Note: Descriptions are shown in the official language in which they were submitted.
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ENHANCED CAFFEINATED BEVERAGE COMPOSITION
Field of the Invention
[0001] The field of the invention is a caffeinated beverage supplemented with
theacrine and
methylliberine.
Background
[0002] The following description includes information that may be useful in
understanding the
present invention. It is not an admission that any of the information provided
herein is prior art
or relevant to the presently claimed invention, or that any publication
specifically or implicitly
referenced is prior art.
[0003] Tea and coffee are the most widely consumed products in the world. Tea
and the different
varieties of tea have been extensively studied. Many epidemiologic and
preclinical studies
suggest that drinking tea may reduce the risk of cancer and cardiovascular
disease. Theacrine, an
alkaloid purine similar to caffeine, is relatively rare and only found in a
few varieties of tea
(kucha tea, genus Camellia), the fruit cupuacu, and other plants related to
coffee and cacao
(genera Coffea and Theobroma), such as Coffea liberica, Coffea dewevrei,
Coffea abeokutae and
Theobroma grandiflorum.
[0004] 1,3,7,9 tetramethyluric acid, commonly known as theacrine, was not
studied until around
1975. However, it has been known of since about 1937, when it was detected in
dry,
decaffeinated Camellia sinensis tea leaves. At this time, the Camellia
assamica var. kucha variety
of tea is the primary source of naturally occurring theacrine and produces the
chemical in higher
concentrations than other known plants. Interestingly, theacrine has not been
detected at all in
more traditional teas strains. It is believed to be formed by methylation of
caffeine and may be an
intermediary in the production of liberine or other purines. Its natural
function, if any, remains
unknown. Theacrine has garnered attention only relatively recently, and often
only as a
secondary consideration when analyzing other compounds. Some studies suggest
it may have
beneficial qualities, such as serving as an effective anti-oxidant, anti-
inflammatory and may have
anti-obesity properties.
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[0005] In the studies involving theacrine, beneficial effects may be at least
partially attributable
to an assortment of purine alkaloids and phenolic compounds. The more common
tea-related
purine alkaloids include caffeine, theobromine, theophyline and theacrine. The
major tea
phenolic compounds are gallic acid and eight naturally occurring tea
catechins, including (+)-
catechin (C), (-)-epicatechin (EC), (+)-gallocatechin (GC), (-)-
epigallocatechin (EGC), (-)-
catechin gallate (CG), (-)-gallocatechin gallate (GCG), (-)-epicatechin
gallate (ECG) and (-)-
epigallocatechin gallate (EGCG).
[0006] Many different biologic and physiologic activities have been attributed
to tea and its
various components. However, only a few of its components have been studied in
depth.
Caffeine is by far the most studied, and the most commonly used stimulant
found in tea.
Theacrine appears to have an opposite effect, despite being very similar in
chemical structure.
Recent experiments have shown that theacrine exhibits a variety of activities,
some of which
seem inconsistent.
[0007] In the past several years, there has been a substantial shift in public
opinion toward using
naturally occurring chemical compounds for a variety of purposes, instead of
synthetic
chemicals. For example, a wide variety of natural chemicals are now commonly
used as
sedatives, e.g. valerian root and chamomile, anti-depressants, e.g. St. John's
wort, stimulants, e.g.
caffeine, and concentration, e.g. ginseng. In general, naturally occurring
compounds may be
easier for the body to digest and interact with and may include minimal and
less severe side
effects.
[0008] It is therefore desirable to identify naturally occurring chemical
compounds and mixtures
thereof that may provide benefits. It is also desirable to provide chemical
compounds and
mixtures thereof that may be used to provide a variety of benefits, varying by
concentration, thus
requiring production or harvesting of fewer materials.
Summary of The Invention
[0009] The inventive subject includes an enhanced caffeinated beverage
supplemented with an
effective blend of theacrine and methylliberine. The enhanced caffeinated
beverage is a
stimulating drink conferring an increase in mood, energy, alertness, focus,
and/or motivation for
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the consumer (person consuming the enhanced caffeinated beverage), while not
adversely
increasing the person's heart rate or blood pressure.
[0010] Notably, in some embodiments, a caffeinated beverage composition is
supplemented with
methylliberine and theacrine. Most advantageously, the methylliberine and
theacrine are in an
effective synergistic combination imparting the desired mood, energy,
alertness, focus, and/or
motivation at increased levels relative to a caffeinated beverage alone as
well as those
experienced from a weight amount of methylliberine (e.g., 100 mg) that is
greater than the total
weight amount of effective blend of methylliberine and theacrine (e.g., 75
mg).
[0011] Embodiments of the contemplated subject matter include a caffeinated
beverage
composition supplemented with methylliberine and theacrine, wherein the
caffeinated beverage
composition includes a caffeinated drink having a caffeine content of between
about 1 mg/oz to
65 mg/oz, theacrine in an amount of between about 1.5 mg/oz to 15 mg/oz, and
methylliberine in
an amount of between about 3.0 mg/oz to 30 mg/oz. In other embodiments, the
caffeinated
beverage composition includes a caffeinated drink having a caffeine content of
between about 1
mg/oz to 65 mg/oz, theacrine in an amount of between about 1.5 mg/oz to 10
mg/oz, and
methylliberine in an amount of between about 3.0 mg/oz to 20 mg/oz. In still
other
embodiments, the caffeinated beverage composition includes a caffeinated drink
having a
caffeine content of between about 1 mg/oz to 65 mg/oz, theacrine in an amount
of between about
1.5 mg/oz to 5 mg/oz, and methylliberine in an amount of between about 3.0
mg/oz to 10 mg/oz.
In preferred embodiments, theacrine and methylliberine are present in a weight
ratio of between
about 1:1.5 to 1:2.75 or 1:1.5 to 1:3Ø In exemplary embodiments, the
theacrine and
methylliberine are present in a weight ratio of between about 1:1.5 to 1:2.75.
[0012] In additional embodiments, the caffeinated drink is brewed coffee, tea,
a cola, or an
energy drink. In preferred embodiments, the caffeinated drink is brewed
coffee. More preferably,
the brewed coffee is a non-espresso coffee having a caffeine content of
between about 10 to 30
mg/oz, or the brewed coffee is an espresso coffee having a caffeine content of
between about 30
to 65 mg/oz in a volume of not more than 3 ounces.
[0013] In notable embodiments, the caffeinated beverage upon consumption by a
person,
increases mood, energy, alertness, motivation, and/or focus in the person
compared to the
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caffeinated beverage alone or the caffeinated beverage supplemented only with
methylliberine of
between about 6 mg/oz or 12.5 mg/oz. In further embodiments, the caffeinated
beverage does not
adversely affect heart rate and/or blood pressure in the person. Additionally,
the increased
mood, energy, alertness, motivation, and/or focus in the person is experienced
by the person up
to about 5 hours after consumption of the caffeinated beverage composition.
[0014] In more specific embodiments, an enhanced coffee beverage includes a
coffee drink
supplemented with methylliberine and theacrine, wherein the coffee drink has a
caffeine content
of between about 1 mg/oz to 65 mg/oz, and the theacrine is in an amount of
between about 1.5
mg/oz to 15 mg/oz, 1.5 mg/oz to 10 mg/oz, or 1.5 mg/oz to 5.0 mg/oz, and the
methylliberine is
added in an amount of between about 3.0 mg/oz to 30 mg/oz, 3.0 mg/oz to 20.0
mg/oz, or 3
mg/oz to 15 mg/oz, and wherein the theacrine and the methylliberine are in a
weight ratio of
between about 1:1.5 to 1:2.75 or 1:1.5 to 1:3Ø
[0015] Additional embodiments include a method of preparing an enhanced
caffeinated
beverage, including adding theacrine and methylliberine to a caffeinated
drink, wherein the
theacrine is added in an amount of between about 1.5 mg/oz to 15 mg/oz, 1.5
mg/oz to 10 mg/oz,
or 1.5 mg/oz to 5.0 mg/oz, and the methylliberine is added in an amount of
between about 3.0
mg/oz to 30 mg/oz, 3.0 mg/oz to 20.0 mg/oz, or 3 mg/oz to 15 mg/oz. In further
embodiments,
the method of preparing an enhanced caffeinated beverage includes a
caffeinated drink selected
from a brewed coffee, a tea, an energy drink, or a cola.
[0016] In preferred embodiments, the method of preparing an enhanced
caffeinated beverage
includes a brewed coffee wherein the adding of the theacrine and
methylliberine are added to
coffee grounds prior to brewing the brewed coffee or the theacrine and
methylliberine are added
to the brewed coffee. For example, the brewed coffee includes non-espresso or
espresso brewed
coffees, and/or the brewed coffee may be hot brewed or cold brewed.
[0017] Various objects, features, aspects and advantages of the inventive
subject matter will
become more apparent from the following detailed description of preferred
embodiments, along
with the accompanying drawing figures in which like numerals represent like
components.
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Brief Description of The Drawings
[0018] FIG. 1 depicts, in one embodiment, a molecular diagram of theacrine in
accordance with
the principles of the invention.
[0019] FIG. 2 depicts, in one embodiment, a graph of results of a trial
showing perceived energy
on a Visual Analogue Scale (VAS) scale (0 to 10 cm) at 1, 2 and 3 hours after
administration of
theacrine or placebo.
[0020] FIG. 3 depicts, in one embodiment, a graph of results of a trial
showing perceived fatigue
on a VAS scale (0 to 10 cm) at 0 minutes and 60 minutes after administration
of theacrine or
placebo.
[0021] FIG. 4 depicts, in one embodiment, a graph of results of a trial
showing systolic blood
pressure at various time intervals after administration of theacrine or
placebo.
[0022] FIG. 5 depicts, in one embodiment, a graph of results of a trial
showing diastolic blood
pressure at various time intervals after administration of theacrine or
placebo.
[0023] FIG. 6 shows, in one embodiment, the results of a 7 day repeated dose
study of 200 mg
theacrine relative to baseline of fatigue, anxiety and libido at various
intervals after dosages (at 0
hr, 1 hr, 4 hr, 6 hr; bars left to right for each measured category).
[0024] FIG. 7 shows, in one embodiment, the results of a 7 day repeated dose
study of 200 mg
theacrine relative to baseline of energy, motivation to exercise, and
concentration at various
intervals after dosages (at 0 hr, 1 hr, 4 hr, 6 hr; bars left to right for
each measured category).
[0025] FIG. 8(A) depicts, in one embodiment, individual plasma concentrations
of theacrine
after single oral dose of theacrine 25 mg.
[0026] FIG. 8(B) depicts, in one embodiment, individual plasma concentrations
of theacrine
after single oral dose of theacrine 125 mg.
[0027] FIG. 8(C) depicts, in one embodiment, individual plasma concentrations
of theacrine
after single oral dose of theacrine 125 mg plus caffeine 150 mg.
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[0028] FIG. 9 depicts, in one embodiment, Forest plot illustrating the
probability of interaction
magnitude between theacrine and caffeine using 90% confidence intervals about
the geometric
mean ratio of the observed pharmacokinetic parameters following a single
theacrine dose (-0-
25 mg theacrine and 125 mg theacrine in combination with 150 mg caffeine).
[0029] FIG. 10(A) depicts, in one embodiment, individual plasma concentrations
of caffeine
after single oral dose of caffeine 150 mg.
[0030] FIG. 10(B) depicts, in one embodiment, individual plasma concentrations
of caffeine
after single oral dose of theacrine 125 mg plus caffeine 150 mg.
[0031] FIG. 11 depicts, in one embodiment, Forest plot illustrating the
probability of interaction
magnitude between caffeine and theacrine using 90% confidence intervals about
the geometric
mean ratio of the observed pharmacokinetic parameters following a single
caffeine dose (150
mg) alone or in combination with theacrine (125 mg).
[0032] FIG. 12(A) depicts, in one embodiment, mean values in heart rate after
single dose
theacrine 25 mg (-04 theacrine 125 mg (4- ), caffeine 150 mg (-4,), or
theacrine 125 mg plus
caffeine 150 mg (-A-).
[0033] FIG. 12(B) depicts, in one embodiment, mean values in systolic blood
pressure after
single dose theacrine 25 mg (-0-) theacrine 125 mg (-0-), caffeine 150 mg (-.-
), or theacrine
125 mg plus caffeine 150 mg (-A-).
[0034] FIG. 12(C) depicts, in one embodiment, mean values in diastolic blood
pressure after
single dose theacrine 25 mg (-s-), theacrine 125 mg OVA caffeine 150 mg (-40-
), or theacrine
125 mg plus caffeine 150 mg (-A-).
[0035] FIG. 12(D) depicts, in one embodiment, mean values in rate pressure
product after single
dose theacrine 25 mg (-04 theacrine 125 mg (*), caffeine 150 mg (-1,-), or
theacrine 125 mg
plus caffeine 150 mg (-A-).
[0036] FIG. 13(A) depicts, in one embodiment, a graph of results of a trial
showing the change
(Delta) in perceived mood as measured using a VAS scale before and 180 minutes
after
consumption of a decaffeinated coffee beverage (DECAFF), caffeinated coffee
(Coffee), Coffee
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with 50 mg methylliberine (Dynamine), Coffee with 50 mg Dynamine and 25 mg
theacrine
(TeaCrine), or Coffee with 100 mg Dynamine, as indicated.
[0037] FIG. 13(B) depicts, in one embodiment, a graph of results of a trial
showing the change
(Delta) in perceived energy as measured using a VAS scale before and 180
minutes after
consumption of a decaffeinated coffee beverage (DECAFF), caffeinated coffee
(Coffee), Coffee
with 50 mg methylliberine (Dynamine), Coffee with 50 mg Dynamine and 25 mg
theacrine
(TeaCrine), or Coffee with 100 mg Dynamine, as indicated.
[0038] FIG. 13(C) depicts, in one embodiment, a graph of results of a trial
showing the change
(Delta) in perceived motivation as measured using a VAS scale before and 180
minutes after
consumption of a decaffeinated coffee beverage (DECAFF), caffeinated coffee
(Coffee), Coffee
with 50 mg methylliberine (Dynamine), Coffee with 50 mg Dynamine and 25 mg
theacrine
(TeaCrine), or Coffee with 100 mg Dynamine, as indicated.
[0039] FIG. 13(D) depicts, in one embodiment, a graph of results of a trial
showing the change
(Delta) in perceived alertness as measured using a VAS scale before and 180
minutes after
consumption of a decaffeinated coffee beverage (DECAFF), caffeinated coffee
(Coffee), Coffee
with 50 mg methylliberine (Dynamine), Coffee with 50 mg Dynamine and 25 mg
theacrine
(TeaCrine), or Coffee with 100 mg Dynamine, as indicated.
[0040] FIG. 13(E) depicts, in one embodiment, a graph of results of a trial
showing the change
(Delta) in perceived fatigue as measured using a VAS scale before and 180
minutes after
consumption of a decaffeinated coffee beverage (DECAFF), caffeinated coffee
(Coffee), Coffee
with 50 mg methylliberine (Dynamine), Coffee with 50 mg Dynamine and 25 mg
theacrine
(TeaCrine), or Coffee with 100 mg Dynamine, as indicated.
[0041] FIG. 13(F) depicts, in one embodiment, a graph of results of a trial
showing the change
(Delta) in perceived focus as measured using a VAS scale before and 180
minutes after
consumption of a decaffeinated coffee beverage (DECAFF), caffeinated coffee
(Coffee), Coffee
with 50 mg methylliberine (Dynamine), Coffee with 50 mg Dynamine and 25 mg
theacrine
(TeaCrine), or Coffee with 100 mg Dynamine, as indicated.
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[0042] FIG. 13(G) depicts, in one embodiment, a graph of results of a trial
showing the change
(Delta) in perceived creativity as measured using a VAS scale before and 180
minutes after
consumption of a decaffeinated coffee beverage (DECAFF), caffeinated coffee
(Coffee), Coffee
with 50 mg methylliberine (Dynamine), Coffee with 50 mg Dynamine and 25 mg
theacrine
(TeaCrine), or Coffee with 100 mg Dynamine, as indicated.
[0043] FIG. 13(H) depicts, in one embodiment, a graph of results of a trial
showing the change
(Delta) in perceived concentration as measured using a VAS scale before and
180 minutes after
consumption of a decaffeinated coffee beverage (DECAFF), caffeinated coffee
(Coffee), Coffee
with 50 mg methylliberine (Dynamine), Coffee with 50 mg Dynamine and 25 mg
theacrine
(TeaCrine), or Coffee with 100 mg Dynamine, as indicated.
[0044] FIG. 14(A) depicts, in one embodiment, a graph of results of a trial
showing the change
(Delta) in mean values of systolic blood pressure (BP) before and 180 minutes
after consumption
of a decaffeinated coffee beverage (DECAFF), caffeinated coffee (Coffee),
Coffee with 50 mg
methylliberine (Dynamine), Coffee with 50 mg Dynamine and 25 mg theacrine
(TeaCrine), or
Coffee with 100 mg Dynamine, as indicated.
[0045] FIG. 14(B) depicts, in one embodiment, a graph of results of a trial
showing the change
(Delta) in mean values of diastolic blood pressure (BP) before and 180 minutes
after
consumption of a decaffeinated coffee beverage (DECAFF), caffeinated coffee
(Coffee), Coffee
with 50 mg methylliberine (Dynamine), Coffee with 50 mg Dynamine and 25 mg
theacrine
(TeaCrine), or Coffee with 100 mg Dynamine, as indicated.
[0046] FIG. 14(C) in one embodiment, a graph of results of a trial showing the
change (Delta) in
mean values of heart rate before and 180 minutes after consumption of a
decaffeinated coffee
beverage (DECAFF), caffeinated coffee (Coffee), Coffee with 50 mg
methylliberine
(Dynamine), Coffee with 50 mg Dynamine and 25 mg theacrine (TeaCrine), or
Coffee with 100
mg Dynamine, as indicated.
[0047] FIG. 14(D) in one embodiment, a graph of results of a trial showing the
change (Delta) in
mean values of rate pressure product before and 180 minutes after consumption
of a
decaffeinated coffee beverage (DECAFF), caffeinated coffee (Coffee), Coffee
with 50 mg
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methylliberine (Dynamine), Coffee with 50 mg Dynamine and 25 mg theacrine
(TeaCrine), or
Coffee with 100 mg Dynamine, as indicated.
[0048] FIG. 14(E) in one embodiment, a graph of results of a trial showing the
change (Delta) in
mean values of mean arterial pressure before and 180 minutes after consumption
of a
decaffeinated coffee beverage (DECAFF), caffeinated coffee (Coffee), Coffee
with 50 mg
methylliberine (Dynamine), Coffee with 50 mg Dynamine and 25 mg theacrine
(TeaCrine), or
Coffee with 100 mg Dynamine, as indicated.
[0049] FIG. 14(F) in one embodiment, a graph of results of a trial showing the
change (Delta) in
mean values of pulse pressure before and 180 minutes after consumption of a
decaffeinated
coffee beverage (DECAFF), caffeinated coffee (Coffee), Coffee with 50 mg
methylliberine
(Dynamine), Coffee with 50 mg Dynamine and 25 mg theacrine (TeaCrine), or
Coffee with 100
mg Dynamine, as indicated.
Detailed Description
[0050] Before explaining at least one embodiment of the invention in detail,
it is to be
understood that the invention is not limited in its application to the details
of construction and to
the arrangements of the components set forth in the following description or
illustrated in the
drawings. The invention is capable of other embodiments and of being practiced
and carried out
in various ways. Also, it is to be understood that the phraseology and
terminology employed
herein are for the purpose of description and should not be regarded as
limiting.
[0051] Disclosed is an invention relating to uses of theacrine, also known as
1,3,7,9-
tetramethyluric acid, Temurin, Temorine, Tetramethyluric acid, Tetramethyl
uric acid and
1,3,7,9-tetramethylpurine-2,6,8-trione. Theacrine may be produced
synthetically or may be
isolated from a natural source. Theacrine isolated from a natural source may
be purified to 95%
or greater. Optionally, less purification may be used such that theacrine
accounts for 50%, or
even less, of the material. In some embodiments, it may be preferable to
utilize theacrine isolated
from a natural source which may include other congeners of theacrine typically
found in
theacrine isolates.
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[0052] Advantageously, the addition of an effective blend of theacrine (e.g.,
TeaCrine) together
with methylliberine (MILL) (e.g., Dynamine) supplemented in a caffeinated
beverage (e.g.,
brewed caffeinated coffee), results in an enhanced caffeinated beverage
providing increased
mood (e.g., positive mood), energy, motivation, alertness, focus, and/or
decreased fatigue
relative to a caffeinated drink supplemented with methylliberine alone at even
greater amounts
(e.g., 100 mg MILL) than the effective blend of methylliberine and theacrine
(e.g., at a total of 75
mg). Furthermore, methylliberine and theacrine in a caffeinated beverage
confers improved and
desirable effects while tempering physiological side effects common to these
stimulants. Most
surprisingly, an effective blend of methylliberine and theacrine in
caffeinated did not adversely
affect blood pressure or heart rate.
[0053] As used herein, a caffeinated beverage is any consumable drink having
caffeine.
Examples of caffeinated drinks include coffee, tea (e.g., black or green), a
cola drink (e.g., Coca-
Cola , Pepsi , etc.), or an energy drink (e.g., Red Bull , Monster , or Wired
). For example,
the energy drink is a non-coffee energy drink and/or a non-cola energy drink.
[0054] As used herein, a coffee drink refers to any type of coffee brewed from
water and coffee
grounds. The coffee drink may be hot brewed or cold brewed. The coffee drink
may be a non-
espresso coffee or an espresso brewed coffee. The coffee drink may be brewed
using any
suitable method. Examples of hot or cold coffee brewing methods include drip
brew, French
press, espresso brewing, modular non-espresso brewing using pods (e.g.,
Keurigg), or modular
espresso brewing (e.g., Nespressog). As well known in the art, brewing methods
vary by size of
coffee grounds, the water temperature passing over the grounds, and/or the
pressure of the water
passing over the grounds.
[0055] Notably, the contemplated caffeinated beverage supplemented with an
effective blend of
theacrine and methylliberine is a stimulating drink without negative
physiological effects (e.g.,
increased heart rate or blood pressure) made of a synergistic combination of
theacrine and
methylliberine added to the caffeinated drink. In particular, the synergistic
combination is an
effective blend in which the theacrine and methylliberine are present in a
weight ratio of between
about 1:1.5 to 1:3.0 resulting in the supplemented caffeinated beverage having
the advantageous
and desired effects.
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[0056] In more specific embodiments, the effective blend of theacrine and
methylliberine in the
enhanced caffeinated beverage is in a weight ratio of between about 1:1.5 to
1:2.75 or 1:1.5 to
1:3.0, and includes theacrine in an amount in milligrams per ounce (mg/oz)
between about 1.5
mg/oz to 15 mg/oz, (0.05 mg/ml to 0.51 mg/ml) and methylliberine in an amount
of between
about 3.0 mg/oz to 30 mg/oz (0.10 mg/ml to 1.02 mg/ml). Accordingly, the
disclosed effective
blend of theacrine and methylliberine includes theacrine at an amount of
between about 1.5, 1.6,
1.7, 1.8, 1.9. 2.0, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3.0, 3.1,
3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8,
3.9, 4.0, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, 5.0, 5.5, 6.0, 6.5,
7.0, 7.5, 8.0, 8.5, 9.0, 9.5, 10.0,
10.5, 11.0, 11.5, 12.0, 12.5, 13.0, 13.5, 14.0, 14.5, or 15.0 gm/oz.
Typically, the effective blend
of theacrine and methylliberine includes theacrine at an amount of between
about 2 mg/oz to 15
mg/oz, 2 mg/oz to 12 mg/oz, 2 mg/oz to 10 mg/oz, 2 mg/oz to 7 mg/oz, or 2
mg/oz to 5 mg/oz.
More typically, the caffeinated drink is supplemented with theacrine at an
amount of between
about 2.5 mg/oz to 4.0 mg/oz. Most typically, the caffeinated drink is
supplemented with
theacrine at an amount of between about 2.75 mg/oz to 3.5 mg/oz. With respect
to
methylliberine, the disclosed effective blend of theacrine and methylliberine
includes
methylliberine in an amount of between about 3.0, 3.1, 3.2, 3.3, 3.4, 3.5,
3.6, 3.7, 3.8, 3.9, 4.0,
4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, 5.0, 5.1, 5.2, 5.3, 5.4, 5.5,
5.6, 5.7, 5.8, 5.9, 6.0, 6.1, 6.2,
6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, 7.0, 7.1, 7.2, 7.3, 7.4, 7.5, 7.6, 7.7,
7.8, 7.9, 8.0, 8.1, 8.2, 8.3, 8.4,
8.5, 8.6, 8.7, 8.8, 8.9, 9.0, 9.1, 9.2, 9.3, 9.4, 9.5, 9.6, 9.7, 9.8, 9.9,
10.0, 10.5, 11.0, 11.5, 12.0,
12.5, 13.0, 13.5, 14.0, 14.5, or 15.0 15.5, 16.0, 16.5, 17.0, 17.5, 18.0,
18.5, 19.0, 19.5, 20.0,
20.5, 21.0, 21.5, 22.0, 22.5, 23.0, 23.5, 24.0, 24.5, 25.0, 25.5, 26.0, 26.5,
27.0, 27.5, 28.0, 28.5,
29.0, 29.5, or 30.0 mg/oz. Typically, the effective blend of theacrine and
methylliberine includes
methylliberine at an amount of between about 3 mg/oz to 25 mg/oz, 3 mg/oz to
20 mg/oz, 3
mg/oz to 19 mg/oz, 3 mg/oz to 18 mg/oz, 3 mg/oz to 17 mg/oz, 3 mg/oz to 16
mg/oz, 3 mg/oz to
15 mg/oz, 3 mg/oz to 14 mg/oz, 3 mg/oz to 13 mg/oz, 3 mg/oz to 12 mg/oz, 3
mg/oz to 11
mg/oz, 3 mg/oz to 10 mg/oz, 3 mg/oz to 9 mg/oz, or 3 mg/oz to 8 mg/oz. More
typically, the
caffeinated drink is supplemented with methylliberine at an amount of between
about 5 mg/oz to
20 mg/oz, 5 mg/oz to 15 mg/oz, 5 mg/oz to 10 mg/oz. Most typically, the
caffeinated drink is
supplemented with methylliberine at an amount of between about 6.0 mg/oz to
8.0 mg/oz. For
example, the caffeinated drink may be supplemented with methylliberine at an
amount of
between about 6.0 mg/oz to 7 mg/oz.
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[0057] In other preferred embodiments, the enhanced caffeinated drink (e.g.,
coffee, tea, cola, or
an energy drink) has a caffeine content in milligrams per ounce (mg/oz) of
between about 1
mg/oz to 65 mg/oz (0.03 mg/ml to 2.2 mg/ml). For example, the caffeinated
drink has a caffeine
content of between about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15,
16, 17, 18, 19, 20, 21, 22,
23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41,
42, 43, 44, 45, 46, 47, 48,
49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, or 65 mg/oz.
Typically, the
caffeinated drink has a caffeine content of between about 10 mg/oz to 65
mg/oz, 15 mg/oz to 65
mg/oz, 20 mg/oz to 65 mg/oz. More typically, the caffeinated drink has a
caffeine content of
between about 10 mg/oz to 25 mg/oz.
[0058] In some embodiments, an enhanced caffeinated beverage is a coffee drink
supplemented
with the disclosed effective blend of theacrine and methylliberine. As
disclosed herein, the
coffee drink may be hot or cold brewed and may be a non-espresso brewed coffee
or an espresso
brewed coffee having a caffeine content of between about 1 mg/oz to 65 mg/oz.
For espresso
brewed coffee, the caffeine content is more typically about 40 to 65 mg/oz for
a volume of not
more than 3 ounces. For example, for an espresso coffee drink, the caffeine
content is about 40
to 65 mg/oz with a total weight amount of both theacrine and methylliberine of
about 15 to 30
mg/oz, e.g., 15-20 mg/oz for a 3.0 oz espresso or about 20-30 mg/oz for a 2 oz
espresso. An
espresso drink is typically not more than 3 oz and may also be 2 oz. For a non-
espresso brewed
coffee, the caffeine content is more typically about 10 to 30 mg/oz, 10 to 25
mg/oz, 10 to 20
mg/oz, or 15 to 25 mg/oz. Preferably, the coffee drink is supplemented with
the disclosed
effective blend of theacrine in an amount of between about 1.5 mg/oz to 15
mg/oz and
methylliberine in an amount of between about 3.0 mg/oz to 30 mg/oz. More
preferably, the
coffee drink is supplemented with the disclosed effective blend of theacrine
in an amount of
between about 1.5 mg/oz to 15 mg/oz, 1.5 mg/oz to 10 mg/oz, or 1.5 mg/oz to
5.0 mg/oz, and the
methylliberine is added in an amount of between about 3.0 mg/oz to 30 mg/oz,
3.0 mg/oz to 20.0
mg/oz, or 3 mg/oz to 15 mg/oz. In an exemplary embodiment, the coffee drink is
supplemented
with the disclosed effective blend of theacrine in an amount of between about
1.5 mg/oz to 15
mg/oz and methylliberine in an amount of between about 3.0 mg/oz to 30 mg/oz,
wherein the
theacrine and methylliberine are present in a weight ratio of between about
1:1.5 to 1:2.75.
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[0059] As understood by skilled person, the effective blend disclosed herein
of theacrine and
methylliberine refers to the ratio of theacrine and methylliberine; however,
the addition of
theacrine and methylliberine to the brewed coffee may be carried out
sequentially. That is, the
effect of the combination of theacrine and methylliberine does not require
that the theacrine and
methylliberine ingredients are mixed prior to addition to the brewed coffee.
Accordingly,
methods for preparing the enhanced coffee beverage include supplementing the
brewed coffee or
coffee grounds with theacrine and methylliberine using any suitable method. In
some
embodiments, theacrine and methylliberine are added either sequentially or
concurrently to
brewed coffee. The theacrine and methylliberine may be added to a single
serving of brewed
coffee or may be added to a large stock of brewed coffee that is then served
or packaged into
smaller volumes. In other embodiments, one or both of the theacrine and
methylliberine are
added to the coffee grounds prior to the brewing process.
[0060] With reference to FIGS. 13A to 13H, results of a trial of volunteers
consuming the
enhance coffee beverage with 50 mg methylliberine and 25 mg theacrine showed
increased
mood (FIG. 13A), energy (FIG. 13B), motivation (FIG. 13C), alertness (FIG.
13D), decreased
fatigue (FIG. 13E), and increased focus (FIG. 13F) as measured using a visual
analogue scale
(VAS) assessment as disclosed herein, compared to the reported effects after
consumption of a
decaffeinated coffee beverage, caffeinated coffee, coffee with 50 mg
methylliberine, or coffee
with 100 mg methylliberine. Accordingly, as shown in FIGS. 13A-13F, a
caffeinated beverage
(e.g., coffee) supplemented with the effective blend of theacrine and
methylliberine, upon
consumption by a person, increases mood, energy, alertness, motivation, and/or
focus in the
person compared to the caffeinated beverage alone or the caffeinated beverage
supplemented
only with methylliberine at 50 mg alone or 100 mg alone, or about 6 mg/oz or
12.5 mg/oz,
respectively.
[0061] The increase in mood refers to an increase in a positive mood in which
the person
experiences increased content. The effects on mood, energy, alertness, focus,
motivation, and/or
decreased fatigue are observed at least as soon as 60 minutes after
consumption of the enhance
coffee beverage and may be experienced up to 5 hours (i.e., 300 minutes) after
consumption.
Not all effects may be experienced at the same time for the same duration. In
typical
embodiments, the effects on increased mood, energy, alertness, focus,
motivation, and/or
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decreased fatigue are experienced at least as soon as 60 minutes from
consumption up to 90
minutes, 2 hours, 2.5 hours, 3 hours, 3.5 hours, 4 hours, 4.5 hours, or 5
hours after consumption.
In more typical embodiments, the effects on increased mood, energy, alertness,
focus,
motivation, and/or decreased fatigue are experienced at least as soon as 60
minutes from
consumption up to 4 hours. In most typical embodiments, the effects on
increased mood,
energy, alertness, focus, motivation, and/or decreased fatigue are experienced
at least as soon as
60 minutes from consumption up to 3 hours (180 minutes).
[0062] Furthermore, with reference to FIGS. 14A-14F, blood pressure (systolic
and diabolic),
heart rate, rate pressure product, mean arterial pressure, and pulse pressure
showed no adverse
effects, and in some cases were tempered relative to coffee supplemented with
methylliberine
alone. Accordingly, a caffeinated beverage (e.g., coffee) supplemented with
the effective blend
of theacrine and methylliberine, upon consumption by a person, increases mood,
energy,
alertness, motivation, and/or focus without adversely affecting blood pressure
(systolic and
diabolic), heart rate, rate pressure product, mean arterial pressure, and
pulse pressure in the
person.
[0063] In one embodiment, theacrine may be combined with other chemical
compounds to
provide a plurality of positive effects on a human or other animal. By
altering the dosage of
theacrine and/or chemical compounds it is combined with, various physiological
effects may be
selected for. The compositions may provide primarily a single benefit, or may
provide multiple
benefits simultaneously.
[0064] In another embodiment, theacrine may be used at lower dosage levels
and/or in
conjunction with compounds that modulate or antagonize its activity. Such
compositions may
induce an improved mood, higher energy, a reduction in fatigue, increased
focus, increased
concentration, increased mobility, decreased appetite, and increased stamina.
[0065] An advantage of using the invention may be the reduced likelihood that
a person
develops a tolerance to chemical compositions in accordance with the
principles of the invention.
That is, a person may not become desensitized to the effects induced.
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[0066] In another embodiment, theacrine may be used at higher dosage levels
and/or with
synergistic compounds. These compositions may increase a person's
basal/resting metabolic rate,
increase thermogenesis, decrease appetite, enhance cognitive performance,
increase Alpha wave
brain activity, and/or induce euphoria. Without being bound by theory, the
inventors believe that
at higher dosage levels, theacrine may be noradrenergic and dopaminergic, and
may exhibit
increased adenosine receptor inhibition.
[0067] In another embodiment of the invention, theacrine may be combined with
ephedrine,
caffeine, salicylic acid or the like. These may be used to either modulate the
more sedative
effects of theacrine or optionally to interact synergistically with the more
stimulating effects of
theacrine. For example, theacrine may be combined with caffeine in order to
modulate the
excessive stimulatory effects of caffeine, thereby stabilizing heart rate and
other metabolic
activity. That is, a combination of theacrine and caffeine may result in a
composition that imparts
the increased focus and energy induced by caffeine, but without the higher
heart rate and blood
pressure due to modulation of caffeine by theacrine. Thus the combination may
result in
heightened awareness and calmness without the jitters caffeine may cause.
[0068] Theacrine and caffeine administered in combination has unexpected
effects. Indeed, it
has been unexpectedly found that a combination of theacrine and caffeine
administered to human
subjects results in increased levels of focus, concentration and energy as
measured by 100 mm
VAS scales while also decreasing measures of anxiety, irritability or feelings
of overstimulation.
Such decrease in anxiety, irritability, jitters and/or feelings of
overstimulation is reflected by
patients on standardized 100 mm VAS at durations of 30 minutes, 60 minutes,
120 minutes and
180 minutes as compared with administration of caffeine alone. The combination
also exhibits a
prolonged duration of action in increased energy, focus and/or concentration
as compared to
either caffeine or theacrine alone.
[0069] Furthermore, theacrine also has unexpected effects on the development
of tolerance and
habituation of caffeine. In a fourteen day study of repetitive dosing of
theacrine and caffeine, it
was found that the subjects maintained heightened psychometric indices of
energy, focus,
concentration, motivation to exercise, motivation to accomplish and finished
tasks, and improved
mood at Day 14 as compared to caffeine alone, and absolute levels of energy
and motivation
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were greater than with theacrine alone. Those taking theacrine alone still
maintained elevated
subjective energy, focus, concentration, motivation to exercise, motivation to
accomplish and
finish tasks, sexual desire and improved mood with decreased anxiety as
compared to Day 1.
Subjects taking caffeine alone saw decreasing levels of energy, focus and
concentration by Day 5
of the study and had increased anxiety scores throughout the study.
[0070] In another embodiment of the invention, theacrine may be combined with
one or more
bioavailability enhancers, including for example bioperine, piperine, black
pepper, bergamottin,
dihydroxybergamottin (CYP3A4 inhibitors), flavonoids (including hesperidin,
naringin,
tangeritin, quercetin and nobiletin both in isolation and in combination),
pterostilbenes, fisetin,
nanoencapsulation, microencapsulation, liposomes and/or phytosomes. Which
enhancers are
combined with theacrine may depend on which qualities of theacrine are desired
for a particular
use.
[0071] In another embodiment of the invention, theacrine may be introduced
using one or more
delivery methods, including, for example transdermal patches and/or creams,
ready to mix
powders, intravenous methods, capsules, tablets, liquid (including liquids for
mixing with other
beverages), softgels, shot format, and/or cosmetic applications including
soaps, lotions and
shampoos. Theacrine's anti-inflammatory qualities may be desired for a variety
of topical
applications.
[0072] In another embodiment of the invention, theacrine may be used to
provide sports
performance enhancers that may reduce fatigue, improve mobility, and improve
alertness.
[0073] In another embodiment of the invention, theacrine may be used as a
topical agent for
incorporation into body creams or lotions to produce a cream or lotion for
lightening skin,
firming skin, and/or improving skin elasticity. A theacrine topical agent may
also be used to
promote localized transdermal fat loss. Theacrine may also be used in a cream
or lotion to
promote localized enhanced metabolism and/or enhanced thermogenesis.
[0074] In another embodiment of the invention, theacrine may be combined with
one or more of
an analgesic, for example ibuprofen or salicylic acid, anti-inflammatory
agents, salicin, fish oil
(omega-3 fatty acids and specialized, small lipid pro-resolving derivatives),
tart cherry, krill oil,
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astaxanthin, proteolytic enzymes, glucosamine sulfate, chondroitin sulfate,
MSM (methyl
sulfonylmethane), SAMe (S-adenosylmethionine), ASU (avocado-soybean
unsapponifiable
fraction), cetyl myristoleate, Dolichos falcate and/or triterpenoids.
[0075] Theacrine itself can reduce biomarkers of inflammation in humans in
response to acute
inflammatory stressors (e.g., intense exercise) or chronic consumption.
Theacrine is shown to
decrease C-reactive protein (CRP), Erythrocyte sedimentation rate (ESR),
interleukin-6 (IL-6)
and TNF-alpha.
[0076] In another embodiment of the invention, theacrine may be combined with
extracts from
one or more of Acacia catechu, Andrographis paniculata, Scutalleria
baicalensis, agmatine
sulfate, Stinging Nettle, Sea Buckthorn, curcumin, Cissus Quadrilangularis,
Boswellia Serrata,
Wasabia japonica (wasabi extract for Tea Tree Oil), Emu Oil, Arnica, Mangifera
indica L.
(Anacardiaceae), Lagenaria breviflora, and/or Zingiber officinale (ginger &
gingerols/shogaols).
Such a combination may be used in, for example, methods of augmenting and
enhancing pain
modulation, and controlling the inflammatory response.
[0077] In another embodiment of the invention, theacrine may be combined with
one or more
metabolic enhancers including Hoodia gordonii, caffeine, yohimbine,
synephrine, theobromine,
flavonoids, flavanone glycosides such as naringin and hesperidin, tocopherols,
theophylline,
alpha-yohimbine, conjugated linoleic acid (CLA), octopamine, evodiamine,
passion flower, red
pepper, cayenne, raspberry ketone, guggul, green tea, guarana, kola nut, any
beta-
phenethylamines, Acacia rigidula, and/or forskolin (Coleus forskohlli). Such a
combination may
be used in, for example, methods of enhancing 1) thermogenesis/fat and
carbohydrate
metabolism; 2) fat loss, weight management and improving body composition
(loss of body fat,
while retaining or sparing lean body mass/fat free mass/muscle); and/or 3)
appetite
control/appetite modulation.
[0078] Combinations of theacrine and, for example, caffeine, theobromine, or
flavanone
glycosides such as naringin or hesperidin, upon administration to subjects
show decreased VAS
100 mm ratings of perceived physical exertion with exercise as compared to
ingredients alone.
Theobromine is used by some for improvement of breathing or a subjective
feeling of improved
breathing, but is also known to increase feelings of anxiety, jitters and an
elevated heart rate in
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some subjects. A combination of theobromine and theacrine retains the
beneficial effects while
reducing the unwanted anxiety, jitters and/or elevated heart rate effects.
[0079] In another embodiment of the invention, theacrine may be combined with
anti-fatigue,
focusing and/or energy enhancing ingredients including caffeine, theobromine,
theophylline,
synephrine, yohimbine, rhodiola, ashwagandha, ginseng, Ginkgo biloba, siberian
ginseng,
astragalus, licorice, green tea, reishi, dehydroepiandrosterone (DHEA),
pregnenolone, tyrosine,
N-acetyl-tyrosine, glucuronolactone, taurine, choline, CDP-choline, alpha-GPC,
acetyl-L-
carnitine, 5-hydroxytryptophan, tryptophan, any beta-phenethylamines,
Sceletium tortuosum
(and Mesembrine alkaloids), Dendrobium sp., Acacia rigidula, PQQ
(Pyroloquinoline quinone),
Ubiquinone(o1), nicotinamide riboside, picamilon, Huperzine A (Chinese
clubmoss) or Huperzia
serrata, L-dopa, Mucuna pruriens, forskolin (Coleus forskohlli). Such a
combination may be used
in, for example, methods for enhancing cognitive function, including focus,
concentration,
sustained attention, working memory, choice and non-choice reaction time,
executive function,
verbal and non-verbal learning, visuospatial memory and verbal fluency.
[0080] In a further embodiment, theacrine may be combined with a nutritional
cholinergic
ingredient such as 2-(dimethylamino)ethanol (DMAE), DMAE bitartrate, choline
bitartrate,
alpha-GPC (alpha-glycerophosphorylcholine), Huperzine A, CDP choline, or
combinations
thereof. One of skill in the art will recognize that these are merely examples
of cholinergic
ingredients and that other such cholinergic ingredients not listed are also
contemplated by the
present invention. The combination of a nutritional cholinergic ingredient
with theacrine can
result in a synergistic effect of increased psychometric measures for
attention, focus and
concentration beyond either the theacrine alone or cholinergic ingredient
alone.
[0081] In another embodiment, any of the above combinations may be used with
an isomer of,
congener of, derivative of and/or a metabolite of theacrine such as, for
example, liberine or
methylliberine. Other suitable examples include methylated theacrine, nitrate
salts of theacrine,
oxidized theacrine, reduced theacrine and/or theacrine salts. Agglomerated
theacrine,
microencapsulated theacrine, liposomal theacrine, esterified theacrine,
theacrine glycerides, and
mixtures of theacrine with propylene glycol, lauroyl Macrogol, polyethylene
glycol, theacrine
derivatives, and/or theacrine co-crystallization products may also be used in
accordance with the
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principles of the invention. Such use of these, as well as co-crystals or
other conjugates (such as
quercetin or pterostilbenoids), theacrine salts including citrate, salicylate,
malate, tartrate,
fumarate, succinate, nitrate, sulfate, phosphate and the like, or PEG-ylated
(Macrogol)
preparations may increase the functional efficacy of the theacrine.
[0082] In another embodiment, congeners of theacrine, for example catechins
and other
flavonoids, may be used an isolated, either independently or in combination
with theacrine-based
compositions.
[0083] The dosage of theacrine may range from about 5 mg to about 850 mg. In
another
embodiment, the range may be from about 65 mg to about 300 mg. In relation to
the weight of
the human subject, in one embodiment the dosage may be expressed as about 0.75
mg/kg of
body weight to about 3 mg/kg of body weight. In initial trials the human ED90
appears to be
about 1 mg/kg to about 3 mg/kg.
[0084] In one aspect of the invention, the theacrine may be administered with
caffeine. When
administered with caffeine, the ratio of caffeine to theacrine, weight to
weight, may range from
about 0.5:1 to about 50:1, and in another embodiment, from about 1:1 to about
10:1, and in a
further embodiment, from about 2:1 to about 4:1. In administration, the
theacrine may be
administered in an amount of about 5 mg to about 800 mg with caffeine amounts
ranging from
about 25 mg to about 650 mg. In another embodiment the theacrine may be
administered in an
amount of about 5 mg to about 650 mg with the caffeine, and in other
embodiments may be any
amount in that range. Such administration provides an increase, as measured by
100 mm VAS
scales, in at least one of focus, concentration and energy, while also
providing a decrease in at
least one of anxiety, irritability, and feelings of overstimulation.
Recommended dosages
expressed in terms of amount per body weight can range from about 0.75 mg/kg
to about 3
mg/kg of theacrine when administered in combination with caffeine, although
theacrine may be
administered in the ranges described above up to about 850 mg regardless of
whether it is
administered in combination with caffeine.
[0085] The invention may be used for the treatment of a variety of conditions,
such as
improvement of mood, energy, focus, or concentration. The invention may also
promote a
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reduced appetite, reduce the perceived exertion from exercise, decrease the
discomfort associated
with intense exercise, and may also improve sexual desire.
[0086] The discussion herein provides many example embodiments of the
inventive subject
matter. Although each embodiment represents a single combination of inventive
elements, the
inventive subject matter is considered to include all possible combinations of
the disclosed
elements. Thus, if one embodiment comprises elements A, B, and C, and a second
embodiment
comprises elements B and D, then the inventive subject matter is also
considered to include other
remaining combinations of A, B, C, or D, even if not explicitly disclosed.
[0087] In some embodiments, the numbers expressing quantities of ingredients,
properties such
as concentration, reaction conditions, and so forth, used to describe and
claim certain
embodiments of the invention are to be understood as being modified in some
instances by the
term "about." Accordingly, in some embodiments, the numerical parameters set
forth in the
written description and attached claims are approximations that can vary
depending upon the
desired properties sought to be obtained by a particular embodiment. In some
embodiments, the
numerical parameters should be construed in light of the number of reported
significant digits
and by applying ordinary rounding techniques. Notwithstanding that the
numerical ranges and
parameters setting forth the broad scope of some embodiments of the invention
are
approximations, the numerical values set forth in the specific examples are
reported as precisely
as practicable. The numerical values presented in some embodiments of the
invention may
contain certain errors necessarily resulting from the standard deviation found
in their respective
testing measurements.
[0088] As used in the description herein and throughout the claims that
follow, the meaning of
"a," "an," and "the" includes plural reference unless the context clearly
dictates otherwise. Also,
as used in the description herein, the meaning of "in" includes "in" and "on"
unless the context
clearly dictates otherwise.
[0089] Unless the context dictates the contrary, all ranges set forth herein
should be interpreted
as being inclusive of their endpoints and open-ended ranges should be
interpreted to include only
commercially practical values. Similarly, all lists of values should be
considered as inclusive of
intermediate values unless the context indicates the contrary.
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[0090] Furthermore, the recitation of ranges of values herein is merely
intended to serve as a
shorthand method of referring individually to each separate value falling
within the range.
Unless otherwise indicated herein, each individual value with a range is
incorporated into the
specification as if it were individually recited herein. All methods described
herein can be
performed in any suitable order unless otherwise indicated herein or otherwise
clearly
contradicted by context. The use of any and all examples, or exemplary
language (e.g. "such
as") provided with respect to certain embodiments herein is intended merely to
better illuminate
the invention and does not pose a limitation on the scope of the invention
otherwise claimed. No
language in the specification should be construed as indicating any non-
claimed element
essential to the practice of the invention.
[0091] Groupings of alternative elements or embodiments of the invention
disclosed herein are
not to be construed as limitations. Each group member can be referred to and
claimed
individually or in any combination with other members of the group or other
elements found
herein. One or more members of a group can be included in, or deleted from, a
group for reasons
of convenience and/or patentability. When any such inclusion or deletion
occurs, the
specification is herein deemed to contain the group as modified thus
fulfilling the written
description of all Markush groups used in the appended claims.
[0092] It should be apparent to those skilled in the art that many more
modifications besides
those already described are possible without departing from the inventive
concepts herein. The
inventive subject matter, therefore, is not to be restricted except in the
spirit of the appended
claims. Moreover, in interpreting both the specification and the claims, all
terms should be
interpreted in the broadest possible manner consistent with the context. In
particular, the terms
"comprises" and "comprising" should be interpreted as referring to elements,
components, or
steps in a non-exclusive manner, indicating that the referenced elements,
components, or steps
may be present, or utilized, or combined with other elements, components, or
steps that are not
expressly referenced. Where the specification claims refers to at least one of
something selected
from the group consisting of A, B, C ... and N, the text should be interpreted
as requiring only
one element from the group, not A plus N, or B plus N, etc.
EXAMPLES
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[0093] Example 1
[0094] In order to examine the beneficial experiential effects and
psychometric properties of
theacrine supplementation in healthy subjects, explore optimal dosing and
potential cumulative
effects in a healthy human cohort with a 7-day, sub-acute repetitive dosing
protocol, and acquire
preliminary data on various biomarkers of safety and tolerability, an
experiment was performed.
[0095] 15 healthy subjects (mean +SD age, height, wgt, BMI: 28.3 +6.1 y, 175.7
+11.5 cm,
89.8 +21.7 kg, 29.1 +4.7) ingested 200 mg of TeaCrineTm(Compound Solutions,
Inc., Carlsbad,
Calif.) (TC) or Placebo (PLA). Anchored VAS questionnaires were used to detect
changes in
various aspects of physical and mental energy and performance; side effect
profiles,
hemodynamics and biochemical markers of safety were also collected over a 3-hr
post-dosing
period. A subset of 6 subjects underwent a separate 7-day, open-label,
repeated dose study
comparing 100 mg, 200 mg and 400 mg of TC.
[0096] The experiment was a randomized, placebo-controlled, double-blind,
within-subject
crossover clinical trial (for N=15 study). A further subset study was open-
label, sub-acute (7-
day), repetitive dosing trial (for N=6 subset).
[0097] Six (6) subjects provided written and dated informed consent to
participate in the 7-day
repetitive dosing study between Dec. 15, 2012 and Feb. 21, 2013. A separate
cohort of fifteen
(15) subjects provided written and dated informed consent for the acute dose,
placebo-controlled,
crossover clinical trial. All subjects were in good health as determined by
physical examination
and medical history, between the ages of 18 and 45 (inclusive). Subjects'
caffeine intake from
foods/beverages was limited to <300 mg daily. Subjects were willing and able
to comply with
the experimental and supplement protocol.
[0098] Excluded subjects included subjects who were pregnant or lactating,
subjects with a
history of hepatorenal, musculoskeletal, autoimmune, or neurologic disease,
diabetes, thyroid
disease, adrenal disease, hypogonadism, inborn error of metabolism, personal
history of heart
disease, high blood pressure (systolic >140 mm Hg & diastolic >90 mm Hg),
psychiatric
disorders, cancer, benign prostate hypertrophy, caffeine sensitivity, gastric
ulcer, reflux disease,
or any other medical condition deemed exclusionary by the medical staff,
subjects currently
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taking thyroid, hyperlipidemic, hypoglycemic, anti-hypertensive, anti-
coagulant medications or
OTC products containing pseudoephedrine or other stimulants, subjects who had
used any
weight-loss supplements within 30-days prior to the study, subjects who had
gained or lost more
than 10 lbs within the past 30 days, subjects who drank more than one cup of
percolated coffee
or 2 cups of tea per day, subjects who smoked or had quit smoking within the
past six months,
subjects who had a known allergy to any of the ingredients in the supplement
or the placebo, and
subjects who did not demonstrate a verbal understanding of the Informed
Consent document.
[0099] Physical activity levels and health history were determined using
standardized
questionnaires. Heart rate and blood pressure were measured using an Omron HEM-
780.
Standing height was determined using a wall-mounted stadiometer. Body weight
was measured
using a Seca 767.TM. Medical Scale. A 100 mm anchored VAS questionnaire for
energy,
fatigue, and concentration was distributed at each acute lab session;
additional VAS
questionnaires were distributed for the daily assessment over a 6-hour period
during the 7-day
subset study. Quest Diagnostics (Pittsburgh, Pa.) was utilized to transport
and analyze all blood
samples. For each laboratory session, subjects reported to the lab well
hydrated, 10-12 hours
postprandial, and at least 24-hours after their last exercise session.
[00100] Statistical Analyses for Example 1. Descriptive statistics (mean,
median, SD, 95%
CIs) were used to quantify subjects physical characteristics. RM ANOVA, as
well analyses of
co-variance (ANCOVA), using baseline scores as the co-variate (respectively),
were used to
analyze between trial differences. Alpha was set to 0.05 (P.1toreqØ05) for
statistical
significance, and <0.10 for trends. Effect sizes were also calculated. Upon
arrival for the first
testing session, subjects were randomly assigned to receive their respective
supplement/placebo.
Each subject ingested the sponsor recommended dosage of their respective
supplement (1
capsule prior to schedule of assessments). Supplements were prepared in
capsule form and
packaged in coded generic containers for double-blind administration.
[00101] The 200 mg dose of TC caused significant improvements in energy (TC:
+8.6% vs.
PLA: -5.7%, P=0.049) and reductions in fatigue (TC: -6.7% vs. PLA: +5.8%,
P=0.04). A trend
for improved concentration was also noted (TC: +2.4% vs. PLA: -1.3%, P=0.07).
No changes in
systemic hemodynamics or side effect profiles were noted. The N=6 cohort study
demonstrated
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moderate to large effect sizes (0.50 to 0.71) with the 200 mg dose of TC over
a 7-day period of
assessment for the following subjective measures: energy, fatigue,
concentration, anxiety,
motivation to exercise and libido.
[00102] The results of the experiment are also shown graphically in FIGS. 2
through 7.
[00103] As shown in FIG. 2, individuals who were administered theacrine
reported higher
levels of energy at each time increment measured. FIG. 3 shows that while
individuals given the
placebo reported higher fatigue at 60 minutes after administration, those
administered theacrine
reported lower levels of fatigue. FIGS. 4 and 5 show that no substantial
change in systemic
hemodynamics occurred.
[00104] FIGS. 6 and 7 show the results of the N=6 cohort study. With a 200 mg
dose of
theacrine over a 7 day period of assessment, it was observed that theacrine
has a positive effect
on each of energy, fatigue, concentration, anxiety, motivation to exercise,
and libido. That is,
fatigue and anxiety were decreased substantially, while energy, concentration,
motivation to
exercise and libido were increased substantially.
[00105] Thus, the experimental data shows that theacrine supplementation
appears to
favorably impact several subjective and psychometric indices of energy and
fatigue. These
findings, as well as the potential cumulative effects on focus, concentration,
and libido are
worthy of future study.
[00106] Although previously published animal data suggested much larger doses
of "TC"
would be necessary to exert its neurophysiological effects, this first-in-
human data suggests
much lower doses of 1.5 mg to 2.5 mg/kg bodyweight (for example, approximately
200 mg in a
100 kg individual) provide optimal benefit. Follow-up studies should confirm
these results,
explore other objective measures of physical and cognitive function, and
clarify the mechanisms
by which theacrine exerts the observed salutary effects.
[00107] Assessment of the Drug-Drug Interaction Potential Between Theacrine
and Caffeine
in Humans
[00108] Example 2
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[00109] Theacrine pharmacokinetics in humans has not been systematically
characterized.
Therefore, one purpose of this study, among others, was to determine theacrine
pharmacokinetics
and dose-linearity following oral administration in humans. Another purpose of
this study is to
determine whether or not caffeine alters theacrine pharmacokinetics and/or
pharmacodynamics,
when both ingredients are ingested together.
[00110] Eight healthy nonsmokers, including 4 men and 4 women, were recruited
for the
experiment. The test subjects regularly consumed stimulants (i.e., caffeine,
50-400 mg/day) with
beverages or nutritional supplements. The same test subjects did not have a
history of adverse
reactions to caffeine or other stimulants.
[00111] Study Design and Procedures. This study was a randomized, double-
blind, 4-arm
crossover design with each subject receiving 4 treatments consisting of
theacrine (25 mg),
theacrine (125 mg), caffeine (150 mg), and theacrine (125 mg) plus caffeine
(150 mg),
respectively. Theacrine, administered as iTeaCrine®, was provided by
Compound Solutions
(Carlsbad, Calif). Caffeine, administered as caffeine anhydrous, was obtained
from Nutravative
Ingredients (Allen, Tex.). Treatment sequence was randomized using a 4×4
Latin square.
There was an approximate 1-week washout period between treatments for all
subjects.
[00112] Test Visit Procedures. Each study day, subjects reported to the lab
between 6:00 and
7:00 am after a 10-hour fast and abstinence from beverages, drugs, or
supplements containing
alcohol or caffeine (72-hours) and strenuous physical exercise (24-hours). A
catheter was
inserted into the forearm vein for blood sampling. Duplicate measurements of
resting heart rate
and blood pressure were taken pre-dose and prior to each timed blood sample.
In addition,
respiratory rate was counted in one minute and body temperature was measured
using an ear
scanning thermometer (dual readings taken at each time). At approximately 8:00
am, each
subject received a single oral dose of a theacrine, caffeine, or combined
theacrine-caffeine
composition accompanied by water. Blood samples at 0 minute (5 samples
obtained for baseline
prior to administration of the oral compositions), 15 minutes, 30 minutes, 60
minutes, and 90
minutes, and 2, 4, 6, 8, and 24 hours post-administration. Collected samples
were processed and
stored in multiple aliquots (.about.500 [tL, -70° C.) until analyzed
for theacrine, caffeine,
and paraxanthine using LC-MS/MS.
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[00113] All subjects were instructed to consume their usual diet throughout
the study period,
with the exception of the actual days of testing. During the two days prior to
each test day,
subjects recorded all food and drink consumed and attempted to mimic this
intake for the two-
day period prior to subsequent visits. Diet records were analyzed using
nutrient analysis software
(Food Processor SQL, version 9.9; ESHA Research, Salem, Oreg.). For the actual
test days,
standardized meals (meal replacement food bars [Clif "Builder's 20 g Protein
Bar"] and ready-to-
drink shakes [Orgain Organic NutritionTm]) were provided to the subjects after
sample collection
at hour 2 and hour 6 (one shake and one-half bar at each time). Subjects were
also provided with
adequate meal replacement bars and shakes to consume following the 8 hour
sample collection.
(during their time outside the lab). Each bar contained 280 calories, 10 grams
of fat, 29 grams of
carbohydrate, and 20 grams of protein. Each shake contained 250 calories, 7
grams of fat, 32
grams of carbohydrate, and 16 grams of protein. No food other than what was
provided to the
subjects was allowed during each study day, including both time spent in the
lab and outside the
lab. The only beverage that the subjects were allowed to consume was water and
the volume
consumed while in the lab was matched for each test day (men: 94 +25 ounces;
women: 78 +17
ounces). The subjects returned the following morning for the 24 hour blood
collection, again in a
hour fasted state. The same volume of meal replacement bars or shakes was
consumed by
each subject during each visit (both in lab and outside lab). All the subjects
except one female
consumed 3 shakes and 3 bars during the period of time outside the lab. Said
female subject only
consumed 2 bars and 2 shakes. Physical activity remained similar for all the
subjects throughout
the study period, with the exception of refraining from strenuous physical
activity during the 24-
hour period prior to each test day and for the actual test day itself.
[00114] Pharmacokinetic Study. Plasma concentration-time data were evaluated
using
noncompartmental methods in Phoenix WinNonlin (version 7.0; Pharsight
Corporation,
Mountain View, Calif.) with adjustment for lag time after oral administration.
The maximum
concentration (C.), lag time (tfrig), and time of maximum concentration (t.)
were determined
from the plasma concentration versus time data. The area under the plasma
concentration-time
curve from time 0 to infinity (was calculated using the trapezoidal rule
extrapolated to time
infinity). The terminal half-life (tv2) was calculated using the following
function: ti/2=0.693/k,
wherein k is the constant of terminal rate elimination estimated from the
slope of the linear
portion of the log plasma concentration versus time curve. The oral clearance
(CL/F) was
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calculated by dividing the oral dose by AUG)-00. The apparent volume of
distribution during the
terminal elimination phase (Vz/F) was calculated by dividing CL/F by k.
[00115] Statistical Analysis for Example 2. Differences between treatment
group values were
determined for systolic blood pressure (SBP), diastolic blood pressure (DBP),
rate pressure
product, and heart rate. Parametric data were analyzed by paired Student's t
tests of mean
differences in values between treatment groups. Statistical significance was
defined a priori as a
2-sided or <0.05. The probability of interaction magnitude between theacrine
and caffeine was
determined using 90% confidence intervals about the geometric mean ratio of
the observed
pharmacokinetic parameters.
[00116] Results. Subject characteristics. Eight physically active and healthy
men (n=4; age
34.5 +7.0 years; weight 94.3 +13.1 kg) and women (n=4; age 22.5 +3.9 years;
weight 66.4
+10.1 kg) completed this study. Men ingested a daily amount of caffeine equal
to 143.8 +168.7
mg, while women ingested 144.3 +139.7 mg. All the subjects tolerated the
treatments well and
no adverse events were noted. Dietary intake was not different across
treatment conditions for
calories, macronutrients, or micronutrients (p>0.05).
[00117] Pharmacokinetics. Mean plasma concentration time profiles for
theacrine, caffeine,
and paraxanthine are shown in FIGS. 8, 9, and 10. Theacrine is well absorbed
following oral
administration of theacrine alone reaching maximal concentration within
approximately 2 hours.
Dose-adjusted theacrine pharmacokinetic parameters were not significantly
different (Table 1).
Theacrine absorption rate (T.) and half-life (ti/2) were unaffected by
caffeine co-administration.
However, caffeine co-administration significantly increased both mean
theacrine exposure
parameters Cmax, (38.6 +16.6 versus 25.6 +5.5 ng/mL) and AUC (1.2 +1.1 versus
0.74 +0.31
hr*[tg/mL/mg) as well as geometric mean ratios (1.1 +0.06 and 1.1 +0.03)
(Table 2). Moreover,
caffeine decreased both theacrine oral clearance (CL/F, 1.6 +0.49 versus 1.2.
+0.56 L/hr) and
oral volume of distribution (Vd/F, 50.5 +0.49 versus 35.4 +12.4 L) by
approximately 30%. Of
note, theacrine exposure (AUC) was consistently higher in Subject 8 than all
other subjects in all
treatment arms. However, caffeine pharmacokinetics in Subject 8 was similar to
the other seven
subjects. Caffeine pharmacokinetics is similar following caffeine alone or
caffeine plus theacrine
co-ingestion (FIGS. 10 and 11 and Table 2). Likewise, theacrine co-ingestion
did not alter
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paraxanthine exposure parameters suggesting caffeine metabolism was unaffected
by theacrine
(Table 3).
[00118] TABLE 1
Theaaine Plumacokinetics
Panunetee Condition I 2:c Condition 44
(flgituL) 34.1 38.9 .25.6 *5.5 373
16,5
choun) 1.8 015-6,0 1,8 (1,0-4õ0) 1,0 (0,3-2.Q)
11/2 *muss) 16.5 tz 2.4 2J 117 29,2
253
Mir (hr * rigirriL'img) a09 zt.: 92.3 736 Az M.2 1,24.2
I.: 10.29
.CI.LF (UM 10 It 89 1,6 t 03 Ii O6
VdiF (L) 48.1 234 51.0 8.5 354 124
MAT (hours) 24S) st .36,8 18,9 41-7 38A
=
'*1-....õ,..vakw,I= extuewd.,;.0 mediae (wage), AI/ other ViikleS= stiv
expres-wd meau . SD
and repaiwnt desti-aditsted pharauftvkinetie peramtem.
brheaeritie 25 mg
'Themilat 125 mg
411mo-ix t.25 x.rig + Caffeine 1.50 mg
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[00119] TABLE 2
=
CairCine Pharruoki Wks
Panmetee Condition 36' Condition 4'
(4'ml) 33.4 .37.4 t. 1L8
frõ,õõ t,tiours) 0.8 (0.54.5) 1.0 (134.5)
4:1,2 (how) 6.2 t 3. 55t22
AIX (hr niOntiffig) 2610 t 74.1 323 I: 209
CLIF (1..thr) 4A t 1.1. 43 t
Vd.IF (L) 33.5 t 133 30.2 114
MRT (hour 0 8,4 4,3 8,0 3,2
val.N4 1I1Cdiala (lauge),
Qtilicx vk&Q exp.rmed a$.; mean SD
ajida-q.igcw.nt dowattitmettpbannacokinclig pmametus,
'Calkiiie 150 mg
qfienaine 125 mg + Caffeine 150 m.g
[00120] TABLE 3
_____________________________________________________________________ w
Paraxanthine Pharmacokinoties
Parametef Condition 3'4 Condition 4'
Oglatt) 7,3 t 1_5 8,4 15
Choum,) 5,0 (4k04,0) 7.0
Olows) 123 123 14.8 1:-.=1 73
AUC atr 174 152 209 -4- 201
mu (hours) 19.1 t 18.6 21.7 t
vdms art, wtpretmd ;as imam (Imago; All other values exprewed Olt:MR SD
..and remewitf. close-adjusted pharmaeokinetie, parameters,
'Caffeine 150m*
'Theacrint 125 mg + Caffeine 150 mg
[00121] Pharmacodynamics. Hemodynamic parameters such as blood pressure and
heart rate
are elevated following co-administration of caffeine and other stimulants such
as ephedrine. To
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determine the potential for a pharmacodynamics interaction between theacrine
and caffeine, we
evaluated systolic and diastolic blood pressure, heart rate, and rate pressure
product following
administration of both theacrine (25 mg and 125 mg) and caffeine (150 mg)
alone and in
combination (theacrine 125 mg plus caffeine 150 mg). Heart rate decreased
slightly over the first
two hours following administration for each of the four conditions returning
to baseline by 24
hours post-ingestion (FIG. 12A). Systolic/diastolic blood pressure and rate
pressure product
remained relatively constant across the 24 hour evaluation period for each of
the four conditions
(FIGS. 12B, 12C, and 12D).
[00122] The experimental results reveal that the pharmacokinetics of
theacrine, when ingested
alone, were similar between the two doses tested. However, following co-
ingestion with caffeine,
theacrine disposition was significantly altered. Specifically, caffeine
decreased theacrine's oral
clearance (CL/F), which correlated with enhanced theacrine exposure
parameters, area under the
plasma concentration time curve (AUC) and maximum concentration (C.). It is
impossible to
determine with certainty the exact mechanism for enhanced theacrine exposure,
viz., decreased
CL and/or increased oral bioavailability (F), in the absence of intravenous
data. However, the
finding that theacrine's elimination half-life (ti/2 or Vd/CL) was unaffected
by caffeine indicates
that caffeine enhances theacrine's oral bioavailability (F), which is also
consistent with the
decreased oral volume of distribution (Vd/F) of theacrine. Theacrine had no
impact on the
pharmacokinetics of caffeine or paraxanthine, which is the primary caffeine
metabolite in
humans formed via CYP1A2-mediated 3-N-demethylation. Caffeine is completely
absorbed
following oral administration. Such results indicate that theacrine would not
have a reciprocal
effect on caffeine bioavailability. Determination of whether or not theacrine
is a CYP1A2
substrate will provide further insight into caffeine's effect on theacrine
disposition, viz.,
enhanced fraction absorbed and/or reduced first-pass hepatic metabolism.
[00123] One study subject was found to have exaggerated theacrine exposure in
all treatment
arms. It is unclear, however, whether the finding is genetic and/or
environmental. The presence
of a 5-methyl substituent and a carbamide at the 6-position distinguish
theacrine from caffeine.
Because theacrine contains a 3-methyl sub stituent, the primary site of
caffeine metabolism via
CYP1A2-mediated demethylation, it is possible that theacrine is also
susceptible to CYP1A2-
mediated metabolism. Caffeine exposure (AUC0-00) is controlled by both
environmental, as well
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as genetic factors. In particular, the CYP1A2 polymorphism (rs2470893),
located in the common
promoter region between CYPJA] and CYP1A2, significantly associated with
caffeine exposure
in non-smokers, but not in smokers. Non-smokers heterozygous or homozygous for
the
CYPJAPCYP1A2 A allele had a significantly lower caffeine exposure compared to
nullizygous
individuals. Additional environmental factors including oral contraceptive use
mask the effect of
genetics on caffeine metabolism. The role of pharmacogenetics in theacrine
pharmacokinetics
and pharmacodynamics is of potential importance should CYP1A2 prove to be an
important
theacrine elimination pathway.
[00124] At the doses tested, the results reveal no effect on baseline
hemodynamic parameters,
e.g. heart rate and blood pressure, among the subjects receiving theacrine or
caffeine
administered alone or in combination. Such data are consistent with other
studies demonstrating
that theacrine supplementation (up to 400 mg/day for 8 weeks) appears to be
safe in humans with
no adverse effects on hemodynamic parameters. It is surprised to find that in
repeat dose
theacrine studies there is an absence of either sensitization or
pharmacodynamic tolerance.
Caffeine is a mixed A1/A2, adenosine receptor (AR) antagonist. It is believed
that the acute
psychostimulatory activity of caffeine is related to its ability to antagonize
the AAR, which
removes inhibition of the A2A AR leading to NMDA-dependent release of
glutamate and
dopamine. Following chronic caffeine administration, however, caffeine's
primary effects shift
from Ai-dependent to A2A-dependent antagonism in tolerant individuals due to
AAR
desensitization. Administration of a cocktail containing both Ai and A2A AR
antagonists blocks
theacrine stimulating activity in rats. However, simultaneous administration
of Ai and A2AAR
antagonists prevents the determination of individual contribution of Ai and
A2AAR to the
pharmacologic effects of theacrine. These data present a hypothesis that
theacrine has different
Ai and A2A binding affinities than caffeine, which permits discrimination
between the Al and
A2A receptors at physiologically relevant concentrations. Theacrine's
preferential reliance on A2A
AR antagonism would provide a mechanistic basis for lack of pharmacodynamic
tolerance.
Overall, the experimental data suggest that the interactions between theacrine
and adenosine
receptors are complex.
[00125] Example 3. Improvements in Subjective Feelings, Cognitive Performance,
and
Hemodynamics
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[00126] In one clinical study, the effects of a single dose of theacrine,
caffeine, or their
combination on subjective feelings, cognitive performance, and hemodynamics in
men and
women were examined. In the study, 24 men and 26 women ingested a placebo,
theacrine at 25
mg, theacrine at 125 mg, caffeine at 150 mg, or combination of 125 mg
theacrine and 150 mg
caffeine on five separate occasions, which were separated by approximately one
week. Subjects
rated their subjective feelings using a 10 cm visual analog scale at 30
minutes, 1, 2, 3, 4, and 5
hours post ingestion and performed the trail making test (TMT) of cognitive
performance at
baseline and at hours 2 and 4 post ingestion. Subjective feelings of
attentiveness, sense of focus,
and sense of energy improved with all active treatments. More favorable scores
were generally
associated with the caffeine and theacrine/caffeine combination treatments.
Self-reported
motivation to exercise significantly increased in caffeine and
theacrine/caffeine combination
treatments. Caffeine and theacrine/caffeine combination resulted in a
significant increase in
subjective focus from baseline to 2 hours post-ingestion, while the 125 mg
theacrine treatment
reached statistical significance at 3 hours post-ingestion. Motivation to
exercise and sense of
energy significantly increased from baseline to 2 hours post-ingestion in
caffeine and
theacrine/caffeine combination treatments. No condition effects were noted for
the TMT
(p>0.05), although a trend was present (p=0.069) for theacrine/caffeine
combination treatment,
with TMT time improved at 4 hours post ingestion compared to pre-ingestion.
These findings
indicate that theacrine, when used alone at 125 mg or in combination with
caffeine, is safe and
effective at improving subjective feelings related to energy in healthy men
and women.
Moreover, the data show that the combination of theacrine and caffeine may
improve cognitive
performance as assessed by the TMT.
[00127] Example 4. Improvements in Cognitive Performance
[00128] Another clinical study will demonstrate synergistic improvements in
exercise
performance and time to exhaustion obtained from 125 mg theacrine and 150 mg
caffeine
combination treatment over 275 mg caffeine or 275 theacrine administered
alone. The purpose of
this randomized, placebo-controlled, four-condition, double-blind clinical
trial is to determine
and compare the effects of theacrine to caffeine on various measures of
cognitive performance
under fatiguing conditions of a simulated athletic contest in high level male
and female soccer
players. Secondary purposes are to determine whether there is a synergistic
effect of
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theacrine/caffeine combination as well as the impact on time-to-exhaustion in
an "added time"
scenario. After giving informed consent, 20 (males n=10, females n=10)
Division I and
professional soccer players will undergo baseline performance testing and then
randomly
assigned to order of supplementation of a placebo (P), caffeine (C), theacrine
(T), and
theacrine/caffeine combination (TC). In each condition, subjects will undergo
a 15 minutes
dynamic warm-up and then engage in a simulated soccer game on a high-speed
treadmill. The
"game" will be divided into two 45-minute halves. Simple, choice, and
cognitive-load reaction
time will be assessed immediately following each 45-minute half After the
second assessment,
subjects will immediately be put back on the treadmill and asked to run to
volitional fatigue at
90% V02 max. The experimental results indicated that 125 mg theacrine/150 mg
caffeine
combined treatment outperformed 275 mg pure caffeine or 275 mg pure theacrine
interventions.
At almost half of the pure caffeine or pure theacrine dose, the combined
theacrine/caffeine
treatment resulted in a true synergistic and superior performance in
comparison to the pure
caffeine, the pure theacrine, or placebo group. More specifically, the
combination of 125 mg
theacrine/150 mg caffeine outperformed all other groups, including 275 mg pure
caffeine, 275
mg of pure theacrine, and placebo, in measures of cognitive flexibility,
attention and task
switching, complex-choice reaction time and information processing.
[00129] Routes of Administration. The compounds may be administered by any
route,
including but not limited to oral, sublingual, buccal, ocular, pulmonary,
rectal, and parenteral
administration, or as an oral or nasal spray (e.g. inhalation of nebulized
vapors, droplets, or solid
particles). Parenteral administration includes, for example, intravenous,
intramuscular,
intraarterial, intraperitoneal, intranasal, intravaginal, intravesical (e.g.,
to the bladder),
intradermal, transdermal, topical, or subcutaneous administration. Also
contemplated within the
scope of the invention is the instillation of theacrine in the body of the
patient in a controlled
formulation, with systemic or local release of the drug to occur at a later
time. For example, the
drug may be localized in a depot for controlled release to the circulation.
[00130] The pharmaceutical compositions of the present invention may be
administered in
combination with a pharmaceutically acceptable carrier. The active ingredients
in such
formulations may comprise from 1% by weight to 99% by weight, or
alternatively, 0.1% by
weight to 99.9% by weight. "Pharmaceutically acceptable carrier" means any
carrier, diluent or
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excipient that is compatible with the other ingredients of the formulation and
not deleterious to
the user. Useful excipients include microcrystalline cellulose, magnesium
stearate, calcium
stearate, any acceptable sugar (e.g., mannitol, xylitol), and for cosmetic use
an oil-base is
preferred.
[00131] The nutraceutical compositions of the present invention may be
administered in
combination with a nutraceutically acceptable carrier. The active ingredients
in such
formulations may comprise from 1% by weight to 99% by weight, or
alternatively, 0.1% by
weight to 99.9% by weight. "Nutraceutically acceptable carrier" means any
carrier, diluent or
excipient that is compatible with the other ingredients of the formulation and
not deleterious to
the user. Useful excipients include microcrystalline cellulose, magnesium
stearate, calcium
stearate, any acceptable sugar (e.g., mannitol, xylitol), and for cosmetic use
an oil-base is
preferred.
[00132] Example 5. Enhanced Coffee Beverage Study
[00133] Summary of Enhance Coffee Beverage Study. With reference to FIGS. 13A-
13H and
14A-14F, this study is a randomized, four-arm, within-subject crossover trial
of N=12 apparently
healthy male and female subjects to be recruited at a single investigational
center in Northeast
Ohio (i.e. The Center for Applied Health Sciences).
[00134] The volunteer subjects attended 5 study visits. At Visit 1,
subjects were screened for
participation (i.e., medical history, physical exam, routine blood work,
background baseline
diet). At Visits 2, 3, 4 and 5 subjects ingested four different kinds of
coffee, and then fill out
questionnaires that assess subjective changes in mood, energy, fatigue,
productivity, alertness,
jittery, and focus.
[00135] Subjects were tested using Visual analogue scales (VAS) to assess
subjective changes
in mood, energy, fatigue, motivation, alertness, and focus. (FIGS. 13A-13H).
In addition, the
vitals of the subjects were tested. (FIGS. 14A-14F).
[00136] Description of Dataset. A blinded dataset of 15 cases was received on
06/03/20. All
cases appeared to be complete with no missing data. One independent variable:
Supplementation
status was used in this study. This independent variable had three levels: A
(decaffeinated
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coffee), B (caffeinated coffee) C (coffee with 50 mg methylliberine), D
(coffee with 50 mg
methylliberine and 25 mg theacrine), and E (coffee with 100 mg
methylliberine). The
decaffeinated coffee was 8 ounces of Tim Hortons medium roast. The brewed
coffee was 8
ounces (8 oz) (236.59 mls) of Tim Hortons Original Blend, medium roast. All
dependent
variables assessed for all cases are outlined below along with an indication
of when they were
assessed. Vitals including systolic blood pressure, diabolic blood pressure,
heart rate, rate
pressure product, mean arterial pressure, and pulse pressure were also taken
prior to the beverage
(A, B, C, D, or E) consumption and at 60, 120, and 180 minutes after as set
forth in Table 5.
Assessments of VAS Mood, VAS Energy, VAS fatigue, VAS Motivation, VAS
Alertness, VAS
Focus, VAS Creativity, and VAS Concentration were assessed prior to the
beverage (A, B, C, D,
or E) consumption and at 60, 120, and 180 minutes after as set forth in Table
6. Comparisons of
A, B, and C with D at 180 minutes were calculated as set forth in Table 7.
[00137] The provided dataset (Table 4) includes baseline screening data for
age, body mass
(in pounds and kilograms), height (in inches and centimeters), body mass
index, systolic blood
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pressure, diastolic blood pressure, and heart rate for all study participants
(Females, n=8; Males,
n=7).
[00138] Table 4. Data of Volunteer Subjects
Mean - SD Minim UM
Maximurr
, Age Femae( +
ln=8) 35.0 8.9
, .. n..%
c 44
Male (ri=7) 28.9 10.0 1,8 42
Total tn=15) , 32.1 9.6 18 44
_ 1
'Weight Fer&e 150,2 25.3 120 194
(lbs). Male 194,5 48.1 144 280
Total 170.9 42.8 120 280
Weight Female 68.1 i- 11.6 54 88
(kg) Male 88.2 21.8 66 127
Total 77.5 19.5 54 127
+ .
Height Female 66.0 4- 3.2 60 69
(Inches) Male 70.4 + 2.9 67 75
Total 68.1 31 60 75
Height Female 167,7 8,0 152.4 175.3
1
(cm). Male 178.9 7.5 170.2 1905.
Total 172.9 9.5 152.4 1905.
. .
Body Mass Index Female 24,3 2.2 .4.-1,4,-,
28.6
Male 27,3 4,8 20 34.8
(kgim2)
_ Total 25.7 3.8 20 34.8
Systolic Blood Female 120.0 57 112 127
;
Pressure Male 1234 11.0 108 136
imm Hg) _Total 121,6 8,4 108 136
.
,--
Diastolic Blood Female 75,5 8.7 I 67 90
Pressure Male 75.3 6.4 i 67 86
(mm Hg) Total 75,4 7.5 I 67 90 :
' Heart Rate Female 794 13.8 I 53
98
l.bPrn) Male 74.6 34 I 50 90
Total 77.1 13.3 { 50 98
.. ..
,.
36
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[00139] Table 5. Hemodynamic Variables.
11-iernaclynarnic Variables .W1h3r.o8p.
=riel.ta b-vafue..
Van abies Pre 60 min 120 rrgn ISO in i:190 -
Pre} f+TV0-WO) Condition Time .. *Time
systok. Blood Pressure (r.rim Hc
A. .116 1 12..3 1161 12.5 1194 .1- .10.2 119.1 .3.1.1-10:3 044
0..16 0,0 0:$6.
1'17 1.?.33 113.7 11.1 115.1 Io.a 113.7 2.3 1..1 k 145
a1:7
C: 1117 11.0 117.7 0.5 123.6 11,2 122,3
k 10:2. 4,9 9:5. Ø02
= 1l95 14 121_3 S 4 121_3 10.4 i1.2 2 9
0:66
= 11.3.S 11.5 118.9 '10.2 1200. 13.6
119.1 8.2 03 8 095
Dastcdc BIC.al Pressure fµrnrn Hg')
A T 176.2: k 76.3 2.3 477.2.: S.SS 0..02 .0_53.
0:04.
= 76.0 &.3 76.1 6.9 79..2 k 9.7 .76.9102
0:969 0.95
C. 79.1 .9.4 i8 4 -82.1 k 7.7. .9`.2.3 .8.4 4.3 k 5.1.
15 72 911.9. 79.0! 5.9. 7.9.0 10..5 1.5 6.4.
0.17
= 751 78.4 .7.1 .15.9 7.1 152 &9= -t4. 6.7
0:27
Head Rate (beatgblin)
A 7:"45 13 Ø 7fl' i46 10.5 I-14_9 71.7.1.15,8 29 IIB
0.19 C5 0005 045
= 74.8 12 9. 70 7 + 67.9 13.4 71.7 + i4.
t 92 0iO4
C. 7511 12 2 72 3 12. 6 .69.7 11O 72.4 k 11.6 7.0
0.0?
74,5k 12.4 68.3 1-12.3 69 5 12 3 f5 112 01Y35.
= 73,9: 11.9 71.1 /1.0 70.5 + 17 2 72.5
1=.'; 1 -1.3 10.7 054
Rate Pressufe Pfoduct
A 06.9. 19.5. &i 2).3 44= 21.=i6 i315.9 211 -1,0 0.2
0.58 0:.-31 .0_07 0.52
8S .2 1r,1 1: 80,2 1.6.0 :781 17..3 .84.8 15.8 73.6 k
12,1 0_004:
= 987 IS 5 86:3 i176 89.2 1T9 99.4 15.1 -
0:.3 1 1..5 057
= 8-4.3 + 1'3.9 82 + 14 3 8O 15:9 mi 16.1 -
F.: 15.1 0.04
= 87.9 17.1 84.9 17.7 25,6 25,6 S6.5 19,9
-1.2 17.4 0.90
Mean Anefial Piessure
A 1.67.6 14:9 .197.2.: 17,.7 .1 .70.04-.13.4. 171 Ø
15...5 = ;.3.4
19E > 1B2 1e44 15:9 165.91.14,Q 170.0 11.9. 1.7 k 127 0.28
169 156 I70,0 13,5. 179.3:. :14.3
177.2 12 4 2 004::
171 2 141. 17.5 2 121 172iO 8:8. 174.4 7.9 31 12.2
0.48
E 1'D 15171,1 1.9 1.706 t 170 199.3 k 12.9.= 4.67 . .1Z4 0,93
Puise PresTore
= 387 11.9 40...R.t &JO 42:9q..10.4 41...3..
.81 2. W.9 Ø51 o...sa 032. 0:64:
= 0.6 10.S. 371 :38...9 41.7 10.3 .G.1 f
017.
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[00140] Table 6. VAS Assessments
Vista' Analog Scales
Y'Attlin7Group=
Delta p;value. Gond
:x
Venablea Pie.. 8.0=011. 120 .min 180 nlh (1=00 7 Fre) W8 W0
co.nch0 on. Ticne= lime
Mood
A 38 13 62 15. 0,1 2A 5.9 2.4. 0_14... 1,05.
0.57 0_19: <0.,001 0.02
^ 54 6 1.7 '61 1:.5 0 9 1 6: '1,54 18.
<000/.
C .5.2 15 65 1.3 .7.0 1.8 7:2 1.8. p.05
6.2 1.5 82 1.2 7:3 1.6 2.06 49 <6001
52 + 1 4,&6 11 57 12 6.9 2 1) 1.27 1.76
IfLei
Elle:fgy
A '42 1,7 5.9 1.0 5.7 2.1 5.6 2 3 Ø64 .2.00
0:00 024 .03:001 .001.
B. 4.5 1 4 66 657 1.5 6 5 1 4 2C0 15 = <0.901
4.0 1.9. 8.5 1.6 .89 177.2 1.6 2..3.1 166
<0.001
D 4.0 + 6,4 1.5: 8.9 + 1.9 69 + 1.1 2.83 + 2.15.
.<6001.
4.5 1.7 6.0 1 7 5,7 1_7 6.41-1.9 1)37 2,36 <0601
Fatigue
A. 3.9 3.8.- 2Ø3.5 2.1 a..8 2.4 0.00 2.60
p.93 0,44 <0:001 0.00
B: 4.6 2.3 2.8 2.0 3.1 2.0 3.9 2.1 0L 1C1 .1001
G 4.3 2.1. 2:5 . 27 23 .,2.6 2.0 -1.73. 1 1
601
D 4.5 2.4. 1 8 2.2 t8 2.3 12 -2..27 2.41 <000
E 4.6. 1,9 3..G 1::.9 3:0 2.0 2.8 2.4 2 76
0;005.
Mititiyatien
A .5.21.21 5.9 52 22 2,.3. 014 231 04.5 Ø46 .<0.001 0.03
= .4..3 1.8= 62+15 82 15. 6:2 17
1,87 1.71 <.0:001.
C 4,8 22 63 1.6 6.6 + 2.3 6.9 2.2 2.15
2..04 <0001
D 4.4 + 1.9 8:4 1.6 513 + 17 6.6 2./7. .1 85. 0..001.
= 4.9 2,1 6.1 1.8 6.6 1.8 6.6 2.1 1.61
2.41 0.003.
Alertness
A 54 l,7 5..9. .1.7 .6.1 2.2 58 22. 0.30,1.190 0.22
U19 <0.001
.B.=$ 1 .5 80 1.3 6.5 1.4 83 1.7 1.93. .1.58
<0.001
C 5.1 1.9 6.7 1.3 .7.3 1,5 7,1. 1.9 1:98 1:91
<0.001
D 4.6 + 2 3 6.6 1.5 6.9 + 1.4 6:9 + 11 2.73 + 2.17.
,.0=:001
5.1 + 2:0 a 6 +. 1.4 5,9 + 1_5 8.9 1.9 199 2.22 <0.001
38
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[00141] Table 7. Comparative Analysis of Groups A, B, and C with D.
Hemodynamic
Between-Group Comparisons - Delta @ 180 minutes.
--
Cc:rnpared Mean Effect Sze %
Chanbe
Variable Groups Difference 955/n GI p-value M
Systolic B.lioad D vs A -0.97 31 (-7.5, 5.8} 0.73 -0 08
-0.8
Pressure :mm H) L-3 vs B 1.13 3 8 (77 O. , 9 3). 0.77 0.12
0.9
D vs. C -2 40 2 8 (-8 4 0 6) 040 0.04
Diastolic Blood 0 vs. A 1.07 23 (-3.8, 6.01 065 -0 -
16 .15'
Pres-sure 0 vs. -3 0:60 -I- 2..4 (4.5, 5.7). 0.81 -0.20
-22.
0 v--7; C" -2/3 1.5" (5.9õ. 0.4) " 0.08" -0 61"
Heart Rate D vs A -51 t 31 (-5.1, 3.1) 0.12 -038 -
6.9
(beatsimln) 0 vs B-v -4_9 2 6' (-4.3, 2.6) " 0 Oa" -0.37
-5 3 2.3# (-5 3, 2 .3. 0.04# -O4 -
72#
D vs. A" -0 40"
Rate Pressure -7.6 - 4.2" (7157, 1 ;1=.:', '"
Preduct
4.9 4.1: (-13.8 4.0) 025 -0.28:
,5 5
Mean Arterial D vs A -016 3.0 (-8 3, ft O) 097 -001 -
0.1
Pressure 0 vs B 1 53 4- 4 9 (-9 0,12.1) 0.76 0.12
0:9
2_31 0.22 -0.33 -2 5
Rise Pressure 0 vs. A -1.9 3,3 (,9.0, 52) =057 -0.21
Oren Hq11 0 VS.':6 0.5 3.5 (-.6.1, 7.1) 0.37 0.06
1,3
D vs. C 0.3 + 2.6 (-5.3, :6.0) 0.30 0 04
0.7
[00142] Summary of Statics for Enhance Coffee Study (Example 5). A significant
level of
0.05 was used for all statistical determinations and a p-value from 0.05 -0.10
was deemed a
trend or tendency. Normality of the frequency distributions were assessed
using the Shapiro-
Wilk test. Nearly all variables were confirmed to have a normal distribution.
Due to the repeated
nature of the study design, the variables who were found to be non-normal were
not transformed
and a traditional parametric approach to statistical analysis was employed. 5
x 4 mixed factorial
ANOVAs were completed to assess condition, time, and condition x time
interaction effects.
LSD post-hoc procedures were used to assess individual comparisons between
groups. In all
instances where the sphericity assumption was not met, the Greenhouse-Geiser
correction was
applied. All statistically significant outcomes are denoted with #, while all
statistical tendencies
or trends are denoted with **.
[00143] Whereas, the present invention has been described in relation to
certain embodiments
thereof, and many details have been put forth in its illustration, it should
be understood that other
and further modifications, apart from those shown or suggested herein, may be
made within the
spirit and scope of this invention. Descriptions of the embodiments shown in
the drawings
39
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should not be construed as limiting or defining the ordinary and plain
meanings of the terms of
the claims unless such is explicitly indicated.
[00144] As such, those skilled in the art will appreciate that the conception,
upon which this
disclosure is based, may readily be utilized as a basis for the designing of
other structures,
methods and system for carrying out the several purposes of the present
invention. It is
important, therefore, that the claims be regarded as including such equivalent
constructions
insofar as they do not depart from the spirit and scope of the present
invention.
[00145] All references cited herein are incorporated by reference in their
entirety. The present
invention may be embodied in other specific forms without departing from the
spirit or essential
attributes thereof and, accordingly, reference should be made to the appended
claims, rather than
to the foregoing specification, as indicating the scope of the invention.
