The Neurobiology of Methamphetamine Addiction and the Potential to Reduce Misuse Through Conjugate Vaccines Targeting Toll-Like Receptor 4.

The methamphetamine epidemic continues to worsen each year and has contributed to more overdose deaths than opioids. Methamphetamine was listed in the top ten lethal drugs in 2021 in the United States. The drug has been shown to cause health problems such as addiction and neurological and behavioral changes. One possible solution to address this crisis is through vaccinations. Vaccinations consist of injecting a controlled substance with the goal of creating compound-specific antibodies. Although still early in development, vaccinations have been found to improve withdrawal symptoms and decrease drug-seeking behavior with minimal health side effects in rodent studies. This paper provides an overview of the clinical presentation and neurobiology of methamphetamine addiction and drug-seeking behaviors. The responses and adverse effects of conjugate vaccines IXTv-100 with adjuvant glucopyranosyl lipid A administered in oil-water stable emulsion and tetanus-toxoid conjugated to succinyl-methamphetamine adsorbed on aluminum hydroxide combined with adjuvant E6020 are examined.

Use of Adult Sensory Panel to Study Individual Differences in the Palatability of a Pediatric HIV Treatment Drug.

PURPOSE: The recommended first-line treatment for young children infected with HIV includes the liquid formulation of the co-formulated protease inhibitors lopinavir/ritonavir (Kaletra® [Abbott Laboratories, Chicago, Illinois]). Clinical reports indicate that some children readily accept the taste of Kaletra, whereas others strongly reject it, which can deter therapeutic adherence and outcomes. METHODS: As a proof-of-concept approach, a sensory panel of genotyped adults was used to document the range of individual differences in the taste and palatability (hedonics) of the liquid formulation of Kaletra and other taste stimuli, including common excipients. Panelists rated taste sensations using generalized labeled magnitude scales to determine genotype-phenotype relationships. Several months later, the panelists were retested to assess response reliability. FINDINGS: Not all panelists had the same sensory experience when tasting Kaletra. Palatability ratings varied widely, from moderate like to strongest imaginable dislike, and were reliable over time. The more irritating and bitter Kaletra tasted, the more disliked by the panelist. The more they disliked the taste of Kaletra, the more they disliked the taste of its excipient ethanol and the bitter stimulus denatonium. Those who experienced less bitter and sweeter taste sensations had a different genetic signature than the other panelists. Bitterness and irritation ratings of Kaletra varied by the orphaned bitter receptor gene (TAS2R60), whereas sweetness ratings of Kaletra varied according to the cold receptor gene (TRPM8), which is activated by menthol, an excipient of Kaletra. Neither genotype related to ratings for ethanol or denatonium, however. IMPLICATIONS: The use of a sensory panel holds promise as a first step in determining the nature of individual differences in the palatability of existing pediatric drug formulations and sources of variation. In this era of personalized medicine, the need is great to develop psychophysical tools to determine which drugs will show variation in acceptance by children and whether patterns of individual variation in taste as assessed by adults mirror those of young patients. ClinicalTrials.gov identifier: NCT01841710.

Children's perceptions about medicines: individual differences and taste.

BACKGROUND: Bitter taste receptors are genetically diverse, so children likely vary in sensitivity to the "bad" taste of some pediatric formulations. Based on prior results that variation in a bitter taste receptor gene, TAS2R38, was related to solid (pill) formulation usage, we investigated whether this variation related to liquid formulation usage and young children's reports of past experiences with medicines and whether maternal reports of these past experiences were concordant with those of their children. METHODS: We conducted retrospective interviews of 172 children 3 to 10 years old and their mothers (N = 130) separately in a clinical research setting about issues related to medication usage. Children were genotyped for the TASR38 variant A49P (alanine to proline at position 49). Children's responses were compared with their TAS2R38 genotype and with maternal reports. RESULTS: Children (>4 years) reported rejecting medication primarily because of taste complaints, and those with at least one sensitive TAS2R38 allele (AP or PP genotype) were more likely to report rejecting liquid medications than were those without a taster allele (AA genotype; χ(2) = 5.72, df = 1, p = 0.02). Children's and mothers' reports of the children's past problems with medication were in concordance (p = 0.03). CONCLUSIONS: Individual differences in taste responses to medications highlight the need to consider children's genetic variation and their own perceptions when developing formulations acceptable to the pediatric palate. Pediatric trials could systematically collect valid information directly from children and from their caregivers regarding palatability (rejection) issues, providing data to develop well-accepted pediatric formulations that effectively treat illnesses for all children. TRIAL REGISTRATION: Clinicaltrials.gov protocol registration system (NCT01407939). Registered 19 July 2011.

"A spoonful of sugar helps the medicine go down": bitter masking by sucrose among children and adults.

Sweeteners are often added to liquid formulations of drugs but whether they merely make them better tasting or actually reduce the perception of bitterness remains unknown. In a group of children and adults, we determined whether adding sucrose to urea, caffeine, denatonium benzoate, propylthiouracil (PROP), and quinine would reduce their bitterness using a forced-choice method of paired comparisons. To better understand individual differences, adults also rated each solution using a more complex test (general Labeled Magnitude Scale [gLMS]) and were genotyped for the sweet taste receptor gene TAS1R3 and the bitter receptor TAS2R38. Sucrose suppressed the bitterness of each agent in children and adults. In adults, sucrose was effective in reducing the bitterness ratings from moderate to weak for all compounds tested, but those with the sensitive form of the sweet receptor reported greater reduction for caffeine and quinine. For PROP, sucrose was most effective for those who were genetically the most sensitive, although this did not attain statistical significance. Not only is the paired comparison method a valid tool to study how sucrose improves the taste of pediatric medicines among children but knowledge gleaned from basic research in bitter taste and how to alleviate it remains an important public health priority.

Age-related differences in bitter taste and efficacy of bitter blockers.

BACKGROUND: Bitter taste is the primary culprit for rejection of pediatric liquid medications. We probed the underlying biology of bitter sensing and the efficacy of two known bitter blockers in children and adults. METHODS: A racially diverse group of 154 children (3-10 years old) and their mothers (N = 118) evaluated the effectiveness of two bitter blockers, sodium gluconate (NaG) and monosodium glutamate (MSG), for five food-grade bitter compounds (quinine, denatonium benzoate, caffeine, propylthiouracil (PROP), urea) using a forced-choice method of paired comparisons. The trial was registered at clinicaltrials.gov (NCT01407939). RESULTS: The blockers reduced bitterness in 7 of 10 bitter-blocker combinations for adults but only 3 of 10 for children, suggesting that efficacy depends on age and is also specific to each bitter-blocker combination. Only the bitterness of urea was reduced by both blockers in both age groups, whereas the bitterness of PROP was not reduced by either blocker in either age group regardless of TAS2R38 genotype. Children liked the salty taste of the blocker NaG more than did adults, but both groups liked the savory taste of MSG equally. CONCLUSIONS AND RELEVANCE: Bitter blocking was less effective in children, and the efficacy of blocking was both age and compound specific. This knowledge will pave the way for evidence-based strategies to help develop better-tasting medicines and highlights the conclusion that adult panelists and genotyping alone may not always be appropriate in evaluating the taste of a drug geared for children.