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WO2020039383A1 - Procédés d'amélioration de la sensation euphorique et d'amélioration des capacités cognitives - Google Patents

Procédés d'amélioration de la sensation euphorique et d'amélioration des capacités cognitives Download PDF

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Publication number
WO2020039383A1
WO2020039383A1 PCT/IB2019/057078 IB2019057078W WO2020039383A1 WO 2020039383 A1 WO2020039383 A1 WO 2020039383A1 IB 2019057078 W IB2019057078 W IB 2019057078W WO 2020039383 A1 WO2020039383 A1 WO 2020039383A1
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Prior art keywords
alcohol
neurotransmitter
precursor
subject
wine
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PCT/IB2019/057078
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English (en)
Inventor
Daniel Hakim
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Euphoria Research And Development Ltd
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Euphoria Research And Development Ltd
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Priority to US16/799,457 priority Critical patent/US20200190449A1/en
Publication of WO2020039383A1 publication Critical patent/WO2020039383A1/fr
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    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12G—WINE; PREPARATION THEREOF; ALCOHOLIC BEVERAGES; PREPARATION OF ALCOHOLIC BEVERAGES NOT PROVIDED FOR IN SUBCLASSES C12C OR C12H
    • C12G3/00—Preparation of other alcoholic beverages
    • C12G3/04—Preparation of other alcoholic beverages by mixing, e.g. for preparation of liqueurs
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/26—Psychostimulants, e.g. nicotine, cocaine

Definitions

  • the present disclosure in some embodiments thereof, relates to methods of elevating pleasurable effects associated with alcohol consumption, and improving a cognitive ability in a subject, more specifically, but not exclusively to methods comprising the use of at least one neurotransmitter or a precursor thereof and alcohol.
  • the element which accounts for the psychotropic affect caused by alcoholic products such as alcoholic beverages is ethanol, a two-carbon chain alcohol molecule that interacts with neurotransmitter systems in the brain, and directly affects brain chemistry by altering the levels of some neurotransmitters.
  • Ethanol has dual properties both of a stimulant and a depressant since it affects both "excitatory” neurotransmitters and "inhibitory” neurotransmitters.
  • Ethanol is one of man’s most commonly used and abused substances, but the effects on mood are paradoxical as relaxation and pleasurable effects of moderate intoxication may rapidly change to dysphoria and anxiety.
  • a low-to-medium dose of alcohol has a depressant effect on the central nervous system, including the frontal and prefrontal cortical circuits, which leads to the reduced psychomotor functioning and cognitive abilities such as inhibition, attention control, and planning.
  • cognitive control seems especially sensitive to alcohol effects since loss of cognitive cotrol may lead to loss of control over drinking and unintentional excessive consumption.
  • Ethanol effects on the dopaminergic system directly affects levels of dopamine (DA) in the synapses. Increased release of this neurotransmitter is prominent in the rewarding and positive reinforcing effects.
  • the present disclosure is based on a discovery by the present inventor that the effects associated with consumption of alcoholic food products, for example, alcoholic beverages, particularly the pleasurable effects such as an euphoric perception and“high feeling”, may be enhanced and prolonged without the need to increase the amount of alcohol in the product merely by the concomitant consumption of a neurotransmitter precursor. Moreover, it has been discovered by the present inventor that consumption of both alcohol and at least one neurotransmitter precursor, and optionally, one or more psychostimulant substance such as caffeine minimized and even circumvented at least some of the non-pleasurable effects associated with alcohol consumption, particularly the undesired physical and emotional sensations of intoxication.
  • tyrosine a precursor of dopamine, which is provided, in accordance with a contemplated method, together with alcohol, for example by the provision of an alcoholic beverage such as beer, alcopop, wine or spirit.
  • (1) a method for enhancing and prolonging a euphoric sensation associated with alcohol consumption comprising providing to the subject, upon alcohol consumption, an effective amount of at least one neurotransmitter or a precursor thereof, thereby enhancing and prolonging a euphoric sensation in the subject.
  • a method for boosting or enhancing a desired emotion and/or a desired mental function in a subject comprising providing to the subject alcohol and an effective amount of at least one neurotransmitter and/or a neurotransmitter precursor, thereby boosting or enhancing the desired emotion in the subject.
  • the desired emotion is euphoric perception or feeling.
  • a method for enhancing or strengthening a desired emotion and/or a desired mental function in a subject brought upon, initiated, kicked off or triggered by alcohol consumption comprising consuming alcohol together with one or more neurotransmitters and/or one or more neurotransmitter precursors, thereby enhancing or strengthening the desired emotion and/or mental function.
  • a method for boosting or improving a cognitive ability in a subject comprising providing to the subject an effective amount of at least one neurotransmitter and/or neurotransmitter precursor, and alcohol, thereby boosting or improving the cognitive ability in the subject.
  • the cognitive ability is selected from perception, attention, memory, motor skills, language, visual and spatial processing, auditory processing, logic and reasoning, processing speed and executive functions.
  • cognitive abilities that can be improved by a disclosed method include: (i) motivation, preferably to work, learn and take part in rewarding activities; (ii) improved concentration and focus; (iii) higher self-confidence; (iv) arousal; (v) wakefulness; (vi) elevated alertness; (vii) improved creativity and creative thinking (viii) curiosity and openness to new experiences; (ix) sense of self-fulfillment, self contempt; (x) relaxation; (xi) improved capacity to switch attention efficiently between tasks; (xii) improved sociability and extroversion behavior; (xiii) mood attention span; (xiv) emotional and physical sense of well-being; (xv) stress relief; (xvi) ability to cope with negative mood; (xvii) learning ability; (xviii) pain processing; and (xix) cognitive performance particularly
  • a method for ameliorating, mitigating or reducing an adverse or negative effect associated with alcohol consumption comprising consuming alcohol together with one or more neurotransmitters or neurotransmitter precursors, thereby ameliorating, mitigating or reducing the adverse or negative effect of alcohol.
  • Adverse or negative effects associated with alcohol consumption include, for example, intoxication, sedative effects, dysphoria, anxiety, depression, pessimism, negative mood, reduced psychomotor functioning and cognitive abilities such as inhibition, attention control, and planning.
  • An aspect of the present disclosure provides the use of alcohol and at least one neurotransmitter and/or at least one neurotransmitter precursor for exerting, improving, enhancing, boosting and/or strengthening in a subject one or more of: a desired emotion, a desired mental function and a desired cognitive ability.
  • a further aspect of the disclosure provides the use of at least one neurotransmitter and/or at least one neurotransmitter precursor for enhancing or strengthening one or more of: a desired emotion, a desired mental function and a desired cognitive ability in a subject, brought upon, initiated, kicked off or triggered by alcohol consumption.
  • the neurotransmitter is selected from norepinephrine, epinephrine, serotonin, dopamine, endorphin, acetylcholine, gamma-aminobutyric acid (GABA), and the neurotransmitter precursor is selected from a norepinephrine precursor, an epinephrine precursor, a serotonin precursor such as 5-hydroxytryptophan, a dopamine precursor, an endorphin precursor, an acetylcholine precursor, a GABA precursor, and any combination thereof.
  • GABA gamma-aminobutyric acid
  • the neurotransmitter precursor is a dopamine precursor selected from L-phenylalanine, L-tyrosine, or levodopa.
  • the neurotransmitter precursor is L-tyrosine (Tyr).
  • a disclosed method or use may further comprise the provision, consumption or use of one or more psychostimulant substances, such as, but not limited to, caffeine, omega-3 fatty acids, magnesium, soluble fibers, folate, olive oil or monounsaturated fats extracted therefrom, green tea or theanine extracted therefrom, pregnenolone or a derivative thereof, uridine-5w-monophosphate, curcumin, oregano or an extract thereof, Rhodiola rosea or an extract thereof, vitamin C, vitamin B6, and any combination thereof.
  • the psychostimulant substance is caffeine.
  • any of the substances selected form neurotransmitter, neurotransmitter precursor, alcohol and psychostimulant substance may be administered or provided to a subject being“treated” by a disclosed method by any rout known and suitable for a particular purpose pursued.
  • the subject may orally consume and/or inhale at least some of these substances.
  • the neurotransmitter, neurotransmitter precursor, alcohol and/or psychostimulant substance are orally consumed as an alcoholic food product comprising edible base material in a liquid, solid or semi-solid form.
  • the alcoholic food product may comprise alcohol is in amount of from about 0.5% to about 98% by volume or by weight.
  • the alcoholic food product is an alcoholic beverage selected from: (i) a beer selected from ale, stout, porter, or lager; (ii) a wine selected from dry red wine, dry white wine, semi-dry red wine, semi-dry white wine, rose wine, dessert wine, Port wine, Champagne, sparkling wine and vermouth; (iii) a spirit selected from brandy, liquor, saki, Ouzo, arrack, rum, vodka, tequila, schnapps, whiskey, gin, cordial, Cachaca or slivovitz; (iv) cider or perry; and (v) an alcopop selected from beer cooler, wine cooler and spirit cooler.
  • the alcohol in the alcoholic beverage may be in amount of from about 1% to about 5%, from about 3% to about 8%, from about 5% to about 10%, from about 8% to about 12%, from about 10% to about 15%, from about 15% to about 25%, from about 20% to about 30%, from about 25% to about 40%, from about 30% to about 50%, from about 40% to about 60%, from about 60% to about 80%, or from about 70% to about 95% by volume.
  • the alcoholic beverage is beer or alcopop.
  • the alcoholic beverage comprises tyrosine in an amount which is in the range of from about 100 mg to about 5000 mg per 1 liter.
  • the amount of Tyr is about 350 mg/L, about 500 mg/L, about 750 mg/L, or from about 100 mg/L to about 1000 mg/L.
  • the alcoholic beverage may comprise caffeine in an amount of from about 10 mg/L to about 900 mg/L, about 35 mg/L, about 50 mg/L, about 100 mg/L or about 350 mg/L.
  • the method or use in accordance with any of the aspects disclosed herein may enhance, boost, strengthen or improve, a desired cognitive ability, desired emotion, and/or desired mental function, for a period of time which may last from about 5 minutes up to about 48 hours after consumption of alcohol.
  • Figs. 1A-1B are bar graphs showing STIM (short for“stimulant effects”) values obtained in an exemplary Biphasic Alcohol Effects Scale (BAES) test conducted with beer enriched with tyrosine and caffeine (IB) and a corresponding non-enriched beer (1A); and
  • BAES Biphasic Alcohol Effects Scale
  • Figs. 2A-2B are bar graphs showing SED (short for“sedative effects”) values obtained in an exemplary Biphasic Alcohol Effects Scale (BAES) test conducted with beer enriched with tyrosine and caffeine (2B) and a corresponding non-enriched beer (2A).
  • BAES Biphasic Alcohol Effects Scale
  • the present disclosure in some embodiments thereof, relates to means and methods of elevating pleasurable effects associated with alcohol consumption and, optionally, improving cognitive abilities in a subject, for example short-term cognitive abilities.
  • methods described herein comprise the use of at least one neurotransmitter or a precursor thereof upon alcohol consumption.
  • Alcohol is one of the favorite commonly used, yet a somehow dangerous psychoactive substance.
  • the prevailing and predominant way alcohol is consumed is by drinking alcoholic beverages, usually over a few hours.
  • People consume alcohol for several reasons such as the association alcoholic beverages have with other aspects of life such as food and friendship, but mostly due to the psychological and psychotropic affects associated with alcohol consumption.
  • Consuming alcohol often confers upon the consumer a euphoric sensation or a“high feeling”, a cheerful mood, relaxation, and a reduced self-awareness.
  • Part of the pleasure of alcohol - at least for the non-dependent consumer - is the taste and the associated rituals of consumption that may fill primitive appetitive functions.
  • the present disclosure is based on the discovery by the present inventor that some emotional and mental situations, as well as some cognitive abilities, mediated by release of certain neurotransmitters in the central nervous system (CNS) and boosted by alcohol consumption, may be strengthened, enhanced or benefit if one or more of these neurotransmitters or precursors thereof are provided to a subject when alcohol is consumed.
  • cognitive abilities such as concentration, focus, alertness, motivation, learning, creativity, curiosity, pursuing rewarding feelings of satisfaction and/or pleasure as well as feelings or emotions such as joy, euphoria and the like, which are mediated by the same neurotransmitters that are affected by, or related to, alcohol consumption, may be manipulated, for example, enhanced or improved.
  • the effects associated with alcohol consumption may be enhanced and prolonged by consuming alcohol together with at least one neurotransmitter or a precursor thereof, which is directly or indirectly associated with positive psychotropic affects, even without increasing the amount of alcohol in the product.
  • certain desired cognitive effects or qualities associated with alcohol consumption may be improved by combining the consumption of both alcohol and at least one such neurotransmitter or precursor thereof.
  • euphoric perception or feeling accompanying alcohol consumption may be enhanced and prolonged when alcohol is consumed together with a precursor of dopamine, optionally with further consumption of a psychoactive stimulant like caffeine.
  • This euphoric feeling lasts longer than that induced by consuming alcohol alone, and, furthermore, it is not accompanied by undesired physiological and psychological short-term effects associated with intoxication such as gastric irritation, numbing, stupor or daze, and mood swings.
  • the present disclosure provides a method for enhancing and prolonging in a subject a euphoric sensation associated with alcohol consumption, the method comprising providing to the subject, upon alcohol consumption, an effective amount of at least one neurotransmitter or a precursor thereof, thereby enhancing and prolonging a euphoric sensation in the subject.
  • the terms“euphoria”,“euphoric sensation”,“euphoric feeling”, and“a high feeling” are interchangeable and refer to the experience (or affect) of pleasure or excitement, and intense feelings of well-being and happiness.
  • a method for boosting or improving a cognitive ability in a subject comprising providing to the subject an effective amount of at least one neurotransmitter or a precursor thereof and alcohol, thereby boosting or improving a cognitive ability in the subject.
  • the present disclosure relates to a method for boosting or enhancing a mental process in a subject, the method comprising providing to the subject an effective amount of at least one neurotransmitter or a precursor thereof and alcohol, thereby boosting or enhancing a mental process in the subject.
  • the enhanced euphoric sensation, the improved cognitive ability and/or the enhanced mental process, in accordance with a disclosed method lasts, for example, for up to 24 or 48 hours after consumption of alcohol and at least one neurotransmitter or a precursor thereof.
  • Cognition refers herein to a conscious mental activity such as thinking, reasoning, understanding, learning, and remembering. Cognition has to do with how a person understands the world and acts in it.“Cognitive abilities” or“cognitive skills”, interchangeably used herein, are foundational brain-based skills needed to carry out any task from the simplest to the most complex. They relate not to actual knowledge but rather to the mechanisms of learning, remembering, problem-solving, and paying attention. Cognitive abilities or skills are supported by specific neuronal networks. For example, memory skills rely mainly on parts of the temporal lobes and parts of the frontal lobes (behind the forehead).
  • Non-limiting examples of cognitive abilities which may be boosted upon consumption of alcohol and at least one neurotransmitter or a precursor thereof include perception, attention, memory, motor skills, language, visual and spatial processing, logic and reasoning, auditory processing, processing speed and/or executive functions.
  • Perception is recognition and interpretation of sensory stimuli such as smell, touch, hearing, and the like.
  • “Attention”, as used herein, is the ability to sustain concentration on a particular object, action, or thought, the ability to ignore distractions and ability to manage competing demands. Attention also includes divided attention and sustained attention. Sustained attention is the ability to stay focused and on task for an extended period of time. Signs that sustained attention skills may be weak include jumping from project to project, and/or always being surrounded by unfinished projects. Divided attention is the ability to remember information while doing two things at once. Signs that divided attention skills may be weak include not being able to multitask or making frequent mistakes.
  • “Memory”, as used herein, is short-term/working memory and long-term memory.
  • Working memory is the ability to hang on to information while being in the process of using it. Signs that working memory skills may be weak include having to read the directions again in the middle of a project, experiencing difficulty following multi-step directions, forgetting what was just said in a conversation.
  • Long-term memory is the ability to hang on to, and access, stored information that was learned in the past. Signs that long-term memory skills may be weak include, for example, forgetting names, doing poorly on tests, forgetting known things.
  • “Motor skills”, as used herein, is ability to mobilize muscles and body, and ability to manipulate objects.
  • “Language”, as used herein, is skills allowing a subject to translate sounds into words and generate verbal output.
  • Visual and spatial processing is the ability to process incoming visual stimuli, to understand spatial relationship between objects, and to visualize images and scenarios. Signs that visual processing skills may be weak include, for example, struggling to understand and/or remember what has been just read, following directions, and reading maps.
  • auditory processing is the ability to analyze, blend, and segment sounds, and is a critical skill for successful reading. Signs that auditory processing skills may be weak include, for example, having difficulties learning to read, or struggling with reading fluency or comprehension. “Logic and reasoning”, as used herein, is the ability to reason, form ideas, and solve problems. Signs that logic and reasoning skills may be weak include frequently asking“What do I do next?” or say“I don’t get this,” struggling with math, feeling stuck or overwhelmed.
  • Processing speed is the ability to perform tasks quickly and accurately. Signs that processing speed is weak include the ongoing feeling that tasks are more difficult for one self than for other people, taking a long time to complete tasks for school or work, frequently being the last one in a group to finish something.
  • Executive functions is abilities that enable goal-oriented behavior, such as the ability to plan, and execute a goal.
  • Abilities that enable goal- oriented behavior include: flexibility in switching to the appropriate mental mode; theory of mind; anticipation and prediction based on pattern recognition; problem solving; decision making; working memory or the capacity to hold and manipulate information in real time; emotional self-regulation or the ability to identify and manage one’s own emotions for good performance; sequencing and prioritizing; and inhibition or the ability to withstand distraction, and internal urges.
  • mental relates to the mind and its activity, i.e., occurring or experienced in the mind, or involving the process of thinking. Specifically, mental relates to the total emotional and intellectual responses of an individual to external reality. Mental also refers to intellectual activity as contrasted with emotional activity or with overt physical activity.
  • “mental process” or“mental function”, as used herein, refers to all the things that individuals can do with their minds. These include perception, judgement memory, thinking (such as ideation, imagination, belief, reasoning and the like), volition, and emotion.
  • Emotion is any conscious experience characterized by intense mental activity and a certain degree of pleasure or displeasure.
  • Emotion herein, is the affective aspect of consciousness, and is interchangeable with the terms “state of mind” and“feeling”.
  • state of mind For example, anger or fear, which are subjectively experienced as strong feeling usually directed toward a specific object and typically accompanied by physiological and behavioral changes in the body. Emotions may sometimes be intertwined with mood, temperament, disposition, and motivation.
  • cognition is an aspect of emotion.
  • examples of emotions or states of mind include, affection, anger, angst, anguish, annoyance, anticipation, anxiety, apathy, arousal, awe, boredom, confidence, contempt, courage, curiosity, depression, desire, despair, disappointment, disgust, distrust, ecstasy, embarrassment, empathy, enthusiasm, envy, euphoria, fear, frustration, gratitude, grief, guilt, happiness, psychologist, hope, horror, hostility, humiliation, interest, ashamedy, joy, loneliness, love, lust, outrage, panic, passion, pity, pleasure, pride, rage, regret, rejection, remorse, resentment, sadness, self-confidence, shame, shock, shyness, sorrow, suffering, surprise, trust, wonder, and worry.
  • a contemplated method by providing to a subject in need thereof an effective amount of at least one neurotransmitter or a precursor thereof and alcohol, imparts, enhances, elevates boosts and/or improves in the subject one or more of: concentration ability, focus, alertness, motivation, learning ability, pain processing, mood attention span, creativity, curiosity, physical and cognitive performance particularly under stress, ability to cope with negative mood, pursuing rewarding feelings of satisfaction and/or pleasure, euphoria, joy and happy feelings, relaxation, and optimism.
  • the present disclosure relates to the use of alcohol and at least one neurotransmitter or a precursor thereof as psychoactive means for imparting or bestowing to a subject a desired emotional and/or mental effect.
  • a desired emotional and/or mental effect is selected from: euphoric feeling, elevated positive and social mood, joyfulness, satisfaction, pleasure, stress relief, relaxation, optimism, creativity, stimulation, blissfulness, sense of being rewarded.
  • the present disclosure relates to the use of alcohol and at least one neurotransmitter or a precursor thereof as psychotropic means for improving a desired cognitive ability or skill in subject.
  • the desired cognitive ability is selected from: (i) higher motivation, e.g., to work, learn and take part in rewarding activities; (ii) improved concentration and focus; (iii) higher self-confidence; (iv) arousal; (v) wakefulness; (vi) elevated alertness; (vii) improved creativity and creative thinking (viii) curiosity and openness to new experiences; (ix) sense of self-fulfillment, self-contempt; (x) relaxation; (xi) improved capacity to switch attention efficiently between tasks; (xii) improved sociability and extroversion behavior; (xiii) sense of well-being; (xv) stress relief; and (xvi) ability to cope with negative mood.
  • a method for enhancing or strengthening a desired psychoactive effect and/or psychotropic affect brought upon, initiated, kicked off or triggered by alcohol consumption comprising consuming alcohol together with one or more neurotransmitters and/or one or more neurotransmitter precursors, thereby enhancing or strengthening a desired psychoactive effect and/or psychotropic affect of alcohol consumption.
  • desired psychoactive effects and/or psychotropic affects include euphoric feeling, elevated positive and social mood, joyfulness, satisfaction, pleasure, stress relief, relaxation, optimism, creativity, stimulation, blissfulness, and sense of being rewarded.
  • the present disclosure relates to a method for ameliorating, mitigating, reducing, lowering or nulling an adverse or negative effect associated with alcohol consumption, the method comprising consuming alcohol together with one or more neurotransmitters and/or neurotransmitter precursors, thereby ameliorating or reducing an adverse or negative effect of alcohol consumption.
  • Negative effects of alcohol consumption which can be mitigated, lowered, reduced and even nulled are, for example, intoxication, sedative effects, dysphoria, anxiety, depression, despair, pessimism, negative mood, reduced psychomotor functioning and impaired or adversely affected cognitive abilities such as inhibition, attention control, and planning.
  • administering means providing, supplying, dispensing or giving.“Administer to a subject” in a context herein means providing a subject with, supplying, giving or dispensing to the subject.
  • Administration in a broad meaning, as sometimes applies in embodiments described herein, is further referred to as introduction of an active compound or of a formulation comprising it to a subject by a chosen route, for example introduction of a neurotransmitter and/or a neurotransmitter precursor, or a pharmaceutical composition comprising it.
  • Administration of the active compound or pharmaceutical composition can be by any route selected from local or systemic administration as well known to one of skill in the art, and as appropriate for the particular condition.
  • provision of an effective amount of at least one neurotransmitter or a precursor thereof and alcohol is by way of consuming, for example, eating, drinking, smoking or inhaling.
  • oral administration is contemplated.
  • a subject“treated” by a disclosed method is orally provided with alcohol and at least one neurotransmitter and/or at least one neurotransmitter precursor.
  • An effective amount is a quantity of a neurotransmitter and/or a precursor thereof or a formulation or food product comprising same, sufficient to achieve a desired effect in a subject being provided or treated with a method of the present disclosure.
  • a disclosed method is applied by providing to a subject an alcoholic food product, supplemented or enriched with at least one neurotransmitter and/or at least one neurotransmitter precursor, for example, an enriched alcoholic beverage.
  • “food product”, as used herein, refers to an edible composition of a base material defined herein as any substance composed of carbohydrates, fats, proteins and/or water, which can be used or prepared for use as food by humans or non-humans.
  • edible base materials are liquids such as water, juice, e.g., fruit or vegetable juice, and milk.
  • Alcohol is an edible base material as defined herein, and alcohol (ethanol) in the amount of 0-99% by weight or by volume.
  • an alcoholic food product may contain from about 1 % to about 20%, from about 1% to about 5%, from about 3% to about 8%, from about 5% to about 10%, from about 8% to about 12%, from about 10% to about 15%, from about 15% to about 25%, from about 20% to about 30%, from about 25% to about 40%, from about 30% to about 50%, from about 40% to about 60%, from about 50% to about 65%, from about 60% to about 80%, or from about 70% to about 95% alcohol by weight or by volume.
  • the alcoholic food product may be eaten or drunk by humans for nutrition or pleasure.
  • Non- limiting examples of alcoholic food products include beverages such as beer, wine, spirit and the like, and foods prepared therewith such as meat, fish, chicken, fruits, breads, soups, stews, sauces, fondues, backed desserts such as cakes, pastries such as cookies and pies, and no-bake desserts such as creams, ice-cream, puddings and mousses, extract flavoring such as pure vanilla extract and pure almond extract, filled candies such as filled chocolate, snacks and food flamed with alcohol.
  • beverages such as beer, wine, spirit and the like
  • foods prepared therewith such as meat, fish, chicken, fruits, breads, soups, stews, sauces, fondues
  • backed desserts such as cakes, pastries such as cookies and pies
  • no-bake desserts such as creams, ice-cream, puddings and mousses
  • extract flavoring such as pure vanilla extract and pure almond extract
  • filled candies such as filled chocolate, snacks and food flamed with alcohol.
  • an alcoholic food product is an alcoholic beverage selected from beer, wine, spirit and alcopop.
  • the terms“enriched alcoholic food product” and“enriched alcoholic beverage” as used herein refer to an alcoholic food product or alcoholic beverage, respectively, as defined herein, supplemented with at least one neurotransmitter and/or at least one neurotransmitter precursor.
  • a neurotransmitter or a neurotransmitter precursor may be added to the alcoholic food product at any stage of preparation thereof, for example mixed or combined with the ingredients of the base material at the beginning, middle and/or end of a food production process, or added to an already made alcoholic product.
  • “Enrichment” of an alcoholic food product or an alcoholic beverage further means herein enriching the product with desired qualities imparted or bestowed to it by enriching it with at least one neurotransmitter and/or a precursor thereof.
  • neurotransmitter precursor as used herein is interchangeable with the term“at least one neurotransmitter precursor” and means at least one precursor of at least one neurotransmitter.
  • Ethanol being a small molecule, can interact with many neurotransmitter systems in the brain. It directly affects brain chemistry by altering levels of neurotransmitters. Alcohol affects both "excitatory” neurotransmitters and “inhibitory” neurotransmitters and, hence, has the properties of both a stimulant and a depressant.
  • the action of alcohol is biphasic, when blood alcohol concentration (BAC) levels are rising, the stimulant properties of alcohol are more pronounced; when BAC levels are falling, the depressant effects of alcohol are more pronounced.
  • Neurotransmitters play a key role in the function of the central nervous system, being chemical“messengers” that transmit signals throughout the body, signals such as those controlling thinking processes, behavior and emotion. Neurotransmitters are excreted to, and travel through, the synapses, those extremely small gaps between the axon terminal of neurons that release neurotransmitters, and the membrane of adjacent axons, dendrites, muscle or gland cells having the appropriate receptors for binding the neurotransmitters. Neurotransmitters can either prompt or suppress the further signaling of nearby neurons.
  • the main neurotransmitters include norepinephrine, epinephrine, serotonin, dopamine, endorphin, acetylcholine, gamma-aminobutyric acid (GABA), glycine, glutamic acid, aspartic acid, and taurine, the first six of which are neurotransmitters synthesized from amino acids, and the last three are amino acids per se.
  • GABA gamma-aminobutyric acid
  • taurine the first six of which are neurotransmitters synthesized from amino acids, and the last three are amino acids per se.
  • neurotransmitter precursor refers to a substance that can be converted into a neurotransmitter in the body, particularly in the brain, usually through enzymatic reactions such as metabolic processes.
  • tyrosine is a precursor of dopamine
  • 5-hydroxytryptophan is a precursor of serotonin.
  • Neurotransmitters which may be directly or indirectly affected by alcohol include, for example, GABA, endorphins, glutamate, dopamine, norepinephrine and adrenaline (epinephrine).
  • GABA Gamma-aminobutyric acid
  • Drugs like Xanax and Valium increase GABA production in the brain, resulting in sedation.
  • Alcohol enhances GABA levels and affects the GABA system in a manner similar to valium leading to relaxation and drowsiness. Hence, alcohol's effect on the GABA system may culminate in depressant effects.
  • Glutamate is an excitatory neurotransmitter which normally increases brain activity and energy levels. Alcohol suppresses glutamate levels probably by inhibiting the N-methyl-d-aspartate (NMDA) glutamate receptor, resulting in a slowdown along the brain's highways. It is alcohol's effects on the glutamate system which lead to staggering, slurred speech, and memory blackouts.
  • NMDA N-methyl-d-aspartate
  • Endorphins are produced in response to certain stimuli, especially stress, fear or pain. They originate in various parts of the body such as the pituitary gland, spinal cord and throughout other parts of the brain and nervous system and interact mainly with receptors in cells found in regions of the brain responsible for blocking pain and controlling emotion. Alcohol affects the endorphin system in a manner similar to opiates, acting as a painkiller and giving an endorphin "high".
  • Adrenaline epinephrine
  • norepinephrine norepinephrine
  • cortisol norepinephrine
  • Alcohol causes the adrenal glands to release adrenaline and norepinephrine which ultimately enter the brain and promote alertness and“fight response”. This is one reason why alcohol acts as stimulant.
  • Dopamine (DA), 3,4-dihydroxyphenethylamine, is an organic chemical of the catecholamine and phenethylamine families having the chemical structure:
  • This amine is synthesized by removing a carboxyl group from its precursor levodopa (L-dopa; dihydroxyphenylalanine), which is synthesized in the brain and kidneys during the metabolism of the amino acid tyrosine. It is a neurotransmitter in itself, and a precursor of the hormone neurotransmitters epinephrine and norepinephrine.
  • Two main brain areas produce dopamine that relays signals that travel throughout the brain: the substantia nigra, a tiny strip of tissue on either side of the base of the human brain (situated in a region known as the midbrain), and the close by ventral tegmental area (VTA).
  • Dopamine from the substantia nigra regulates movements, speech and emotional responses. When the brain cells that produce dopamine in this area start to die off, a person can have trouble initiating movement.
  • the reward center (also known as the“reward pathway”) is a combination of three brain areas: the nucleus accumbens (NAc), the VTA, and a part of the prefrontal cortex.
  • the ventral tegmental area usually sends dopamine into the brain when humans (and animals) expect or receive a reward, and helps control the brain's reward and pleasure centers.
  • the reward center is affected by virtually all pleasurable activity, including everything from hanging out with friends, going on vacation, ingesting drugs (e.g., cocaine), listening to music, eating and drinking, having sexual activity, and consuming alcohol. All things which give us pleasure, cause a release of dopamine in the reward pathway as well as trigger a number of other events in the brain including endorphin release and activation of the orbitofrontal region of the prefrontal cortex.
  • Dopamine is known as the “motivation molecule” or the “reinforcement molecule” as it is responsible for reward-seeking behavior and helps provide the drive, focus and concentration needed to get things done.
  • Dopamine release tells the brain that whatever it just experienced is worth getting more of, and that helps animals and humans change their behaviors in ways that will help them attain more of the rewarding item or experience.
  • This brain reward system is associated with“feeling good” and promotes survival of the species by rewarding behaviors necessary for continued survival.
  • Dopamine is also involved in many other functions of the brain including motor activity, learning, pain processing, mood, attention span and regulation of sleep. It regulates stress relief. Lowering dopamine levels can make animals and humans lose pleasure in activities like eating and drinking.
  • Alcohol consumption triggers a boost of dopamine release. Alcohol does not lead to an increase of dopamine throughout the brain; it only causes an increase in dopamine in the reward center, leading to the relaxing and carefree experience of the alcohol "buzz". Consumption of even small amounts of alcohol increases the amount of dopamine in the NAc in a dose-response manner. Alcohol increases DA via the promotion of synaptic terminal DA release rather than via the inhibition of DA transporters. Alcohol can also indirectly increase DA levels by affecting the GABA system and the endorphin system. Neurons from the GABA system extend into the reward pathway and when alcohol affects the GABA system these neurons release dopamine into the reward pathway. Likewise, neurons extend from the endorphin system into the reward pathway and these also release dopamine into the reward pathway when alcohol directly stimulates the endorphin system.
  • a boost in the activation of dopaminergic pathways eventually causes a depletion of the dopamine reserves within the brain cells, leaving the brain in an imbalanced state.
  • DA itself is impenetrable to the blood-brain barrier, it must be synthesized in situ from its precursors. Thus, over time, with more drinking, DA reservoirs are exhausted, and the dopamine effect diminishes until it's almost nonexistent.
  • the present inventor envisaged that provision of food products comprising alcohol and a precursor of DA, for example, enriched alcoholic food products such as enriched alcoholic beverages, which may, optionally, further contain a psychostimulant substance such as caffeine, will promote, based on their strong affiliations to the metabolism of DA within the brain, synthesis of DA in the central nervous system and establish a long-lasting steady state of readily available DA. It has been postulated that this sustained supply of DA building blocks from the very first moment of alcohol intake, may increase the positive and enjoyable effects of alcohol consumption, while neutralizing the following negative effects associated with DA depletion.
  • a precursor of DA for example, enriched alcoholic food products such as enriched alcoholic beverages, which may, optionally, further contain a psychostimulant substance such as caffeine
  • Enhancement of the positive effects of alcohol may help reduce the risk of alcohol abuse.
  • Motives of alcohol consumption are classically “enhancing motives” (drinking to enhance positive and social mood) and “coping motives” (drinking to cope with negative mood).
  • enhancing drinkers enjoy the positive effects of alcohol consumption, coping drinkers rely on its sedative effects, and are strongly exposed to risks of alcohol abuse and alcoholism.
  • a contemplated method described herein may be useful in reducing risks of alcohol abuse amongst coping drinkers.
  • a contemplated method is designed to promote at least the levels of dopamine, endorphin, norepinephrine and/or epinephrine in the brain.
  • alcoholic products enriched with one or more of these neurotransmitters and/or their precursors are employed.
  • alcoholic products containing L- phenylalanine (Phe), L- tyrosine (Tyr) and/or levodopa (L-dopa), which are the precursors of dopamine and other catecholamines such as norepinephrine and epinephrine, may be used, in accordance with a disclosed method, for elevating production of DA, endorphin, norepinephrine and/or epinephrine in a subject upon alcohol consumption.
  • dopamine precursor and “dopamine immediate metabolic precursor” as used herein are interchangeable and refer to a substance that can be converted into dopamine in the body through a series of one or more metabolic reactions.
  • the primary and minor metabolic pathways for obtaining DA from its precursors are:
  • L-dopa The direct or immediate metabolic precursor of dopamine, L-dopa, can be synthesized indirectly from the essential amino acid Phe or directly from the non- essential amino acid Tyr. Additionally, or alternatively it can be supplemented form plants (e.g. legumes) and animals. Most of the levodopa is immediately broken down (e.g., in the intestine) before it enters the brain, primarily by decarboxylase enzymes and catecholamine-O-methyltransferase (COMT).
  • CCT catecholamine-O-methyltransferase
  • L-Phenylalanine is converted into Tyr by the enzyme phenylalanine hydroxylase, with molecular oxygen (O 2 ) and tetrahydrobiopterin (THB) as cofactors.
  • L-Tyrosine is converted into L-dopa by the enzyme tyrosine hydroxylase, with tetrahydrobiopterin, O 2 , and iron (Fe 2+ ) as cofactors.
  • L-dopa is converted into dopamine by the enzyme aromatic L-amino acid decarboxylase (also known as dopa decarboxylase), with pyridoxal phosphate (the active form of vitamin B6) as the cofactor.
  • Dopamine is converted into norepinephrine by the enzyme dopamine b- hydroxylase, with O 2 and L-ascorbic acid (vitamin C) as cofactors.
  • Norepinephrine is converted into epinephrine by the enzyme phenylethanolamine N-methyltransf erase with S-adenosyl-L-methionine (SAMe) as the cofactor.
  • SAMe S-adenosyl-L-methionine
  • alcoholic and a DA precursor such as Tyr are provided, e.g., in the context of an enriched alcoholic food product, e.g. an alcoholic beverage
  • the alcohol in the product causes an immediate release of dopamine.
  • Tyr contained in the product reinforces production of the neurotransmitter in the brain, thereby maintaining or even amplifying its level for a prolonged period of time.
  • This prolonged and sustained level of DA in the brain which last long after the alcohol level in the blood has gown down to zero, affords not only a prolonged euphoric feeling but, moreover, quenches or circumvent the unpleasant psychological and physiological sensations associated with alcohol withdrawal such as headache, nausea and depression.
  • a disclosed method may be referred to herein as a“psychoactive method” practiced in order to boost, initiate, exert, promote, improve or enhance positive psychoactive effects in a subject.
  • positive psychoactive effects include, for example, blissful, joyful and euphoric sensation. Often, herein, a positive psychoactive effect is a desired effect.
  • Positive psychoactive effects exerted by a disclosed method may sustain long after consumption of alcohol and a DA precursor such as tyrosine, and it may not be accompanied by drunkenness or intoxication.
  • the euphoric feeling lasts from about 5 minutes up to 24 hours post consumption, with almost no accompanying feeling of intoxication.
  • a euphoric state of mind may last about 5-10 min, about 10-15 min, about 10-20 min, about 20-30 min, about 30-40 min, about 40-50 min, about 0-1 hours, about 1-3 hours, about 1-4 hours, about 2-5 hours, about 3-5 hours, about 4-6 hours, about 5-8 hours, about 5-9 hours, about 6-10 hours, about 7-10 hours, about 8-11 hours, about 9-10 hours, about 9-11 hours, about 9-15 hours, about 10-12 hours, about 12-15 hours, about 15-18 hours, about 15-20 hours, about 18-22, about 20-24 hours, or even longer, after blood alcohol level has already dropped to zero.
  • One of the unique and unexpected properties of a disclosed method is that it does not dim the consumer’s sense of alertness as often happens upon alcohol consumption, but to contrary: combined alcohol and a DA precursor consumption, e.g., by consuming alcoholic food product enriched with tyrosine, keeps the subject well and sharply focused, fully conscious, in-control and with the ability to remain concentrated for extended periods, contrary to the psychotropic affects imparted by regular alcoholic products which do not contain Tyr.
  • a disclosed method affords to the alcohol consumer a better, higher and prolonged focusing and concentration abilities in spite alcohol consumption.
  • a disclosed method may further be referred to herein as a“psychotropic method” practiced in order to boost, initiate, exert, promote, improve or enhance positive psychotropic affects in a subject.
  • the term“psychotropic affect”, as used herein, means the ability to influences the mind or cognitive abilities of a person, and/or to affect mental processes (e.g., emotions, perception) and mental activity (e.g., behavior).
  • the term“positive psychotropic affect” herein means affecting the mind, mental and/or the cognitive abilities is a positive manner.
  • a positive manner may be a desired manner.
  • Positive psychotropic affects exerted by a disclosed method include at least the following: (i) higher motivation, e.g., to work, learn and take part in rewarded activities; (ii) improved concentration and focus; (iii) higher self-confidence; (iv) arousal; (v) wakefulness; (vi) elevated alertness; (vii) improved creativity and creative thinking; (viii) curiosity and openness to new experiences; (ix) sense of self-fulfillment, self contempt; (x) relaxation; (xi) improved capacity to switch attention efficiently between tasks; (xii) improved sociability and extroversion behavior; (xiii) better cognitive and/or mental function; and (xiv) emotional and physical sense of well-being.
  • the positive psychotropic affects provided by a disclosed method may sustain long after consumption of alcohol and a DA precursor such as tyrosine, lasting for hours and even days.
  • a positive psychotropic affect for example, higher motivation, or improved ability, e.g., to concentrate and maintain focused, alert, awaken, self-confident, and/or improved sociability lasts from 10 minutes to about 72 hours after consuming, for example, an alcoholic food product enriched with tyrosine.
  • a person provided with, for example, an alcoholic beverage such as beer or wine enriched with tyrosine may experience higher motivation to conduct rewarding activities, improved sociability, better cognitive and/or mental or emotional function, and/or physical sense of well-being, lasting from about 5 min to about 10 min, from about 8 min to about 15 min, from about 10 min to about 20 min, from about 25 min to about 40 min, from about 0.5 hour to about 2 hours, from about 1.5 hours to about 4 hours, from about 2 hours to about 5 hours, from about 3 hours to about 6 hours, from about 4 hours to about 7 hours, from about 4 hours to about 9 hours, from about 5 hours to about 8 hours, from about 6 hours to about 9 hours, from about 6 hours to about 10 hours, from about 7 hours to about 12 hours, from about 9 hours to about 15 hours, from about 8 hours to about 16 hours, from about 10 hours to about 15 hours, from about 15 hours to about 20 hours, from about 18 hours to about 22 hours, from about 20 hours to about 25 hours, from about 25 hours to about 35 hours,
  • a person consuming e.g., an enriched alcoholic beverage such as beer, wine or spirit may experience higher motivation, focus, better or improved creative thinking, concentration, sharper memory, particularly working memory, wakefulness, self-confident and/or joyful self-contentment that lasts from about 0.25 day to about 0.5 day, from about 0.5 day to about 0.75 day, from about 0.5 day to about 1.0 day, from about 0.5 day to about 1.25 days, from about 0.75 day to about 1.0 day, from about 1.0 day to about 1.5 days, from about 1.5 days to about 2.0 days, from about 1.5 days to about 2.5 days, from about 2.0 days to about 2.5 days, or from about 2.5 days to about 3.0 days, and even longer, after consuming the alcoholic beverage.
  • a disclosed method comprises administration, as defined herein, of alcohol dopamine and/or one or more dopamine precursors.
  • a disclosed method comprises administration of alcohol and at least one dopamine precursor.
  • a contemplated method comprises administration of an enriched alcoholic beverage, as defined herein, comprising at least one DA precursor selected from Phe, Tyr or L-dopa.
  • the DA precursor is Tyr.
  • the amounts of a neurotransmitter or of a neurotransmitter precursor used in a disclosed method is determined depending on some variables, for example, the amount of alcohol provided, the amount and type of other supplements contained, for example, in a food product used in the method.
  • Such supplements include supplements that may cross react with a given neurotransmitter (or a precursor thereof), and/or supplements that may further affect the levels of dopamine and/or other neurotransmitter such as norepinephrine, endorphin, acetylcholine, GABA, glycine, glutamic acid, aspartic acid, and/or taurine.
  • the amount of Tyr may be in the range of 10 mg to 5000 mg per 1 liter of beverage, for example, from about 10 mg to about 30 mg, from about 20 mg to about 50 mg, from about 30 mg to about 60 mg, from about 50 mg to about 70 mg, from about 60 mg to about 100 mg, from about 100 mg to about 150 mg, from about 150 mg to about 200 mg, from about 100 mg to about 250 mg, from about 200 mg to about 400 mg, from about 200 mg to about 300 mg, from about 200 mg to about 500 mg, from about 300 mg to about 400 mg, from about 300 mg to about 700 mg, from about 400 mg to about 800 mg, from about 500 mg to about 900 mg, from about 500 mg to about 1000 mg, from about 800 mg to about 1000 mg, from about 900 mg to about 1100 mg, from about 1000 mg to about 1200 mg, from about 1000 mg to about 1500 mg, from about 1000 mg to about 1600 mg, or from about 1500 mg to about 2000 mg
  • the amount of tyrosine is about 350 mg/L, about 500 mg/L, about 750 mg/L or from about 100 mg/L to about 1000 mg/L.
  • a contemplated method may comprise the provision to a subject of alcohol, at least one neurotransmitter and/or a precursor thereof, and at least one psychostimulant substance.
  • neurotransmitter supplement and“psychostimulant substance”, herein used interchangeably, refer to an edible substance that has a direct or indirect effect in increasing the levels of one or more neurotransmitters in the body, particularly in the brain, or in maintaining elevated neurotransmitter levels brought about, for example, by in situ conversion of a neurotransmitter precursor into a neurotransmitter, and/or by consuming alcohol.
  • a psychostimulant substance may be directly or indirectly involved in neurotransmitter synthesis and/or neurotransmitter stability, for example, upregulate a neurotransmitter, e.g., by upregulating enzymes that synthesize the neurotransmitter or protect the neurotransmitter from metabolic degradation.
  • a psychostimulant substance may, additionally or alternatively, be directly or indirectly involved in inhibition of neurotransmitter reuptake and/or neurotransmitter degradation, for example, by inhibiting or down regulating a neurotransmitter metabolic enzyme.
  • a psychostimulant substance increases a metabolism rate in the body, thereby increasing metabolic conversion of a neurotransmitter precursor into a neurotransmitter.
  • a psychostimulant substance inhibits or blocks metabolic enzymes that degrade a neurotransmitter precursor in the blood stream or in the digestive system.
  • Non-limiting examples of psychostimulant substances include caffeine, omega- 3, fatty acids such as docosahexaenoic acid (DHA), magnesium, soluble fibers, folate, olive oil or monounsaturated fats extracted therefrom, green tea or theanine extracted therefrom, pregnenolone and any derivative thereof, uridine, iron, spices such as turmeric or curcumin extracted therefrom, Rhodiola rosea or an extract thereof, oregano or an extract thereof, co-factors, vitamins such as vitamin C and vitamin B6, minerals and the like.
  • DHA docosahexaenoic acid
  • Caffeine is the most widely consumed psychostimulant substance.
  • Caffeine has a wide variety of effects on the dopaminergic system, and is known to highly effects the metabolism within the central nervous system via the blockade of adenosine receptors, which modulate the neurotransmission of glutamate, serotonin, acetylcholine and dopamine. Caffeine is known to exert a wide variety of effects on the dopaminergic system, crucial for the expression of caffeine's stimulating properties (see, for example, Voiculescu et al., 2014, J. Med. Life, 4: 30-38; Fisone et al., 2004, Cell. Mol. Life Sci., 61(7-8): 857-872).
  • caffeine promotes tyrosine hydroxylase activation via cellular Ca 2+ entry stimulation mechanism, and it has been shown that chronic caffeine intake increases tyrosine hydroxylase mRNA expression.
  • tyrosine hydroxylase is the rate-limiting enzyme in the biosynthesis of DA and other catecholamines, caffeine may accelerate DA synthesis through upregulation of this enzyme.
  • Caffeine may provide an energy boost just like sugar and alcohol, and indirectly promotes DA level elevation, but only temporarily.
  • a DA precursor such as tyrosine promotes enhanced and continued conversion of immediate metabolic DA precursors to DA, thus supporting stable and elevated levels of DA in the brain for a prolonged time, hence a prolonged duration of desired psychoactive effect such as euphoric and bliss feelings, high motivation and energy, that would last long after consumption of alcohol ceased.
  • the amount of caffeine that may be provided to a subject in accordance with a contemplated method, for example, in an enriched alcoholic beverage or a DA precursor-containing alcoholic liquid formulation, may range from about 0 mg/liter to about 2 gr per 1 liter.
  • from about 5 mg/L to about 10 mg/L from about 10 mg/L to about 20 mg/L, from about 10 mg/L to about 50 mg/L, from about 50 mg/L to about 80 mg/L, from about 60 mg/L to about 100 mg/L, from about 200 mg/L to about 300 mg/L g, from about 200 mg/L to about 400 mg/L, from about 300 mg/L to about 500 mg/L, from about 500 mg/L to about 800 mg/L, from about 600 mg/L to 900 mg/L, from about 700 mg/L to 750 mg/L, from about 800 mg/L to about 1000 mg/L, from about 800 mg/L to about 1200 mg/L, from about 900 mg/L to about 1200 mg/L, from about 1100 mg/L to about 1400 mg/L, from about 1200 mg/L to about 1500 mg/L, from about 1500 mg/L to about 1700 mg/L, from about 1500 mg/L to about 2000 mg/L, or from about 1700 mg/L to
  • enriched alcoholic beverages such as enriched beers or alcopops are used in a contemplated method, to provide the exact combination of alcohol, tyrosine and caffeine that affords an optimal rate of brain dopamine level increase, as well as optimal, stable DA level that provide to the consumer intensified, long lasting pleasure and a pleasant drinking experience, while circumventing the“down” feeling often associated with alcohol consumption.
  • pregnenolone and/or its sulfate derivative are the psychostimulants substances used in a contemplated method.
  • Pregnenolone is the main steroid produced from cholesterol in the brain, gonads and adrenal glands.
  • Pregnenolone and pregnenolone sulfate are excitatory neurosteroids that stimulate the brain and can increase DA, they have anti-stress and mood-elevating effect, they enhance learning and memory and increase the amount of deep sleep, improve energy, vision, clarity of thinking, wellbeing, and often sexual enjoyment or libido.
  • the amount of pregnenolone and/or derivatives thereof, particularly pregnenolone sulfate, that may be provided to a subject in accordance with an exemplary embodiment of a disclosed method is in the range of from about 0 mg to 3.0 mg per liter, for example, 0.1-0.5 mg/L, or about 1 mg/L of, e.g., an enriched alcoholic beverage or an alcoholic liquid formulation containing a DA precursor such as Tyr.
  • curcumin is the psychostimulant substance used in a contemplated method.
  • Curcumin is known to be the most active phytochemical in yellow dietary spice turmeric. Curcumin has been proven to have anti-oxidant, anti inflammatory, anti-microbial, hypoglycemic, anti-rheumatic, wound healing and anti cancer activities. Curcumin further possesses antidepressant properties by way of interacting with dopamine receptors and increasing brain dopamine levels. For example, curcumin increases DA concentration in the brain by inhibiting monoamine oxidase (MAO)-mediated DA break down. Curcumin may be taken daily in large amounts, even up to 8 gr/day.
  • MAO monoamine oxidase
  • the amount of curcumin that may be provided to a subject in accordance with exemplary embodiments of a disclosed method may be in the range of from about 0.1 mg/ml to 2.0 g/ml, for example about 0.2-0.5 g/ml of, e.g., an enriched alcoholic beverage, or an alcoholic liquid formulation containing a DA precursor such as Tyr.
  • L-theanine is the psychostimulant substance used in a contemplated method.
  • L-theanine is an amino acid uniquely found in green tea and can create an alert state of relaxation without drowsiness.
  • L-theanine is known to cross the blood-brain barrier and increase dopamine levels in the brain. As such, it may have anti depressant and anti-anxiety effects, it may reduce mental and physical stress, and lead to improvements in learning and memory. Even just a single, small dose of L-theanine (100 mg) significantly improves the ability to pay attention and maintain focus.
  • the amounts L-theanine that may be provided to a subject in accordance with exemplary embodiments of a disclosed method is in the range of from about 0 mg to about 2000 mg per 1 liter of beverage, for example, from about 10 mg/L to about 30 mg/L, 20 mg/L to about 50 mg/L, 50 mg/L to about 100 mg/L, 80 mg/L to about 150 mg/L, 100 mg/L to about 150 mg/L, 150 mg/L to about 200 mg/L, 150 mg/L to about 400 mg/L, 300 mg/L to about 600 mg/L, 550 mg/L to about 750 mg/L, 500 mg/L to about 1000 mg/L, 700 mg/L to about 1200 mg/L, 1100 mg/L to about 1250 mg/L, 1200 mg/L to about 1500 mg/L, 1550 mg/L to about 1850 mg/L, or 1700 mg/L to about 1000 mg/L, of.
  • an enrich alcoholic beverage such as beer or alcopop containing Tyr, may further contain 600 mg/L, 1200 mg/L or 1800 mg/L of L-theanine.
  • Rhodiola rosea is the psychostimulant substance used in a contemplated method.
  • the golden root is a popular plant in traditional medicine in Eastern Europe and Asia, with a reputation for improving depression, enhancing work performance, eliminating fatigue and treating symptoms resulting from intense physical and psychological stress.
  • Rhodiola exerts its benefits via multiple effects on the central nervous system, including enhancing the stability of dopamine and supporting its reuptake. This leads to notable decreases in depression, anxiety, and fatigue, as well as an increased ability to handle stress.
  • Rhodiola extract derived from Rhodiola rosea root and standardized to contain 3% total rosavins and a minimum 1% salidrosides may be provided to a subject in accordance with exemplary embodiments of a disclosed method in amounts which range from about 300 mg to about 2000 mg per liter, for example, 510 mg/L, 800 mg/L or 1100 mg/L of, e.g., an enriched alcoholic beverage, or an alcoholic liquid alcoholic formulation containing a DA precursor such as Tyr.
  • Further psychostimulant supplements useful in a contemplated method include: certain minerals and B-vitamins, especially zinc, vitamin B6, and folate, which are necessary for dopamine synthesis and neurotransmission; antioxidants such as vitamins C and E that may inhibit dopamine oxidation and may assist in maintaining desired levels of DA; magnesium which help in maintaining proper basic levels of dopamine; nutritional or brewer’s yeast which is rich in uridine - 5w-monophosphate that may increase DA levels in the brain; oregano, which increases DA levels by decreasing DA break down and reuptake; and resistant starch, a type of soluble fiber that increases butyrate, which may increase dopamine levels.
  • certain minerals and B-vitamins especially zinc, vitamin B6, and folate, which are necessary for dopamine synthesis and neurotransmission
  • antioxidants such as vitamins C and E that may inhibit dopamine oxidation and may assist in maintaining desired levels of DA
  • magnesium which help in maintaining proper basic levels of dopamine
  • an enriched alcoholic food product used in accordance with a described method comprises one or more psychostimulant substances that directly or indirectly affect DA brain levels, selected from caffeine, theanine, curcumin, uridine, pregnenolone, and/or oregano.
  • the amounts of psychostimulant substances provided to a subject in accordance with a contemplated method vary and depend on the psychostimulant substance itself as well an on the other ingredients provided to the subject, particularly to the amount of alcohol, the amount and type of DA precursor(s), the presence of other neurotransmitter or precursors thereof, and/or the amount and type of other supplements that may cross react or enhance the effect of a particular psychostimulant substance. Excess dopamine is dangerous and needs to be avoided, and a skilled person would appreciate that the amount and number of psychostimulant substances provided to the subject are to be adjusted so as to avoid secretion, production and/or otherwise promotion of excess DA.
  • the amount of one or more psychostimulant substances, e.g., in a food product, for example, an enrich alcoholic product, provided to a subjected in accordance with embodiments described herein, may be in a range of from 0 to about 10% by weight or by volume.
  • from about 0.01% to about 0.05% from about 0.01% to about 1.00%, from about 0.05% to about 1.00%, from about 0.1% to about 0.3%, from about 0.2% to about 0.5%, from about 0.5% to about 1.0%, from about 1.0% to about 3.0%, from about 1.0% to about 5.0%, from about 5.0% to about 10.0%, from about 8% to about 10.0%, by weight or by volume of total, e.g., an enriched alcoholic food product, and any sub-ranges and/or individual values therebetween.
  • a disclosed method comprises the provision of an enriched alcoholic beverage comprising a base liquid, alcohol, one or more neurotransmitter and/or one or more neurotransmitter precursors as defined herein.
  • the enriched alcoholic beverage optionally further comprises one or more psychostimulant substances as defined herein.
  • the enriched alcoholic beverage comprises a base liquid, alcohol, dopamine and/or at least one dopamine precursor and, optionally, one or more psychostimulant substances as described herein, for example, caffeine.
  • the term“base liquid” describes a liquid form of a substance or a mixture of substances which either alone or when mixed with other additives can form a beverage.
  • the base liquid is a base beverage.
  • the base beverage is an alcohol-free base beverage comprising less than 0.01% or less than 0.005%, or less than 0.001%, of alcohol by volumes, or even null, for example, natural or artificially flavored fruit juice (such as grape, mango, elder, apple, orange juice, and the like), vegetable juice, fruit syrup, concentrate or nectar from fruits, plant materials such as agave, jello, carbonated beverages such as cola, optionally with addition of roasted malt beer, caffeinated beverages, specialized flavor formulations emulating the taste of existing wines and spirits, non-alcoholic cocktails ("mocktails"), malt beer, dealcoholized ciders, dealcoholized wines, deal coholi ed beers, dealcoholized spirits, tonic water and water.
  • the base alcoholic liquid is an alcoholic beverage.
  • alcoholic beverage encompasses any beverage having an alcohol (ethanol) content of at least 2% by volume, whether distilled, fortified, brewed, or produced by fermentation, and includes, but is not limited to, wine, beer, fermented liquids derived in whole or in part from fruit juices, such as cider and perry (pear cider), spirits, flavored alcoholic beverages collectively termed herein and in the art as“alcopops”, and the like.
  • the enriched alcoholic beverages used in accordance with a contemplated method provide the drinker with the palatability effect of common alcoholic beverages, and further provide the drinker with a sustained euphoric feeling, pleasure and overall sensation of wellbeing and vitality which far exceed the effects provided by corresponding alcoholic beverages which do not contain the enriching supplements and additives described herein.
  • the enriched alcoholic beverages provide a substantial relief of the adverse effects associated with alcohol consumption, particularly the“down” feeling or depression associated with intoxication and sobering up. A boost of energy and motivation, while affording a substantial reduction in drunkenness symptoms.
  • the enriched alcoholic beverage used in accordance with a disclosed method is selected from enriched beer, enriched wine, enriched cider, enriched spirit and/or enriched alcopop beverage.
  • these enriched alcoholic beverages comprise one or more neurotransmitter precursors.
  • the neurotransmitter precursor is a precursor of dopamine, for example, L-tyrosine.
  • beer as used herein and in the art means an alcoholic beverage obtained by malting and fermenting one or more of the cereal grains, and includes ale, stout, porter and lager.
  • Typical alcoholic beer beverages include an alcoholic content of 3-8%.
  • Some high-alcohol content beers comprise 8-12% alcohol, for example 10% alcohol by weight of by volume.
  • the beer is a“reduced alcohol beer”, namely a beer as defined herein comprising up to 3.5% alcohol, for example, up to 3.0%, up to 2.2%, up to 2.0%, up to 1.5%, up to 1.0%, up to 0.5%, up to 0.3%, up to 0.1%, up to 0.05%, up to 0.01% alcohol by volume, or the beer is devoid of alcohol.
  • the amount of dopamine precursor is within a range of from about 0.1 mg/ml to 5.0 mg/ml, for example, from about 0.10 mg/ml to about 0.20 mg/ml, from about 0.10 mg/ml to about 0.30 mg/ml, from about 0.25 mg/ml to about 0.45 mg/ml, from about 0.30 mg/ml to about 0.50 mg/ml, from about 0.30 mg/ml to about 0.60 mg/ml, from about 0.45 mg/ml to about 0.65 mg/ml, from about 0.50 mg/ml to about 0.70 mg/ml, from about 0.50 mg/ml to about 0.80 mg/ml, from about 0.60 mg/ml to about 0.90 mg/ml, from about 0.80 mg/ml to about 1.00 mg/ml, from about 0.90 mg/ml to about 1.10 mg/ml, from about 0.95 mg/ml to about 1.25 mg/ml, from about 1
  • the amount of psychostimulant substance may be within a range selected from 0.01 mg/ml to 0.04 mg/ml, 0.02 mg/ml to 0.05 mg/ml, 0.05 mg/ml to 0.08 mg/ml, 0.05 to 0.10 mg/ml, 0.08 to 0.10 mg/ml, 0.08 to 0.12 mg/ml, 0.09 to 0.15 mg/ml, 0.10 to 0.15 mg/ml, 0.12 to 0.18 mg/ml, 0.12 to 0.20 mg/ml, 0.15 to 0.25 mg/ml, 0.20 to 0.25 mg/ml, 0.25 to 0.45 mg/ml, 0.25 to 0.50 mg/ml, 0.45 to 0.60 mg/ml, 0.50 to 0.75 mg/ml, 0.65 to 0.85 mg/ml, 0.85 to 0.95 mg/ml, 0.95 to 1.00 mg/ml, 0.95 to 1.30 mg/ml
  • the enriched beer used in accordance with a contemplated method comprises from about 0.01 mg/ml to about 0.9 mg/ml (or 10 mg/L to about 900 mg/L), about 50 mg/L, about 100 mg/L or about 350 mg/L caffeine.
  • an enriched beer is provided to a subject in a disclosed method, comprising a lager beer (3-8% alcohol), from about 0.1 mg/ml to about 0.6 mg/ml tyrosine and from about 0.01 mg/ml to about 0.4 mg/ml caffeine.
  • Typical alcoholic wine beverages include an alcoholic content of 10-14% by volume.
  • the wine is a“reduced-alcohol wine”, namely a wine comprising up to 8% alcohol, for example, up to 7%, up to 6%, up to 5%, up to 4.5%, up to 4%, up to 3.5%, up to 3%, up to 1%, up to 0.5%, up to 0.1%, up to 0.05% by volume, or the wine is devoid of alcohol.
  • a“reduced-alcohol wine” namely a wine comprising up to 8% alcohol, for example, up to 7%, up to 6%, up to 5%, up to 4.5%, up to 4%, up to 3.5%, up to 3%, up to 1%, up to 0.5%, up to 0.1%, up to 0.05% by volume, or the wine is devoid of alcohol.
  • the amount of dopamine precursor may be within a range of from about 0.10 mg/ml to 5.0 mg/ml, for example, from about 0.10 to about 0.30 mg/ml, from about 0.25 to about 0.45 mg/ml, from about 0.30 to about 0.50 mg/ml, from about 0.30 to about 0.60 mg/ml, from about 0.35 to about 0.65 mg/ml, from about 0.45 to about 0.65 mg/ml, from about 0.50 to about 0.70 mg/ml, from about 0.50 to about 0.80 mg/ml, from about 0.60 to about 0.90 mg/ml, from about 0.80 to about 0.95 mg/ml, from about 0.80 to about 1.00 mg/ml, from about 0.90 to about 1.10 mg/ml, from about 0.95 to about 1.25 mg/ml, from about 1.00 to about 1.30 mg/ml, from about 1.10 to about 1.50 mg/ml,
  • an enriched wine comprises from about 0.1 mg/ml to about 1.80 mg/ml of tyrosine.
  • the amount of psychostimulant supplement may be within a range selected from 0.01 mg/ml to 0.04 mg/ml, 0.02 to 0.05 mg/ml, 0.05 to 0.10 mg/ml, 0.08 to 0.10 mg/ml, 0.08 to 0.12 mg/ml, 0.09 to 0.15 mg/ml, 0.10 to 0.15 mg/ml, 0.12 to 0.18 mg/ml, 0.12 to 0.20 mg/ml, 0.15 to 0.25 mg/ml, 0.20 to 0.25 mg/ml, 0.25 to 0.45 mg/ml, 0.25 to 0.50 mg/ml, 0.45 to 0.60 mg/ml, 0.50 to 0.75 mg/ml, 0.65 to 0.85 mg/ml, 0.85 to 0.95 mg/ml, 0.95 to 1.00 mg/ml, 0.95 to 1.30 mg/ml, 1.00 to 1.30 mg/ml, 1.00 to 1.50 mg/
  • an enriched wine comprises from about 0.01 mg/ml to about 0.75 mg/ml (or 10 mg/L to about 750 mg/L) caffeine.
  • spirit refers to a distilled alcohol beverage obtained, for example, by distilling starchy material, and includes, but not limited to, variety of raw grain alcohols, brandies, liquors, saki, Ouzo, arrack, rum, vodka, tequila, schnapps, whiskey, gin, cordial, Cachaca, absinthe, baijiu, eau de vie, soju, aguardiente, palinka, fernet and slivovitz.
  • the spirit is a“reduced alcohol spirit”, namely a spirit as defined herein comprising up to 80% alcohol, for example, up to 60%, up to 50%, up to 45%, up to 40%, up to 35%, up to 30%, up to 25%, up to 20%, up to 15%, up to 10%, up to 8%, up to 7%, up to 6%, up to 5%, up to 4%, up to 3.5%, up to 3%, up to 2%, up to 1%, up to 0. 5% by volume, or the spirit is devoid of alcohol.
  • the amount of dopamine precursor may be within a range of from about 0.10 mg/ml to 5.0 mg/ml, for example, from about 0.10 to about 0.30 mg/ml, from about 0.25 to about 0.45 mg/ml, from about 0.30 to about 0.50 mg/ml, from about 0.30 to about 0.60 mg/ml, from about 0.35 to about 0.65 mg/ml, from about 0.45 to about 0.65 mg/ml, from about 0.50 to about 0.70 mg/ml, from about 0.50 to about 0.80 mg/ml, from about 0.60 to about 0.90 mg/ml, from about 0.80 to about 0.95 mg/ml, from about 0.80 to about 1.00 mg/ml, from about 0.90 to about 1.10 mg/ml, from about 0.95 to about 1.25 mg/ml, from about 1.00 to about 1.30 mg/ml, from about 1.10 to about 1.50 mg/ml, from about 1.
  • an enriched spirit comprises from about 0.1 mg/ml to about 2.5 mg/ml of tyrosine.
  • the amount of psychostimulant supplement may be within a range selected from 0.01 mg/ml to 0.04 mg/ml, 0.02 mg/ml to 0.05 mg/ml, 0.05 to 0.09 mg/ml, 0.05 to 0.10 mg/ml, 0.08 to 0.10 mg/ml, 0.08 to 0.12 mg/ml, 0.09 to 0.15 mg/ml, 0.10 to 0.15 mg/ml 0.10 to 0.17 mg/ml, 0.12 to 0.18 mg/ml, 0.12 to 0.20 mg/ml, 0.15 to 0.25 mg/ml, 0.20 to 0.25 mg/ml, 0.23 to 0.35 mg/ml, 0.25 to 0.45 mg/ml, 0.25 to 0.50 mg/ml, 0.45 to 0.60 mg/ml, 0.50 to 0.75 mg/ml, 0.65 to 0.85 mg/ml, 0.70 to 0.95 mg/ml, 0.
  • an enriched spirit comprises from about 0.01 mg/ml to about 0.75 mg/ml (or 10 mg/L to about 750 mg/L) of caffeine.
  • Desi darn made by fermenting molasses or high sugar containing fruits
  • Huangjiu Choinese, made from rice, millet, or wheat using a special starter culture of yeast, mold, and bacteria
  • Icariine Liquor Icariine Liquor
  • Kasiri made from cassava
  • Kilju Frju
  • Kumis central asia, traditionally made from horse milk but now primarily cow milk
  • Mead made from honey
  • Nihamanchi South America
  • nijimanche (Ecuador and Peru) (made from cassava); Palm wine (made from the sap of various palm trees); Parakari (made from cassava); Pulque (originally made by the natives of Mexico, made from the sap of the maguey plant); Sakura (made from cassava); Sake (made from rice); Sonti; Tepache; Tiswin (made from corn or saguaro, a large cactus); and Tonto.
  • Alcopop beverages also termed herein and in the art“coolers” or“spirit coolers”, are flavored alcoholic beverages or flavored malt beverages based on fruit juice or nectar, and/or a variety of naturally and/or artificially flavored syrups.
  • Exemplary alcopop beverages include, but are not limited to (i) a malt beverage, designate herein“a beer cooler”, containing a malt base or beer and at least 5% by volume of added natural or artificial blending material, such as fruit juice, flavors, flavorings, colorings, and, optionally, preservatives; (ii) a wine cooler which is a beverage containing wine and more than 15% by volume of added natural or artificial blending material, such as fruit juices, flavors, flavorings, adjuncts, water (plain, carbonated, or sparkling), colorings, and, optionally, preservatives; and (iii) a beverage designated herein“a spirit cooler”, containing distilled alcohol, and added natural or artificial blending material, such as fruit juices, flavors, flavorings, colorings, and, optionally, preservatives.
  • a malt beverage designate herein“a beer cooler”, containing a malt base or beer and at least 5% by volume of added natural or artificial blending material, such as fruit juice, flavors,
  • Alcopop brands are numerous, and their alcoholic base vary greatly. Most alcopop beverages contain 3.8-7% alcohol by volume, and some may even contain as much as 12.5% alcohol by volume.
  • the amount of dopamine precursor is within a range of from about 0.10 mg/ml to 5.0 mg/ml, for example, from about 0.10 mg/ml to about 0.20 mg/ml, from about 0.10 to about 0.30 mg/ml, from about 0.25 to about 0.45 mg/ml, from about 0.30 to about 0.50 mg/ml, from about 0.30 to about 0.60 mg/ml, from about 0.35 to about 0.65 mg/ml, from about 0.45 to about 0.65 mg/ml, from about 0.45 to about 0.70 mg/ml, from about 0.50 to about 0.70 mg/ml, from about 0.50 to about 0.80 mg/ml, from about 0.60 to about 0.90 mg/ml, from about 0.80 to about 0.95 mg/ml, from about 0.80 to about 1.00 mg/ml, from about 0.90 to about 1.10 mg/ml, from about 0.95 to about 1.25 mg/m
  • an enriched alcopop comprises from about 0.1 mg/ml to about 0.45 mg/ml of tyrosine.
  • the amount of psychostimulant supplement may be within a range selected from 0.01 mg/ml to 0.04 mg/ml, 0.02 to 0.05 mg/ml ,0.05 to 0.10 mg/ml, 0.08 to 0.10 mg/ml, 0.08 to 0.12 mg/ml, 0.09 to 0.15 mg/ml, 0.10 to 0.15 mg/ml, 0.12 to 0.18 mg/ml, 0.12 to 0.20 mg/ml, 0.15 to 0.25 mg/ml, 0.20 to 0.25 mg/ml, 0.25 to 0.45 mg/ml, 0.25 to 0.50 mg/ml, 0.45 to 0.60 mg/ml, 0.50 to 0.75 mg/ml, 0.65 to 0.85 mg/ml, 0.85 to 0.95 mg/ml, 0.95 to 1.00 mg/ml, 0.95 to 1.30 mg/ml, 1.00 to 1.30 mg/ml, 1.00 to 1.30 mg/ml, 1.00
  • an enriched alcopop comprises about 5% alcohol by volume and from about 0.01 mg/ml to about 0.75 mg/ml (or 10 mg/L to about 750 mg/L) caffeine.
  • Enriched alcoholic food product used in practicing the methods described herein may be formulated to include additives, such as flavoring agents, colorants, odoriferous agents, enzymes, CO2 and/or other additives such as viscosity modifying agents, foaming agents, antifoaming agents, and preservatives that account for the taste and texture of e.g., wine or beer or spirit.
  • additives used are FDA-approved, and/or edible.
  • a numerical range is indicated herein, it is meant to include any cited numeral (fractional or integral) within the indicated range.
  • the phrases“ranging/ranges between” a first indicate number and a second indicate number and“ranging/ranges from” a first indicate number “to” a second indicate number are used herein interchangeably and are meant to include the first and second indicated numbers and ah the fractional and integral numerals therebetween.
  • the dimensions and values disclosed herein are not to be understood as being strictly limited to the exact numerical values recited. Instead, unless otherwise specified, each such dimension is intended to mean both the recited value and a functionally equivalent range surrounding that value. For example, a dimension disclosed as“10 pm” is intended to mean“about 10 pm”.
  • the term“about” as used herein means within an acceptable error range for a particular value as determined by one of ordinary skill in the art, which will depend in part on how the value is measured or determined, i.e., the limitations of the measurement system. For example, “about” can mean a range of up to 10%, for example, up to 5%, or up to 1% of a given value. Where particular values are described in the application and claims, unless otherwise stated, the meaning of the term“about” is within an acceptable error range for the particular value.
  • a compound or “at least one compound” may include a plurality of compounds, including mixtures thereof.
  • method refers to manners, means, techniques and procedures for accomplishing a given task including, but not limited to, those manners, means, techniques and procedures either known to, or readily developed from known manners, means, techniques and procedures by practitioners of the chemical, pharmacological, biological, biochemical and medical arts.
  • the stimulant and sedative effects caused by consuming a beer enriched with a neurotransmitter precursor such as tyrosine and, optionally, a psychostimulant substance such as caffeine, versus the stimulant and sedative effects exerted by a corresponding non-enriched beer was assessed in self-reporting participants using a Biphasic Alcohol Effects Scale (BAES)-based questionnaire.
  • BAES Biphasic Alcohol Effects Scale
  • the BAES test demonstrates strong psychometric properties, including high internal consistency, reliability and a four-factor structure reflecting the distinctness of the stimulant and sedative constructs during both the ascending and descending limbs of the breath alcohol curve (BrAC).
  • This four-factor structure is invariant to dose, drinking history, and sex, and demonstrates robustness to an instructional set that does not disclose the content of the alcoholic beverage (see, for example, Rueger et al., 2009, Alcohol Clin Exp Res. 33:916-924).
  • the BAES study of alcohol effects in accordance with the disclosed study had multiple assessments. For example, the BAES questionnaire was administered before alcohol was consumed and then the assessment was repeated 3-4 more times after consumption to capture rising and declining BrAC limb effects.
  • each participant was presented with 14 items in alphabetical order, 7 of which describe sensations (feelings, perception) associated with stimulant effects (elevated mood (high spirit), energy, excitement, stimulated, talkativeness, vigorous and vitality), and 7 items describing sensations (feelings, perception) associated with sedative effects (difficulty in concentrating, down feeling, heavy head, heavy body, sedative, slow thinking, sluggishness).
  • the numerical indications of the stimulant and sedative effects were averaged to obtain two numerical values designated STIM and SED, respectively.
  • Healthy nonalcoholic 198 social drinkers participated in the study. Participants were recruited from the wider community via advertising placed, for example, in web sites. Each participant’s eligibility was subjected to the following criteria: (i) age I8 60 years; (ii) no history of alcohol addiction; (iii) not taking medication having a stimulative or sedative action; (iv) moderate to low regular consumption of alcohol.
  • the gender split was equal across both groups. All participants were requested to refrain from alcohol consumption at least 24 hours before the study.
  • the study was a 2-sesssion (2 days) study, wherein the second session (day) was at least a week apart from the first session. Participants were randomly supplied with either one of: (i) beer having 5.2% alcohol and enriched with tyrosine and caffeine; or (ii) a corresponding non-enriched beer. The study was double-blinded, and the participants did not know whether they were supplied with alcoholic beverage (i) or (ii).
  • participant In each session, participants first filled a BAES questionnaire to set up a baseline assessment, followed (about 5 minutes later) by the consumption of either enriched beer (i) or non-enriched beer (ii). For each participant, the amount of beer provided was calculated so as to reach blood alcohol level of 0.35 gr per kg body weight. For example, for a participant weighting 75 kg, 26.25 gr of alcohol are required in order to reach the predetermined blood alcohol concentration, thus this participant was supplied with 504.8 ml beer having 5.2% alcohol.
  • the aim of this study is to assess the effects of combined consumption of alcohol, a neurotransmitter precursor such as tyrosine and, optionally, a psychostimulant substance such as caffeine across a wide range of key cognitive processes and abilities.
  • this study compares the relative sensitivity of different cognitive abilities to the presence and absence of a neurotransmitter precursor and, optionally, a psychostimulant substance in an alcoholic food product.
  • test battery is exemplified herein, comprised of three psychometric tests repeated during a session.
  • the tests employed are indices of a range of key cognitive processes that have previously been shown to be sensitive to the effects of alcohol intoxication, for example, speed of information processing, divided attention, problem solving, working memory, response inhibition and cognitive flexibility, and psychomotor functioning. Participants
  • Each participant’s eligibility is subjected to the following criteria: (i) age 18-45 years; (ii) no major medical or psychiatric conditions; (iii) no visual disorders; (iv) no dependence on any substance (excluding nicotine); (v) not taking medication having a stimulative or sedative action; (vi) moderate regular consumption of alcohol; and (vii) had consumed at least five alcoholic beverages on at least one occasion in the past month.
  • the age range is chosen to ensure that the participants are old enough to be of legal drinking age, but young enough to ensure that they are unlikely to be affected by any deleterious effects of ageing upon cognitive abilities.
  • Criterion (vii) is chosen to ensure that the participants had prior experience with ingesting and functioning under the dose sizes of alcohol employed in the experiment. It is important that the participants are all‘experienced’ drinkers. The gender split is equal across both groups. All participants are requested to refrain from alcohol consumption at least 24 hours before the study.
  • Participants are randomly supplied with either one of: (i) an alcoholic beverage, e.g., beer, enriched with a neurotransmitter precursor (e.g., tyrosine) and, optionally, with a psychostimulant substance (e.g., caffeine); or (ii) a corresponding non-enriched alcoholic beverage.
  • a neurotransmitter precursor e.g., tyrosine
  • a psychostimulant substance e.g., caffeine
  • Tree cognitive ability tests are employed: (i) inspection time (IT); (ii) self- ordered pointing task (SOPT); and (iii) sustained attention to response task (SART).
  • IT inspection time
  • SOPT self- ordered pointing task
  • SART sustained attention to response task
  • computerized versions of the tasks may be employed as described, for example, in Burns and Nettelbeck (2003) ( Intelligence , 31: 237-255) and Robertson et al. (1997) ( Neuropsychologia , 35: 747-758), or generated using MatLab.
  • Inspection time is a measure of speed of information processing. Inspection time is motor free, i.e., it does not require a speeded response on behalf of a participant, rather it measures the minimum display-time necessary for a participant to make two- alternative forced-choice decision (see Deary et al., 2004, Neuroimage 22: 1466-1479).
  • the test is as follows: a shape or a design version, e.g., an inverted U shape having one“leg” shorter than the other, is flickering or repeatedly presented on the computer screen at varying rate.
  • the participant needs to elect/indicate which is the side of the shorter leg.
  • the shortest display-time needed for a participant to correctly identify the shorter leg with clear statistical significance (about 90% of times) is scored.
  • the participant is advised prior to testing that the purpose of the test is to identify the correct forced-choice decision (short leg) but there is no time constraint.
  • the self-ordered pointing task is a measure of working memory function. Performance on the task requires participants to hold visual information in short-term storage while executing a response strategy and continuously monitoring performance.
  • the test is as follows: participants are presented with, for example, 10, 12 and 16 design versions (images) in a continuously changing order relative to each other with each design version repeated three times per test run. Prior to each change of order, the participant is asked to select a different design version and avoid from choosing the same version again in subsequent presentations. The participant is practicing this test several times, each time having to handle increasing number of images changing their location on the screen relative to the other images. The number of incorrect image selections by the participant is scored. Prior to the test, a participant is advised that image selection is to be performed at intermediate rate, namely not too slow or too fast.
  • the sustained attention to response task is a measure of response inhibition and cognitive flexibility. Participants are required to respond quickly to a commonly occurring set of stimuli but withhold responding to a rarely occurring target stimulus. Performance on the task involves regions of the prefrontal cortex associated with inhibitory control, performance monitoring and error processing.
  • the test is as follows: shapes, e.g., numbers, are flickering or repeatedly presented on the computer screen at constant rate. The participant is asked to press a certain key on the keyboard after each presentation, unless a predetermined shape appears on the screen, in which case the participant should refrain for pressing the keyboard. The number of faults (namely, pressing the key when shouldn’t and not pressing it when should) is scored. Prior to the test, a participant is advised that accuracy is important, while key pressing is to be done at minimum time. Each of tests (i)-(iii) lasts about 5 minutes. All three tests are conducted sequentially, in a predetermined and fixed order, over a total time of 15-20 minutes. Tests are conducted double blindingly.
  • shapes e.g., numbers
  • Each study is a 3 days study, wherein Day 1 is a familiarization session, and alcohol manipulation is applied on the second and third days as follows:
  • Day 1 acquaintanceship. Participants are first screened for drug and alcohol use, then presented with the tests and practice them, for simulation, three times in a row with l-hour interval between each tests sequence.
  • brief intellectual ability (BIA) scales are taken for each participant.
  • This measure may comprise, for example, three tests from the Woodcock-Johnson III (Woodcock et al., (2001) Woodcock-Johnson III. Itasca, IL: Riverside): Verbal Comprehension (crystallized ability), Concept Formation (fluid ability), and Visual Matching (perceptual speed). It takes approximately 15-20 min to complete.
  • the BIA is conducted once only on the first day in order to gauge each participant’s level of intellectual ability.
  • Day 2 participants (after being screened for drug and alcohol use) first practice the sequence of tests and then conduct them sequentially for scores at least about 30 minutes before the actual study commences, in order to obtain reference data (i.e., baseline record or control data) for each participant, before alcohol consumption.
  • reference data i.e., baseline record or control data
  • each participant in groups (i) and (ii) is provided either with five 100 ml portions of beer enriched, for example, with tyrosine and, optionally, caffeine, or the corresponding non-enriched beer, respectively, and instructed to consume each portion in 2 minutes such that after all 5 portions are consumed, blood alcohol level reaches 3.5 gr per kg body weight.
  • Day 3 at least 48 hours after Day 1. Study is performed exactly as in Day 2, except the participants will consume the beer they did not consume on Day 2 (e.g., participants who were provided with enriched beer on Day 2, will be provided with non-enriched beer on Day 3). Scores for all three tests will be statistically analyzed so as to obtain relevant results regarding the influence or effects on cognitive abilities exerted by the enriched beer as compared to the non-enriched beer.
  • Further cognitive ability tests and/or assessments that may be used to assess and/or quantify the effects of consuming alcohol together with a neurotransmitter and/or a precursor thereof on cognitive, mental and/or emotional abilities include, for example, the following tests:
  • the traveling salesperson problem (TSP) test The traveling salesperson problem (TSP) (Dry et al., 2006, J. Problem Solving 1 : 20-32; 51) is a measure of strategic problem solving. Solving a TSP requires participants to continuously monitor their performance whilst making sequential decisions subject to multiple interacting constraints.
  • the useful field of view (UFOV) test is a measure of processing speed and divided visual attention. Task performance is reliant upon both the integrity of the viewer’s visuo-sensory input, as well as higher-level cognitive functions.
  • Each of the tasks taken in these tests have been widely employed in the literature, is well-known and easily accessible. Participants require no special prior knowledge to perform the tasks and are able to perform them with a minimum of instructions. Each of the tasks can be completed in a short period of time (about 10 minutes) ensuring that a battery of tests can be completed within a time-period that minimizes any variability associated with rising and falling blood alcohol levels.
  • the aim of this study is to assess the psychoactive effects of combined consumption of alcohol, a neurotransmitter precursor such as tyrosine and, optionally, a psychostimulant substance such as caffeine.
  • the tests employed in this study are based on known tests designed to assess the immediate adverse effects of alcohol on various aspects of cognitive functioning, accompanied by questionnaires presenting questions for evaluating the psychoactive effects and personal experience. Participants
  • Healthy nonalcoholic social drinkers between the ages of 21 and 31 years are drawn from the campus student of the Ben-Gurion university via advertisement displayed and distributed in the campus by the university’s mail system and by social medias.
  • Each participant’s eligibility is subjected to the following criteria: (i) not currently pregnant or lactating; (ii) no major medical or psychiatric conditions; (iii) a negative urine drug screen (amphetamines, barbiturates, opiates, cocaine); (iv) no dependence, currently or in the past, on any substance (excluding nicotine); (v) not taking medication having a stimulative or sedative action; and (vi) moderate to low regular alcohol consumption.
  • Participants are assigned with randomized numeric codes that are used during collection and analysis of the data, while being evenly divided between genders with no bias or discrimination for any race or ethnicity.
  • Written consent is obtained from each of the participants. Ah participants are compensated for their time.
  • BAES Biphasic alcohol effects scale
  • the POMS questionnaire is a standard validated psychological rating scale used to assess transient, distinct mood states.
  • the version of the questionnaire used is the POMS 2 for adults aged 18 years and older, available as full-length (65 items) and short versions (35 items).
  • the questionnaires contain a series of descriptive words/statements that describe feelings people have. Participants self-report on each of the items assessed using a 5-point Likert scale (a psychometric scale commonly used in surveys and questionnaires), ranging from 0 (Not at all), 1 (A little) 2 (Moderately), 3 (Quite a bit), to 4 (Extremely).
  • Mood states are interpreted though 6 mood domains: tension or anxiety (9 items), depression or dejection (15 items), anger or hostility (12 items), vigor or activity (8 items), fatigue or inertia (7 items), and confusion or bewilderment (7 items).
  • a total mood disturbance (TMD) score is calculated by summing the totals for the negative subscales (tension, depression, fatigue, confusion, anger) and then subtracting the totals for the positive subscales (vigor and esteem-related affect). Completion of the assessment takes 5-15 minutes, depending on the form. Inspection time (IT). A computerized task that measures the speed of information processing that can be estimated in as little as 5 min. IT measures the minimum display-time necessary for a participant to make a two-alternative forced- choice decision (see Example 2 above).
  • VAS Visual analog scale
  • Buss-Perry aggression questionnaire A 29-item instrument that measures four factors: physical aggression, verbal aggression, anger, and hostility.
  • the aggression questionnaire developed by Buss and Perry is a widely used measure of aggression in research and in applied settings.
  • Buss-Perry Aggression Questionnaire is available, e.g., on https://www.researchgate.net/publication/30l934203 Buss- Perry Aggression Questionnaire Testing Alternative Measurement Models With Assaultive Misdemeanor Offenders.
  • This study is a single-blind, randomized, cross-over study that includes two laboratory visits, at least one week apart.
  • participants are instructed to refrain from alcohol for at least 24 hours as well as from food, caffeine, and nicotine on the morning of testing. Participants arrive at 11:00 AM and are given a low -fat light lunch (juice, sandwich, pretzels).
  • participants undergo a set of baseline assessments, followed by the consumption of either a beer enriched with a neurotransmitter precursor such as tyrosine and, optionally, a psychostimulant substance such as caffeine, or a corresponding on-enriched beer (a 50 ml portion every 15 seconds), in a randomized manner, and are followed for 3 hours post consumption. Each visit is estimated to last about 5 hours.
  • Baseline assessments are performed for each participant based on one or more of the following tests or assessments:
  • Post consumption assessments for both visits is based on one or more of the following tests:
  • blood pressure and heart rate are assessed every 30 minutes.
  • the primary outcome measures will be the subjective alcohol effects (BAES) and mood states (POMS) at 30 and 120 minutes post-consumption, as compared to baseline levels. Secondary outcome measures will be changes in IT performance, aggression levels, alcohol craving levels, and physiological parameters.
  • BAES subjective alcohol effects
  • POMS mood states

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Abstract

L'invention concerne des procédés pour améliorer et prolonger une sensation euphorique associée à la consommation d'alcool, comprenant la fourniture à un sujet, lors de la consommation d'alcool, d'une quantité efficace d'au moins un neurotransmetteur et/ou d'au moins un précurseur de neurotransmetteur et, éventuellement, d'une ou plusieurs substances psychostimulantes. L'invention concerne également des procédés d'amélioration, d'amplification et/ou d'amélioration d'une capacité cognitive, d'une émotion et/ou d'une compétence mentale souhaitées, comprenant la fourniture à un sujet d'alcool et d'au moins un neurotransmetteur et/ou d'un précurseur de neurotransmetteur, et, facultativement, d'une ou plusieurs substances psychostimulantes. Le précurseur de neurotransmetteur est, par exemple, la tyrosine, précurseur de la dopamine.
PCT/IB2019/057078 2017-08-22 2019-08-22 Procédés d'amélioration de la sensation euphorique et d'amélioration des capacités cognitives Ceased WO2020039383A1 (fr)

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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20130156872A1 (en) * 2012-10-04 2013-06-20 Invivo Beverages Llc Integrated Neuromodulation System for Mood Enhancement of a Living Human Subject
WO2019038687A1 (fr) * 2017-08-22 2019-02-28 Euphoria Beer Development Ltd Boissons alcoolisées enrichies

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