedthatglycomacropeptide(GMP), which contains no aromatic amino acids, may be asuitable protein to use in acute depletion studies and long-termATD and APTD treatments of patients with mania and schizo-phrenia. The review raises a number of interesting issues but hasaspects that are problematic.1. The review suggests that GMP may be an effective nutri-tionaltherapyformanicand psychoticdisorders.Howev-er,thereviewdoesnotraisetheissueofwhetheraproteinwill necessarily be free of adverse effects. GMP lacksaromatic amino acids and, if given chronically, wouldcause the intake of amino acids to be imbalanced. Aspointed out by Young (2008), the extensive animal liter-ature on the effects of imbalanced amino acid diets indi-cates adverse effects including reductions in food intake,growth retardation, and the development of fatty liver.Furthermore, tyrosine (Tyr) and tryptophan (Trp) areessentialaminoacids,anddepletingthemmayhavesubtleeffectsonproteinsynthesis.Thepossibleimplicationsforbrain function of long-term mild disturbances of proteinsynthesisarenotknown.Rulingoutanyadverseeffectsoflong-term ATD or APTD in humans would be difficult,andanylong-termdepletionstudyinhumans,usingeitheramino acid mixtures or a protein such as GMP, would behard to justify ethically.2. The review mentions that GMP is lacking in histidine.This means that GMP would be expected to depletehistidine levels, but the implications of this are not men-tioned. In rats, histidine levels influence brain histaminelevels more than Trp levels influence brain serotoninlevels, and acute histidine depletion in humans, using ahistidine-deficient amino acid mixture, has behavioral ef-fects (van Ruitenbeek et al. 2009). Therefore, if GMP isused for acute ATD or APTD studies, histidine should beaddedtotheGMPinbothdepletionandcontrolconditionsto avoid a study on the combined effects of low histamineand low serotonin or low histamine and low dopamine.3. The review suggests that GMP may be useful for treatingmania by depleting dopamine. This is based on the studyof Scarna et al. (2003) who found a therapeutic effect,relativeto placebo, of giving a mixture of branchedchainamino acids (BCAA) to manic patients everyday for7 days. The effect was attributed to lowered dopamine,as the BCAA will inhibit the uptake of phenylalanine(Phe) and Tyr into the brain. However, the BCAA willalso inhibit the uptake of Trp into the brain. Two studiessuggest that depletion of Trp may have played a moreimportant role than depletion of Phe and Tyr in the ther-apeutic effect of the BCAA. Firstly, the Tyr hydroxylaseinhibitor α-methylparatyrosine had no consistent effecton the symptoms of manic patients (Bunney et al. 1971).Secondly,ATDimprovedthesymptomsofmanicpatientsmore than treatment with a placebo (Applebaum et al.2007). Therefore, if GMP has an effect on manic

Dopaminergic Modulation of Motor Timing in Healthy Volunteers Differs as a Function of Baseline DA Precursor Availability

Although numerous experiments in patients and animals implicate the dopamine (DA) system in timing, there are relatively few studies examining this effect in healthy volunteers. Moreover, the majority of these studies employed tasks of perceptual timing. We therefore investigated the DA modulation of motor timing in healthy volunteers using Acute Phenylalanine/Tyrosine Depletion (APTD), an amino-acid drink that reduces concentrations of the DA precursors tyrosine and phenylalanine. We also examined how APTD’s effects on timing might differ as a function of underlying DA function, as indexed by baseline levels of DA precursors. 18 healthy volunteers performed a Mixed Temporal Reproduction task, in which reproduction of five different sample durations (500 ms–1500 ms) were tested within a single testing block. Reproduction times conformed to Vierordt’s Law, such that the shortest durations were overestimated and the longest ones underestimated. Yet contrary to reported effects in Parkinson’s disease, we found no DA modulation of this ‘migration’ effect in our healthy volunteers. Instead, APTD produced systematic shifts in reproduction time across all durations. However, the direction of the shift differed according to individual differences in baseline levels of DA precursor availability. Specifically, APTD slowed reproduction times in participants with low baseline DA precursor levels whereas it speeded them in participants with high baseline levels. These apparently paradoxical effects can be reconciled in terms of the inverted U-shaped relationship between DA function and cognition. Finally, APTD had no effect on a test of temporal production in which participants were asked to provide spontaneous estimates of a one-second time interval. The differential effect of APTD on the reproduction versus production tasks suggests DA modulates the magnitude of the duration initially encoded into working memory, rather than clock-speed.

The role of dopamine in alcohol self-administration in humans: Individual differences

Objective: To clarify dopamine's role in alcohol self-administration in a heterogeneous sample of drinkers using acute phenylalanine/tyrosine depletion (APTD). Methods: Sixteen men with variable drinking histories were characterized on their ethanol-induced cardiac response, a marker previously proposed to index dopamine system reactivity and vulnerability to alcohol abuse. During separate sessions participants were administered (i) a nutritionally balanced (BAL) amino acid (AA) mixture, (ii) a mixture lacking the dopamine precursors, phenylalanine and tyrosine, and (iii) APTD followed by the dopamine precursor, l-DOPA. Five hours after AA administration, participants could earn units of alcohol using a progressive ratio breakpoint task. Results: Alcohol self-administration was reduced in the APTD and APTD + l-DOPA conditions relative to the BAL condition. In both cases the changes were predicted by ethanol-induced cardiac change. Conclusions: The motivation to drink is likely regulated by more than one neurobiological mechanism. Individual differences in cardiac responsivity to ethanol might provide a peripheral marker of responsiveness to pharmacological manipulations of dopamine.

Mood is indirectly related to serotonin, norepinephrine and dopamine levels in humans: a meta-analysis of monoamine depletion studies

Dysfunction in the monoamine systems of serotonin (5-HT), norepinephrine (NE) and dopamine (DA) may causally be related to major depressive disorder (MDD). Monoamine depletion studies investigate the direct effects of monoamines on mood. Acute tryptophan depletion (ATD) or para-chlorophenylalanine (PCPA) deplete 5-HT, acute phenylalanine/tyrosine depletion (APTD) or alpha-methyl-para-tyrosine (AMPT) deplete NE/DA. Available depletion studies found conflicting results in heterogeneous populations: healthy controls, patients with previous MDD in remission and patients suffering from MDD. The decrease in mood after 5-HT and NE/DA depletion in humans is reviewed and quantified. Systematic search of MEDLINE and EMBASE (1966-October 2006) and cross-references was carried out. Randomized studies applying ATD, PCPA, APTD or AMPT vs control depletion were included. Pooling of results by meta-analyses was stratified for studied population and design of the study (within or between subjects). Seventy-three ATD, 2 PCPA, 10 APTD and 8 AMPT studies were identified of which 45 ATD and 8 APTD studies could be meta-analyzed. 5-HT or NE/DA depletion did not decrease mood in healthy controls. 5-HT or NE/DA depletion slightly lowered mood in healthy controls with a family history of MDD. In drug-free patients with MDD in remission, a moderate mood decrease was found for ATD, without an effect of APTD. ATD induced relapse in patients with MDD in remission who used serotonergic antidepressants. In conclusion, monoamine depletion studies demonstrate decreased mood in subjects with a family history of MDD and in drug-free patients with MDD in remission, but do not decrease mood in healthy humans. Although depletion studies usefully investigate the etiological link of 5-HT and NE with MDD, they fail to demonstrate a causal relation. They presumably clarify a vulnerability trait to become depressed. Directions for further investigation of this vulnerability trait are proposed.

Affective Bias and Response Modulation Following Tyrosine Depletion in Healthy Adults

Acute phenylalanine/tyrosine depletion (ATPD) has been used to transiently lower central nervous system dopamine activity in animals and humans. Findings suggest that ATPD may impact dopamine transmission in limbic and striatal regions. Impact on cognitive functions has varied across studies, although several recent reports suggest that affective processing in the context of a go/no-go response control task may be impaired during ATPD. In this study, response control under affective vs nonaffective conditions was examined in healthy individuals who underwent either ATPD or a balanced condition in a between-subjects design. Effects of ATPD were validated through its effects on serum prolactin secretion. ATPD resulted in significantly increased prolactin levels relative to the balanced mixture. Although there were no differences in self-reported mood between the groups, individuals in the ATPD condition demonstrated diminished sensitivity to positively valenced words and seemingly enhanced sensitivity to negatively valenced words in an affective go/no-go task. They also showed difficulties in modulating ongoing behavior in a nonaffective go/no-go task when responses had to be intermittently inhibited then immediately restarted. Basic motor functions were not impacted. Findings are discussed in relation to dopamine's role in switching signals within neural networks that are important for response modulation and affective control.

Lack of effect of acute dopamine precursor depletion in nicotine-dependent smokers

Rationale Nicotine increases dopamine (DA) release but its role in nicotine dependence remains unclear. Objective To assess the role of DA in nicotine craving and self-administration using acute phenylalanine/tyrosine depletion (APTD). Methods Fifteen nicotine-dependent men ingested, a minimum of 3 days apart, a nutritionally balanced amino acid (AA) mixture (BAL), a mixture deficient in the catecholamine precursors, phenylalanine and tyrosine, and APTD followed by the immediate DA precursor, l-DOPA. Beginning 3 h after ingestion of the AA mixture, subjects smoked 4 cigarettes. Craving, mood, and other aspects of subjective state were assessed with self-report scales. Smoking puff topography was measured with a computerized flowmeter. Results APTD did not change smoking puff topography, cigarette craving, or subjective effects of smoking. Conclusions The findings suggest that in nicotine-dependent smokers craving for cigarettes, subjective effects of nicotine, and the self-administration of freely available cigarettes are largely unrelated to acute changes in DA neurotransmission.

Cocaine craving, euphoria, and self-administration: A preliminary study of the effect of catecholamine precursor depletion.

The authors used the acute phenylalanine-tyrosine depletion (APTD) method to test the effect of transient catecholamine precursor depletion on cocaine craving, euphoria, and self-administration. Eight nondependent, nontreatment-seeking cocaine users self-administered 3 doses of cocaine (0.6, 1.5, 3.0 mg/kg, taken intranasally) following ingestion of (a) a nutritionally balanced amino acid mixture, (b) APTD, and (c) APTD followed by L-dopa/carbidopa (2x100 mg/25 mg). APTD decreased both cue and cocaine-induced drug craving but not euphoria or self-administration. APTD+L-dopa also decreased drug craving, possibly reflecting the ability of L-dopa to transiently decrease dopamine cell firing. Together, these preliminary results suggest that the craving elicited by cocaine and cocaine cues is related to changes in catecholamine neurotransmission. Euphoria and the self-administration of freely available drugs by regular users, in comparison, might be better accounted for by other mechanisms.

Monoamine depletion in psychiatric and healthy populations: review.

A number of techniques temporarily lower the functioning of monoamines: acute tryptophan depletion (ATD), alpha-methyl-para-tyrosine (AMPT) and acute phenylalanine/tyrosine depletion (APTD). This paper reviews the results of monoamine depletion studies in humans for the period 1966 until December 2002. The evidence suggests that all three interventions are specific, in terms of their short-term effects on one or two neurotransmitter systems, rather than on brain protein metabolism in general. The AMPT procedure is somewhat less specific, affecting both the dopamine and norepinephrine systems. The behavioral effects of ATD and AMPT are remarkably similar. Neither procedure has an immediate effect on the symptoms of depressed patients; however, both induce transient depressive symptoms in some remitted depressed patients. The magnitude of the effects, response rate and quality of response are also comparable. APTD has not been studied in recovered major depressive patients. Despite the similarities, the effects are distinctive in that ATD affects a subgroup of recently remitted patients treated with serotonergic medications, whereas AMPT affects recently remitted patients treated with noradrenergic medications. The evidence also suggests that ATD and APTD affect different cognitive functions, in particular different memory systems. Few studies investigated cognitive effects of the procedures in patients. Patients who are in remission for longer may also be vulnerable to ATD and AMPT, but the relationship with prior treatment is much weaker. For these patients, individual vulnerability markers are the more important determinants of depressive response, making these techniques potentially useful models of vulnerability to depression.

Effects on Mood of Acute Phenylalanine/Tyrosine Depletion in Healthy Women

Catecholamines have been implicated in the etiology and pathophysiology of mood and anxiety disorders. In the present study, we investigated the effects of experimentally reducing catecholamine neurotransmission by means of acute phenylalanine/tyrosine depletion (APTD). Healthy female volunteers ingested: (1) a nutritionally balanced amino acid (AA) mixture (n = 14); (2) a mixture deficient in the serotonin precursor, tryptophan (n = 15); or (3) one deficient in the catecholamine precursors, phenylalanine and tyrosine (n = 12). Mood was measured at three times: at baseline and both immediately before and after an aversive psychological challenge (public speaking and mental arithmetic) conducted 5 hours after AA mixture ingestion. Acute tryptophan depletion (ATD) lowered mood and energy and increased irritability scores. These effects were statistically significant only after the psychological challenge. The effect of APTD on mood was similar to that of ATD. APTD did not attenuate the anxiety caused by the psychological challenge. These findings suggest that, in healthy women, reduced serotonin and/or catecholamine neurotransmission increases vulnerability to lowered mood, especially following exposure to aversive psychological events.