The invention relates to the field of medical marijuana.
The use of marijuana is known to cause neuronal, molecular and neuropsychiatric side effects. This complicates the use of marijuana for medical treatment. Δ-9-tetrahydrocannabinol (THC) is the primary psychoactive compound in marijuana (MJ). As demonstrated in both clinical and pre-clinical research, THC is associated with a wide-range of deleterious neuropsychiatric side-effects in both adolescent and adult users of MJ. In particular, chronic or acute THC exposure has been shown to increase anxiety, increase depressive symptoms, increase vulnerability to schizophrenia-related symptoms and to produce profound cognitive side effects such as deficits in cognitive filtering and memory impairments. Given the increasing use of ‘medical’ marijuana for the treatment of wide variety of ailments, there is therefore an urgent need for the development of a safer THC formulation that lacks the neurocognitive and neuropsychiatric side-effects associated with MJ usage. In addition, marijuana and specific THC derivatives are now widely used for a variety of symptoms and disease states, including pain management, control of chemotherapy-related nausea, glaucoma, multiple sclerosis and others.
Importantly, one of the primary concerns (from patients and physicians) associated with therapeutic marijuana use and prescription is the neuropsychiatric side-effects associated with THC.
Forming one aspect of the invention is a method for use with a treatment regime that includes the exposure of a patient to THC, the method comprising the step of: administering Theanine to the patient.
Forming another aspect of the invention is a method for use with a treatment regime involving a plurality of administrations of THC, the method comprising the step of administering Theanine to the patient with each administration of THC.
According to another aspect, the method of administration can be such that the peak bioavailability of THC occurs substantially contemporaneously with the peak bioavailability of Theanine.
According to another aspect, the administration can be by needle, transdermal, ingestion, inhalation, sublingual or by suppository.
Forming another aspect of the invention is a consumer package adapted for carrying out the method, the package being selected from the group consisting of: IV bag, prefilled syringe, cream, patch, pill, capsule, liquid, inhaler, sublingual strip, suppository and edible.
According to another aspect, the Theanine can be L-Theanine.
Advantages, features and characteristics of the invention will become evident to persons of ordinary skill in the art upon review of the following description, with reference to the appended drawings, the latter being briefly described hereinafter.
An embodiment of the invention is a method for use with a treatment regime involving a plurality of THC administrations, the method comprising the administration of L-Theanine with each administration of THC, the administration being such that the peak bioavailability of THC occurs substantially contemporaneously with the peak bioavailability of L-Theanine. This THC exposure regimen is designed to mimic a long-term, chronic exposure period to cannabis use in humans. The dose of THC is gradually increased to account for possible receptor tolerance effects from THC exposure, as would be predicted to occur in long-term human users of cannabis.
Four groups of ten rats were studied. The first group of rats was given twice daily intra-peritoneal doses of THC. The dosage regime was as follows
Immediately preceding each dose of THC, each rat was dosed with 10 mg/kg L-Theanine, administered intra-peritoneally.
The second group of rats was given the same doses of THC and no L-Theanine.
The third group of rats was given twice daily doses of L-Theanine but no THC.
The fourth group of rats was given neither THC nor L-Theanine.
All groups of rats were fed, watered and otherwise housed identically. At the end of the 10 day period, the rats were subject to a serious of tests.
Rats were acclimatized to the startle chambers (Med Associates) for 5 min over 3 days. On the last day of acclimation, rats were tested in an input/output (I/O) function consisting of 12 increasing startle pulses (from 65 to 120 dB, 5 dB increments) to determine the appropriate gain setting for each individual rat. The testing procedure consisted of the following phases: the acclimation phase, a habituation phase (Block 1), and PPI measurement (Block 2). During acclimation, rats were exposed to the chambers and white background noise (68 dB) for 5 min. During Block 1, 10 pulse alone trials (110 dB white noise, 20 ms duration) were delivered at 15-20 s inter-trial intervals. Block 2 consisted of 9 different trials presented 10 times in a pseudo-randomized order at 15-20 s intervals: 10 pulse-alone trials, and 10 of each of the three different prepulse-pulse trial types (72, 76, 80) with interstimulus intervals of 30 and 100 ms. Pulse-alone trials consisted of a startle stimulus-only presentation, whereas prepulse-pulse trials consisted of the presentation of a weaker non-startling prepulse (white noise, 20 ms duration) before the startling stimulus. PPI was calculated for each animal and each trial condition as PPI (%)=(1-average startle amplitude to pulse with prepulse/average startle amplitude to pulse only)×100.
Rats were water-restricted for 12 hrs prior to being given a 2-bottle choice test between a solution containing 2% sucrose vs. plain water. The amounts consumed from each bottle were measured over 24 hr for 4 days. A sucrose preference index was calculated for each rat and averaged across groups by taking the percentage of the volume of sucrose intake over the total volume of fluid intake over the 60-min test phase.
The test sessions consisted of two 3-min trials. During the first trial (T1 acquisition trial), each rat was placed in the center of an arena containing two identical objects placed in the far corners 15 cm from the side wall. After a delay of 60 min during which the rat was returned to its cage, and both objects were replaced (one by an identical copy, the other by a novel object in the same location), the rat was returned to the arena for the second trial (T2 test trial). Between rats, both the role (familiar or novel object) and the relative position of the two objects were randomly counterbalanced. Object exploration was considered when the head of the rat was facing the object or the rat was touching or sniffing the object. Times spent in exploration were videotaped with a video-tracking system (ANY-maze; Stoelting) and analyzed by an experimenter blind to the treatment conditions. Exploration times were recorded and used to calculate object recognition index [time spent with novel object/total time exploring both objects]
Extracellular single-unit electrophysiological recordings were performed in vivo in adult (>PND 75) pretreated rats during adolescence. The recordings were taken from either putative glutamatergic (GLUT) PFC neurons or dopaminergic (DA) VTA neurons. Rats were anesthetized with urethane (1.4 g/kg, i.p., Sigma-Aldrich) and placed in a stereotaxic frame with body temperature maintained at 37° C. A scalp incision was made and a hole was drilled in the skull overlaying the targeted structure at the following coordinates: mPFC: AP: +2.7 to +3.5 mm from bregma, L: ±0.8 to ±1 mm, DV: −2.5 to −4 mm from the dural surface; VTA: AP: −5.2 mm from bregma, L: ±0.8 to ±1 mm, DV: −6.5 to −9 mm from the dural surface. Recordings were taken with glass microelectrodes (average impedance of 6-10 MΩ) filled with 2 M sodium acetate solution containing 2% pontamine sky blue (Sigma-Aldrich). A bone screw was placed over the cerebellum and was connected with the return of the headstage and served as a reference electrode. Extracellular signals were amplified (×5000) using a MultiClamp 700B amplifier (Molecular Devices), digitized at 25 kHz and recorded on the computer using a Digidata 1440 A and pClamp software (Molecular Devices). The wideband signal of PFC recordings was fed to two channels of the digitizer and filtered to obtain single unit recordings (band pass between 0.3 and 3 kHz).
VTA DA neurons were identified according to well established electrophysiological features86: (1) action potential width >2.5 ms, (2) spontaneous firing rate between 2-5 Hz, (3) a triphasic waveform consisting of a notch on the rising phase followed by a delayed after potential, and (4) a single irregular or burst firing pattern.
Putative mPFC pyramidal cells were identified based on established criteria85: (1) firing frequency <10 Hz, (2) waveform shape, and (3) action potential duration >2.5 ms. Cells exhibiting 3 consecutive spikes with inter-spike intervals <45 ms were classified as burst-firing cells85. The electrophysiological properties of spontaneously active pyramidal neurons were sampled in the mPFC by making vertical passes of the electrode through the pyramidal cell body region. These tracks were made in a predefined pattern, with each track separated by 200 μm. After an individual putative pyramidal neuron was isolated, its spontaneous activity was recorded for 5 min. Two parameters of activity were sampled, the basal firing rate and the bursting rate.
The results of the tests were as follows.
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Thus, L-Theanine appears to block the ability of THC to cause cognitive filtering deficits.
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Thus, L-Theanine appears to block the ability of THC to induce anhedonic, depressive-like effects.
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Thus, L-Theanine appears to prevent short term memory deficits associated with THC exposure, with no apparent effects on short-term memory processing in and of itself.
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The Thr308 gene is linked to susceptibility to long-term cannabis-related psychotic effects. The co-administration of L-Theanine appeared to counteract the effects of THC, as indicated by
In this document, use is made of the terms “reverse”, “block”, “prevent”, “counteract”, “improve”, such terms should be interpreted reasonably, with reference to the experimental results; thus, for example, “prevent” should not necessarily be construed to require a complete prevention in all cases.
Whereas in this document, specific dosage regimes are described, it will be appreciated by persons of ordinary skill that the dosages mentioned, which have been proven to be useful in the context of rats and in experimental conditions selected to mimic/approximate chronic THC exposure in humans; routine experimentation will be required to modify the dosages for human use.
Whereas the experimental evidence relates to substantially contemporaneous intra-peritoneal administration, it is reasonable to assume that any other method of administration wherein the peak bioavailability of THC occurs substantially contemporaneously with the peak bioavailability of L-Theanine will have similar utility.
Thus, for example and without limitation, persons of ordinary skill could be expected to produce consumer packages adapted to carry out the method in at least the following forms: intravenous bag, prefilled syringe, cream, patch, pill, capsule, liquid, inhaler, sublingual strip and suppository.
Techniques such as the DehydraTECH™ system of Lexaria Bioscience Corp. would also be expected to be useful to produce edibles. The NANOSTABILIZER™ of Industrial Sonomechanics would also be expected to be useful in formulation.
Further, whereas L-Theanine is specified throughout this specification, other forms of Theanine would be expected to have useful results.
Accordingly the invention should be understood to be limited only by the accompanying claims, purposively construed.
This application is a continuation of U.S. patent application Ser. No. 17/267,003 filed Feb. 8, 2021, which itself is a U.S. nationalization under 35 U.S.C. § 371 of International Application No. PCT/CA2019/051084 filed Aug. 8, 2019, which claims priority to U.S. Provisional Patent Application Ser. No. 62/715,828, filed Aug. 8, 2018, and to U.S. Provisional Patent Application Ser. No. 62/730,253, filed Sep. 12, 2018.
Number | Date | Country | |
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62715828 | Aug 2018 | US | |
62730253 | Sep 2018 | US |
Number | Date | Country | |
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Parent | 17267003 | Feb 2021 | US |
Child | 18925654 | US |