WO2019175290A1

WO2019175290A1 - Cannabis or cannabis derived compositions for promoting cessation of chemical dependence

Info

Publication number: WO2019175290A1
Application number: PCT/EP2019/056360
Authority: WO
Inventors: Celia MORGAN; Tobias STEVENS; Alina IVAN; Chandni HINDOCHA; Amanda FEILDING; Cosmo MELLEN
Original assignee: Beckley Canopy Therapeutics Limited
Priority date: 2018-03-13
Filing date: 2019-03-13
Publication date: 2019-09-19

Abstract

The present invention provides cannabis or cannabis derived compositions comprising consistently controlling the presence, absence or amount of psychoactive compounds in a composition for promoting cessation of chemical dependence. Also provided are methods for selecting useful compositions for promotion of cessation of volitional chemical exposure, in particular, smoking.

Description

CANNABIS OR CANNABIS DERIVED COMPOSITIONS FOR PROMOTING CESSATION OF CHEMICAL DEPENDENCE

Related Application

The present case claims the benefit and priority of US 62/642290 filed on

13 March 2018 (13.03.2019), the contents of which are hereby incorporated by reference in their entirety.

Abstract of the Disclosure

The present invention is directed to compounds, compositions, methods, kits, and the like, for promotion of smoking cessation. Preferred embodiments of the invention are directed to compositions and methods for promotion of smoking cessation based on cannabis or cannabis derived compositions. Particularly preferred embodiments include cannabis and cannabis derived compositions wherein the ratio of principle cannabinoids is controlled to provide optimal utility in the promotion of smoking cessation.

Description

Memory is a functional aspect of the mind by which information is encoded, stored, and retrieved. Memory is vital to experiences and has been experimentally related to the limbic systems, particularly the hippocampus. Memory is the retention of information over time and is used to influencing future action.

Human and other animal dependency on chemical substances has a memory and learning at its core. Cues signalling chemical exposure, including accidental or volitional drug use, and the various experiences, that come as a result of chemical use, such as pleasure, are bound together in memory to create a strong stimulus- response association. When so activated or“cued”, the memories can predispose an individual Human or other animal toward use of the chemical even under circumstances wherein the conscious mind asserts a desire to avoid repeated exposure. This theory is one model of chemical dependence or addictions. The individual is exposed to images associated with substance use which evoke the original association with pleasure and create a strong compulsion to re-enact such behavior. This process is referred to herein as“cueing” or activation of the“cue” of memory.

As used herein, the term“chemical dependence” and the like are understood to apply to any chemical to which physical and/or psychological dependence or addiction can be developed in a Human or other animal. In particular, the phrase is understood to apply to drugs of abuse, alcohol, nicotine, preferably a drug of abuse, alcohol or nicotine, more preferably a drug of abuse or nicotine, more preferably yet an opiate or nicotine.

The salience network is a large-scale network of the Human brain that mediates attention to salient internal/external stimuli to guide behavior. It is composed of the anterior insula (“Al”) and dorsal anterior cingulate cortex (“dACC”), which are involved in detecting and filtering salient stimuli, as well as in recruiting relevant functional networks. The salience network is detectable through independent component analysis of resting state fMRI images, as well as seed based functional connectivity analysis. Besides the Al and dACC, the salience network also consists of the substantia nigra, ventral tegmental area, ventral striatum, amygdala, dorsomedial thalamus, and hypothalamus. The functional connectivity has been linked with structural connectivity through diffusion tensor imaging, which reveals white matter tracts between the Al and dACC. The salience network has been implicated in detection and integration of emotional and sensory stimuli, as well as in modulating the switch between the internally directed cognition of the default mode network and the externally directed cognition of the central executive network.

Accordingly, the components of the salience network are a fruitful target for compounds or compositions directed to promotion of cessation of behavior related to chemical exposure. The present invention is directed to cannabis or cannabis derived compositions for use in promoting the cessation of chemical dependency through altering the cueing of memory and activation of the salience network. Such compositions are useful in a) reducing the salience of cues of learned behaviour and b) altering the strength of the memory itself, which combined allow to reduce relapse into behavior linked to chemical dependence.

Cognitive neuroscientists consider memory as the retention, reactivation, and reconstruction of the experience-independent internal representation. The term of internal representation implies that such definition of memory contains two components: the expression of memory at the behavioral or conscious level, and the underpinning physical neural changes related thereto.

Encoding of working memory involves the spiking of individual neurons induced by sensory input, which persists even after the sensory input is terminated. Encoding of episodic memory involves persistent changes in molecular structures that alter synaptic transmission between neurons. Examples of such structural changes include long-term potentiation (LTP) or spike-timing-dependent plasticity (STDP).

The persistent spiking in working memory can enhance the synaptic and cellular changes in the encoding of episodic memory.

Recent functional imaging studies have detected working memory signals in both medial temporal lobe (MTL), a brain area strongly associated with long-term memory, and prefrontal cortex, suggesting a strong relationship between working memory and long-term memory.

Short-term memory (STM) is temporary and subject to disruption, while long-term memory (LTM), once consolidated, is persistent and stable. Consolidation of STM into LTM at the molecular level presumably involves two processes: synaptic consolidation and system consolidation. The former involves a protein synthesis process in the medial temporal lobe (MTL), whereas the latter transforms the MTL- dependent memory into an MTL-independent memory over months to years. In recent years, the traditional consolidation theory has been re-evaluated because of the studies on reconsolidation. These studies suggest that prevention after retrieval affects subsequent retrieval of the memory. New studies suggest that post-retrieval treatment, in a crucial time window, with protein synthesis inhibitors and many other compounds can lead to an amnestic state. These findings on reconsolidation are consistent with the behavioral evidence that retrieved memory is not a simple copy of the initial experiences, and that memories are updated during retrieval.

Context-dependent memory is the improved recall of specific episodes or information when the context present at encoding and retrieval are the same. An example of context-dependence at work occurs when an individual has lost an item, such as car keys. Among the methods applied to the end of finding the keys is the systematic retracing of steps to determine possible locations where the lost keys might be found. Research describes different types of contextual information that may affect recall such as environmental context-dependent memory, state-dependent learning, cognitive context-dependent memory and mood-congruent memory. Research has also shown that context-dependence may play an important role in numerous situations, such as memory for studied material, or events that have occurred following the consumption of alcohol or other drugs.

One chemical of interest within the context of the present invention is nicotine. The method of nicotine exposure is frequently referred to as“smoking.” However, any method involved in the volitional exposure of an individual to nicotine is, within the context of the present invention,“smoking.” From a Human healthcare perspective, the inhalation of smoke from the burning of plant material such as tobacco is “smoking.”

Memory cues associated with past chemical exposure, such as exposure to nicotine in the volitional use of tobacco, are detected by the salience network. Once activated, these cued memories predispose an individual toward repeated volitional exposure. Therefore, interrupting the cueing of or triggering of salience network components by observational cues linked to volitional chemical exposure is a useful method of promoting the cessation of the volitional exposure. The present invention offers compositions and methods for such utility.

To the extent that relapse into chemical exposure is dependent on persistent memory of past exposure, these systems are targets for the compositions of the invention. Accordingly, in a preferred embodiment, a composition of the invention is useful in effecting, modulating, altering, or the like, Brain systems involved in memory. In particular, the compositions of this embodiment are useful for promoting the cessation of chemical exposure by interacting with brain systems related to memory.

Smoking leads to disease and disability and harms nearly every organ of the Human body. More than 16 million Americans are living with a disease caused by smoking. For every person who dies because of smoking, at least 30 people live with a serious smoking-related illness. Smoking causes cancer, heart disease, stroke, lung diseases, diabetes, and chronic obstructive pulmonary disease (COPD), which includes emphysema and chronic bronchitis. Smoking also increases risk for tuberculosis, certain eye diseases, and problems of the immune system, including rheumatoid arthritis. Smoking is a known cause of erectile dysfunction in males. Smoking is a leading cause of preventable death. Worldwide, tobacco use causes nearly 6 million deaths per year, and current trends show that tobacco use will cause more than 8 million deaths annually by 2030. Cigarette smoking is responsible for more than 480,000 deaths per year in the United States, including more than 41 ,000 deaths resulting from second-hand smoke exposure. This is about one in five deaths annually, or 1 ,300 deaths every day. On average, smokers die 10 years earlier than non-smokers. If smoking continues at the current rate among U.S.

youth, 5.6 million of today’s Americans younger than 18 years of age are expected to die prematurely from a smoking-related illness. This represents about one in every 13 Americans aged 17 years or younger who are alive today.

Cessation of smoking by conventional means is difficult. Data suggest that, of all patients who attempt conventional methods, 80% relapse within a month, 97% relapse within 6 months and 80% relapse 6 months after pharmacologically aided smoking cessation. Cravings are one form of perceptual based relapse factors. No current pharmacotherapy is thought to reduce or prevent cue-induced cravings during or after smoking cessation.

Craving, an almost irresistible urge to use drugs, is one of the most vexing problems associated with drug addiction. Craving can be the result of changes in the brain and may be triggered by physical discomfort associated with abstinence from the drug. Craving also may be triggered by external, environmental factors, such as the sights, sounds, and social situations associated with drug use. In this "cue-induced" craving, the urge to use drugs often is powerful enough to cause a relapse to drug abuse months or even years after a person has stopped using drugs. Neural correlates of nicotine craving are varied. Specific processes impacted by cravings include by way of example: visual processing, emotional processing, memory, attention, reward and goal-directed behaviour. Brain regions implicated in such effects include by way of example the: amygdala, anterior cingulate cortex, orbitofrontal cortex, nucleus accumbens and ventral tegmental area. Inherited differences in nicotine metabolism effect neural responses to smoking cues during early abstinence. In whole brain analysis, normal (compared to slow) metabolizers of nicotine exhibit heightened abstinence-induced neural responses to smoking cues in the left caudate, left inferior frontal gyrus, and left frontal pole.

Nicotine is a principle addictive compound in tobacco smoke and is an alkaloid with potent parasympathomimetic stimulant effects. Nicotine has agonist activity at nicotinic acetylcholine receptors (nAChRs). However, it acts as an antagonist at excepicotinic receptor subunits (nAChRa9 and nAChRod O).

Nicotine is highly addictive. An average cigarette yields about 2 mg of absorbed nicotine which is sufficient to act as a stimulant in Humans. The stimulant effect is thought to be a contributing factor in the addictive properties of tobacco smoking. Nicotine's addictive nature includes psychoactive effects, drug-reinforced behavior, compulsive use, relapse after abstinence, physical dependence and tolerance.

Understanding and manipulation of drug-reinforced behavior is an important factor in development of compositions promoting cessation of smoking. Such behavior involves memory. In one embodiment, the present invention provides compositions for promotion of smoking cessation which effect memory involved in drug-reinforced behavior. A preferred embodiment of the invention is the use of cannabis or cannabis derived compositions in promotion of smoking cessation.

Nicotine habituation involves psychological and physical dependence.

Discontinuation of extended use has been shown to produce both affective and somatic dysfunctions. These so called“withdrawal symptoms” peak in the first day or two but can persist for several weeks. Nicotine has clinically significant cognitive- enhancing effects at low doses, particularly in fine motor skills, attention, and memory. These beneficial cognitive effects may play a role in the maintenance of tobacco dependence. Accordingly, one aspect of the present invention is directed to providing compositions and methods for promotion of smoking cessation by treating memory-based withdrawal effects and behaviors thought to promote relapse.

Cessation of Unwanted Volitional Chemical Exposure

Cannabinoids such as THC and CBD, effect brain activity in different ways. For example, in recent studies these principle cannabinoids have been interpreted to impact observable psychiatric activity in opposite ways. Accordingly, formulation of compositions for use in promoting the cessation of smoking by effecting brain activity requires careful study to define specific ratios of principle cannabinoids. By way of example, ratios of THC to CBD are studied in iterative fashion to discover ratios for use in promotion of cessation of smoking. The present invention provides such methods and compositions discovered through use thereof. THC is thought to disrupt the salience network. Conversely, CBD is thought to restore the disruption. The paradoxical effect of cannabinoids has been rationalized based on the disparate effects of cannabinoids on changes to the brain’s salience network, dopamine and endocannabinoid systems. Anecdotal experience is consistent with these results. For example, CBD is commonly thought not to affect the psycho-activity of THC.

The present invention provides methods for selecting useful compositions for promotion of cessation of volitional chemical exposure, in particular, smoking. One method is an iterative process designed to discover correct ratios of principle cannabinoids in the context of the so-called“entourage effect.”

A cannabis chemotype is a composition comprising extracts of whole cannabis plants wherein the plant material from which the extract is prepared is from a genus, preferably a species of cannabis. The extract of a chemotype is prepared by the methods described herein.

A chemotype is identified by experimental experience. When many extracts have been prepared from a variety of cannabis species, and the performance properties of those extracts have been characterized by the methods described herein, it becomes apparent upon meticulous and detailed analysis that the performance properties of the extract can be group based on the species of plant from which the extract is prepared.

When a chemotype has been identified, it is possible to modify its experimentally observable performance properties by changing the quantities of the compounds of the composition. By quantities the present invention contemplates the presence, absence or amount of the various compounds of the compositions. Any of the separation, purification, reconstitution and chemical methods described herein are suitable for performing the modifications contemplated.

With respect to the active ingredients of a chemotype, cannabinoids, terpenoids and flavonoids are among the among most important compounds to be so modified. One aspect of the invention is the change in the presence, absence or amount of cannabinoids, terpenes and flavonoids of the chemotype. Quantity within this aspect of the invention is intended to include both absolute and relative concentrations. In absolute terms, quantities can be described by a variety of methods to include volume, weight, molar and other concentration measures of cannabinoids, terpenoids or flavonoids. Relative terms are intended to include volume, weight, molar and other relative measures of one compound verse another in the

composition.

In a preferred embodiment, quantity means the relative molar percent of one compound verses another such as the ratio of THC to CBD, total cannabinoid verses total terpenoid and cannabinoid verse all other compounds present in the

composition. In a particularly preferred embodiment, quantity means the molar ratio of THC to CBD.

An important aspect of the present invention is the manipulation of relative amounts of cannabinoids within the compositions of the invention. In this embodiment, the ratio of one primary cannabinoid to another is managed by any of the separation, purification, reconstitution or chemical and biological manipulations described herein. A preferred embodiment of the present invention is direct to the control of the quantity of one primary cannabinoid verse another. By way of example, in this aspect of the invention, THC and CBD ratios are controlled to prepare compositions for the treatment of chemical dependence as described herein. Compositions of this embodiment are optimized, optionally by the iterative methods described by the entourage effect, to yield suitable treatments for promoting the cessation of chemical dependence, preferably drug use, more preferably volitional drug use, more preferably yet volitional nicotine use, more preferably still the dependence on smoking tobacco.

Selected embodiments of this aspect of the invention include by way of example:

1. A cannabis or cannabis derived composition comprising consistently

controlling the presence, absence or amount of psychoactive compounds in a composition for promoting cessation of chemical dependence.

2. The composition of embodiment 1 comprising consistent quantities of

cannabinoids.

3. The composition of embodiment 1 comprising consistent quantities of

terpenoids.

4. The composition of embodiment 1 comprising consistent quantities of

flavonoids. 5. The composition of any of embodiment 1 to 4 comprising consistent quantities of cannabinoids, terpenoids and flavonoids, each selected independently.

6. The composition of any of embodiment 1 to 4 comprising quantities of

cannabinoids and terpenoids, each selected independently.

7. The composition of any of embodiment 1 to 4 comprising consistent quantities of cannabinoids and flavonoids, each selected independently.

8. The composition of any of embodiment 1 to 4 comprising consistent quantities of terpenoids and flavonoids, each selected independently.

9. The composition of any of embodiment 1 to 4 comprising consistent quantities of cannabinoids, terpenoids and flavonoids, each selected independently.

10. The compositions of embodiments 1 to 9 above wherein the composition is optimized for use in the treatment of chemical dependence.

11. Methods of use, manufacture, and kits of embodiments 1 to 10 and iterative methods of finding entourage effects for treating chemical dependence based on the compositions of embodiments 1 to 10.

12. A cannabis containing composition for promoting cessation of chemical

dependence comprising consistent controlling the presence, absence or amount of psychoactive compounds.

13. The composition of embodiment 12 wherein the active compound is a

psychoactive compound.

14. The composition of embodiments 12 or 13 comprising consistent quantities of cannabinoids.

15. The composition of embodiments 12 or 13 comprising consistent quantities of terpenoids.

16. The composition of embodiments 12 or 13 comprising consistent quantities of flavonoids. 17. The composition of any of embodiment 12 to 16 comprising consistent quantities of cannabinoids, terpenoids and flavonoids, each selected independently.

18. The composition of any of embodiment 12 to 16 comprising quantities of

cannabinoids and terpenoids, each selected independently.

19. The composition of any of embodiment 12 to 16 comprising consistent

quantities of cannabinoids and flavonoids, each selected independently.

20. The composition of any of embodiment 12 to 16 comprising consistent

quantities of terpenoids and flavonoids, each selected independently.

21. The composition of any of embodiment 12 to 16 comprising consistent

quantities of cannabinoids, terpenoids and flavonoids, each selected independently.

22. The compositions of embodiments 12 to 21 above wherein the composition is optimized for use in the treatment of chemical dependence.

23. Methods of use, manufacture, and kits of embodiments 12 to 22 and iterative methods of finding entourage effects for treating chemical dependence based on the compositions of embodiments 12 to 22.

Opiate Sparing

The use of opiate drugs in treatment of pain has become a controversial topic among medical practitioners and drug regulators. Government sources in the United States have presented statistics which suggest that opiates alone do not account for the rapid rate of increase in opiate overdose deaths. These data have given rise to a sharp debate regarding the exact nature of the“opiate crisis” in the United States.

National Institute on Drug Abuse provides statistical data indicating that every day, at least 115 Americans die by overdosing on opioids. The Centers for Disease Control and Prevention estimates that the total economic burden of prescription opioid misuse alone in the United States is $78.5 billion a year, including the costs of healthcare, lost productivity, addiction treatment, and criminal justice involvement. Based on data from the US CDC/NCHS, National Vital Statistics System, Mortality, during the period 2002 to 20015, the highest rise was seen for deaths involving heroin, with a 6.2-fold increase. During the same period the numbers of cocaine and benzodiazepine deaths that also involved an opioid; overdoses on these drug combinations have increased by nearly 2- and 5- fold respectively.

The US CDC, National Center for Health Statistics, Vital Statistics Rapid Release, data from the period August 2016 to 2017 indicate drug deaths involving fentanyl more than doubled from 2015 to 2016, accompanied by an upturn in deaths involving cocaine and methamphetamine. Together they add up to an epidemic of drug overdoses that is killing people at a faster rate than the H.I.V. epidemic at its peak. Deaths involving prescription opioids continue to rise, but many of those deaths also involved heroin, fentanyl or a fentanyl analogue. There is a downward trend in deaths from prescription opioids alone. At the same time, there has been a resurgence in cocaine and methamphetamine deaths. Many of these also involve opioids, but a significant portion of drug deaths, roughly one-third in 2015, do not.

By August 2017 the data indicate that since 2011 overdose deaths from prescription opioids have leveled off. None-the-less, government and media sources continue to assert the crisis has its roots in the over prescription of opioid painkillers, even though deaths from heroin and fentanyl continue to rise.

The ongoing governmental, medical and media focus on medically prescribed opiates has its basis in the belief that, in order to combat the illegal use of opiates, particularly in combination with benzodiazepines, it is essential to decrease the prescription use of opiates.

While many view the number of overdose deaths as the prime motivating factor in reducing opiate prescription use, there is considerable data related to reduction in quality of life for legal opiate users. This data along, regardless of any illegal opiate use, strongly motivate the sparing of opiates in clinical, legal use under medical supervision. Hence, illegal drug use has no necessary connection to the need to reduce opiate use as a means of increasing the quality of life of opiate users.

Opiates are commonly prescribed for a variety of ailments. Morphine is frequently prescribed to alleviate severe pain after surgery (fentanyl also can be prescribed for similar reasons). Codeine can be helpful in soothing milder pain, as are oxycodone (OxyContin, an oral, controlled-release form of the drug), propoxyphene (Darvon), hydrocodone (Vicodin), hydromorphone (Dilaudid) and meperidine (Demerol), which is used less often because of its side effects. Diphenoxylate or Lomotil can also relieve severe diarrhea, and codeine can ease severe coughs.

Cannabinoids, like opiates, produce analgesia through a G-protein-coupled mechanism that blocks the release of pain-propagating neurotransmitters in the brain and spinal cord. The high doses of opiates required to treat chronic, severe pain, are accompanied by undesirable side effects. THC enhances the potency of opioids such as morphine in animal models. The analgesic effect of THC is, at least in part, mediated through delta and kappa opioid receptors, indicating an intimate

connection between cannabinoid and opioid signaling pathways in the modulation of pain perception. Behavioral and molecular experiments suggest the role of opioid receptors in cannabinoid-induced analgesia. Accordingly, an analgesic regimen using low dose combinations of cannabinoids and opioids to effectively treat acute and chronic pain, especially pain that may be resistant to opioids alone. Of similar interest is the use of CBD in the treatment of several conditions which accompany chronic pain. Such conditions include by way of example, anxiety, depression, and insomnia.

Based on all of the above, the present invention provides a method of reducing the opiate burden in the treatment of pain, in particular chronic pain. One embodiment of the invention includes the methods of selecting optimal ratios and absolute amounts of principle cannabinoids for the treatment of pain which simultaneously reduce the need for opiates.

Selection of Compositions of the Invention

Embodiment 1. One embodiment of the present invention comprises, treating one or more test subject exhibiting one or more chemical dependence disorder described herein with one or more composition of the invention. Analytical data determining the presence, absence or amount of compounds described herein is obtained from said subject(s) at one or more points in time characterized as prior to, during or following said treatment. Said subject(s) are subjected to one or more tests, concurrent, prior or after treatment with the composition of the invention,

characterized as interrogation or biometric testing for one or more effect of said treatment on said chemical dependence disorder(s) with said composition. The presence absence or amount said compounds is compared to the effect(s) described above. Compositions of the invention are then rejected or accepted for use by said subject(s) based on the effects on the chemical dependence disorder described above.

Embodiment 2. In another aspect of the present invention, the analytical data of Embodiment 1 is obtained prior to and following treatment with said composition.

Embodiment 3. In another aspect of the present invention, the analytical data of Embodiment 1 is obtained during treatment with said composition.

Embodiment 4. In another aspect of the present invention, the analytical data of Embodiment 1 is obtained prior to, during and following treatment with said composition.

Embodiment 5. In another aspect of the present invention, the analytical data of Embodiments 1 , 2, 3, and 4 is further evaluated for changes in the presence, absence or amount of said compounds over the period from before, during and after treatment with said composition.

Embodiment 6. In another aspect of the present invention, the comparison of Embodiment 5 is used to create a matrix comprising the entourage-effect of said compounds contained in said compositions and the effect of said entourage-effect on any of the chemical dependence characteristics described herein.

Embodiment 7. In another aspect of the present invention, the entourage-effect of Embodiment 6 is used to discover what ratios of said compounds in said

compositions on any of the chemical dependence characteristics described herein.

Embodiment 8. In another aspect of the present invention, the ratios of Embodiment 7 are used to determine which said compositions are most effective in treatment of any of the chemical dependence characteristics described herein.

Embodiment 9. In a preferred embodiment of the invention the test subjects of the Embodiments 1 , 2, 3, 4, 5, 6, 7, and 8 are exposed to a plurality of compositions of the invention and are interrogated to determine the effects on a plurality of chemical dependence experience changes as described herein. Embodiment 10. Preferably the subjects of Embodiments 1 to 9 are Humans or animals, more preferably, Humans, dogs or cats, more preferably yet, Humans.

Embodiment 11. Preferably the analytical data of Embodiments 1 to 10 is taken from a blood fluid, more preferably, urine, plasma, cerebral spinal fluid, blood or saliva, more preferably yet, urine, plasma or blood.

Embodiment 12. Preferably the interrogation of Embodiments 1 to 11 is a survey method or interview, more preferably a survey method, more preferably a self- reporting written questionnaire.

Embodiment 13. Preferably the biometric testing of Embodiments 1 to 11 is a functional testing method, more preferably, a radiological method, more preferably yet a radiological method performed on animals, more preferably still, functional magnetic resonance imagery on animals, more preferably Humans.

Embodiment 14. Preferably, the effects Embodiments 1 to 13 are related to chemical dependence, more preferably, nicotine dependence or chemical dependence co-morbidities as described herein, more preferably yet to nicotine dependence.

Embodiment 15. Preferably the effects of Embodiments 1 to 14 are chemical dependence elimination, reduced chemical dependence severity, minimized discomfort during chemical dependence, or delayed experience of chemical dependence, more preferably chemical dependence elimination, or reduced chemical dependence severity.

Embodiment 16. One embodiment of the present invention comprises, treating one or more test subject exhibiting one or more chemical dependence disorder described herein with one or more composition of the invention. Analytical data determining the presence, absence or amount of compounds described herein is obtained from said subject(s) at one or more points in time characterized as prior to, during or following said treatment. Said subject(s) are subjected to one or more tests characterized as interrogation or biometric testing for one or more effect of said treatment on said chemical dependence disorder(s) with said composition. The presence absence or amount said compounds is compared to the effect(s) described above. Compositions of the invention are then modified to change said effects for use by said subject(s) based on the effects on the chemical dependence disorder described above.

Embodiment 17. In another aspect of the present invention, the analytical data of Embodiment 16 is obtained prior to and following treatment with said composition.

Embodiment 18. In another aspect of the present invention, the analytical data of Embodiment 16 is obtained during treatment with said composition.

Embodiment 19. In another aspect of the present invention, the analytical data of Embodiment 16 is obtained prior to, during and following treatment with said composition.

Embodiment 20. In another aspect of the present invention, the analytical data of Embodiments 16, 17, 18, and 19 is further evaluated for changes in the presence, absence or amount of said compounds over the period from before, during and after treatment with said composition.

Embodiment 21. In another aspect of the present invention, the comparison of Embodiment 20 is used to create a matrix comprising the entourage-effect of said compounds contained in said compositions and the effect of said entourage-effect on any of the chemical dependence characteristics described herein.

Embodiment 22. In another aspect of the present invention, the entourage-effect of Embodiment 21 is used to discover what ratios of said compounds in said

Embodiment 23. In another aspect of the present invention, the ratios of

Embodiment 22 are used to determine which said compositions are most effective in treatment of any of the chemical dependence characteristics described herein.

Embodiment 24. In a preferred embodiment of the invention the test subjects of the Embodiments 16, 17, 18, 19, 21 , 22, and 23 are exposed to a plurality of

compositions of the invention and are interrogated to determine the effects on a plurality of chemical dependence experience changes as described herein.

Embodiment 25. Preferably the subjects of Embodiments 16 to 24 are Humans or animals, more preferably, Humans, dogs or cats, more preferably yet, Humans. Embodiment 26. Preferably the analytical data of Embodiments 16 to 25 is taken from a blood fluid, more preferably, urine, plasma, cerebral spinal fluid, blood or saliva, more preferably yet, urine, plasma or blood.

Embodiment 27. Preferably the interrogation of Embodiments 16 to 26 is a survey method or interview, more preferably a survey method, more preferably a self- reporting written questionnaire.

Embodiment 28. Preferably the biometric testing of Embodiments 16 to 26 is a functional testing method, more preferably, a radiological method, more preferably yet a radiological method performed on animals, more preferably still, functional magnetic resonance imagery on animals.

Embodiment 29. Preferably, the effects Embodiments 16 to 28 are related to chemical dependence, more preferably, nicotine dependence, more preferably yet, nicotine or chemical dependence co-morbidities as described herein, more preferably yet to nicotine dependence.

Embodiment 30. Preferably the effects of Embodiments 16 to 29 are chemical dependence elimination, reduced chemical dependence severity, minimized discomfort during chemical dependence, or delayed experience of chemical dependence, more preferably chemical dependence elimination, or reduced chemical dependence severity.

Embodiment 31. Embodiments 1 to 30 further comprising alternatively obtaining said analytical data in a whole cannabis plant extract being used as said

composition.

Within the context of the present invention are any, a plurality or a single method described herein, preferably those set forth in the section above for selecting compositions of the invention, more preferably those of Embodiment 1 or 16 which further comprise the biometric data as set forth above, More preferably, the application of any of the above recited functional methods to select compositions of claims 1 to 16 of the present invention.

Embodiments of the functional analysis aspect of the invention include, by way of example and not limitation, tests/groups to measure changes in identified outcomes as a result of chemical dependence drug vs. placebo and/or drug vs. drug currently used to treat chemical dependence or related disorder.

In some cases of teenage cannabis use, adult nicotine addiction exemplified by tobacco smoking is thought to be statistically related. Accordingly, the present invention provides a method of selecting cannabis and cannabis derived

compositions and treatment methods for use in promoting the cessation of tobacco smoking in adults with a history of teenage cannabis use.

In this embodiment, adults who have used cannabis as teenagers either

simultaneously or separately with behaviors promoting tobacco smoking are treated with the compositions of the invention by the selection methods utilizing the entourage effect protocol described herein. Results of the two groups are analyzed. Compositions and treatment methods having utility for each group are selected. In this manner, the present invention provides compositions and treatment methods useful for either or both groups.

Embodiment 41. One embodiment of the present invention comprises, treating one or more test subject using opiate pain drugs described herein with one or more composition of the invention. Analytical data determining the presence, absence or amount of compounds described herein is obtained from said subject(s) at one or more points in time characterized as prior to, during or following said treatment. Said subject(s) are subjected to one or more tests, concurrent, prior or after treatment with the composition of the invention, characterized as interrogation or biometric testing for one or more effect of said treatment on said chemical dependence disorder(s) with said composition. The presence absence or amount said

compounds is compared to the effect(s) described above. Compositions of the invention are then rejected or accepted for use by said subject(s) based on the effects on the chemical dependence disorder described above.

Embodiment 42. In another aspect of the present invention, the analytical data of Embodiment 41 is obtained prior to and following treatment with said composition.

Embodiment 43. In another aspect of the present invention, the analytical data of Embodiment 41 is obtained during treatment with said composition. Embodiment 44. In another aspect of the present invention, the analytical data of Embodiment 41 is obtained prior to, during and following treatment with said composition.

Embodiment 45. In another aspect of the present invention, the analytical data of Embodiments 41 , 42, 43, and 44 is further evaluated for changes in the presence, absence or amount of said compounds over the period from before, during and after treatment with said composition.

Embodiment 46. In another aspect of the present invention, the comparison of Embodiment 45 is used to create a matrix comprising the entourage-effect of said compounds contained in said compositions and the effect of said entourage-effect on any of the opiate use characteristics described herein.

Embodiment 47. In another aspect of the present invention, the entourage-effect of Embodiment 46 is used to discover what ratios of said compounds in said

compositions on any of the opiate use characteristics described herein.

Embodiment 48. In another aspect of the present invention, the ratios of

Embodiment 47 are used to determine which said compositions are most effective in treatment of any of the opiate use characteristics described herein.

Embodiment 49. In a preferred embodiment of the invention the test subjects of the Embodiments 41 , 42, 43, 44, 45, 46, 47, and 48 are exposed to a plurality of compositions of the invention and are interrogated to determine the effects on a plurality of opiate use changes as described herein.

Embodiment 50. Preferably the subjects of Embodiments 41 to 49 are Humans or animals, more preferably, Humans, dogs or cats, more preferably yet, Humans.

Embodiment 51. Preferably the analytical data of Embodiments 41 to 50 is taken from a blood fluid, more preferably, urine, plasma, cerebral spinal fluid, blood or saliva, more preferably yet, urine, plasma or blood.

Embodiment 52. Preferably the interrogation of Embodiments 41 to 51 is a survey method or interview, more preferably a survey method, more preferably a self- reporting written questionnaire. Embodiment 53. Preferably the biometric testing of Embodiments 41 to 51 is a functional testing method, more preferably, a radiological method, more preferably yet a radiological method performed on animals, more preferably still, functional magnetic resonance imagery on animals, more preferably Humans.

Embodiment 54. Preferably, the effects Embodiments 41 to 53 are related to opiate use, more preferably, opiate dependence or opiate dependence co-morbidities as described herein, more preferably yet to medically prescribed opiate dependence.

Embodiment 55. Preferably the effects of Embodiments 41 to 64 are elimination, reduced severity, minimized discomfort during opiate use, or delayed experience of opiate withdrawal, more preferably reduced use of opiates.

Embodiment 56. One embodiment of the present invention comprises, treating one or more test subject using opiate pain drugs exhibiting one or more opiate side effects described herein with one or more composition of the invention. Analytical data determining the presence, absence or amount of compounds described herein is obtained from said subject(s) at one or more points in time characterized as prior to, during or following said treatment. Said subject(s) are subjected to one or more tests characterized as interrogation or biometric testing for one or more effect of said treatment on said opiate side effects with said composition. The presence absence or amount said compounds is compared to the effect(s) described above.

Compositions of the invention are then modified to change said effects for use by said subject(s) based on the effects on the opiate side effects described above.

Embodiment 57. In another aspect of the present invention, the analytical data of Embodiment 56 is obtained prior to and following treatment with said composition.

Embodiment 58. In another aspect of the present invention, the analytical data of Embodiment 56 is obtained during treatment with said composition.

Embodiment 59. In another aspect of the present invention, the analytical data of Embodiment 56 is obtained prior to, during and following treatment with said composition.

Embodiment 60. In another aspect of the present invention, the analytical data of Embodiments 46, 47, 48, and 49 is further evaluated for changes in the presence, absence or amount of said compounds over the period from before, during and after treatment with said composition.

Embodiment 61. In another aspect of the present invention, the comparison of Embodiment 60 is used to create a matrix comprising the entourage-effect of said compounds contained in said compositions and the effect of said entourage-effect on any of the opiate use characteristics described herein.

Embodiment 62. In another aspect of the present invention, the entourage-effect of Embodiment 61 is used to discover what ratios of said compounds in said

compositions on any of the opiate use characteristics described herein.

Embodiment 63. In another aspect of the present invention, the ratios of

Embodiment 62 are used to determine which said compositions are most effective in reduction of any of the opiate use characteristics described herein.

Embodiment 64. In a preferred embodiment of the invention the test subjects of the Embodiments 46, 47, 48, 49, 61 , 62, and 63 are exposed to a plurality of

compositions of the invention and are interrogated to determine the effects on a plurality of opiate side effects as described herein.

Embodiment 65. Preferably the subjects of Embodiments 46 to 64 are Humans or animals, more preferably, Humans, dogs or cats, more preferably yet, Humans.

Embodiment 66. Preferably the analytical data of Embodiments 46 to 65 is taken from a blood fluid, more preferably, urine, plasma, cerebral spinal fluid, blood or saliva, more preferably yet, urine, plasma or blood.

Embodiment 67. Preferably the interrogation of Embodiments 46 to 46 is a survey method or interview, more preferably a survey method, more preferably a self- reporting written questionnaire.

Embodiment 68. Preferably the biometric testing of Embodiments 46 to 66 is a functional testing method, more preferably, a radiological method, more preferably yet a radiological method performed on animals, more preferably still, functional magnetic resonance imagery on animals. Embodiment 69. Preferably, the effects Embodiments 41 to 53 are related to opiate use, more preferably, opiate dependence or opiate dependence co-morbidities as described herein, more preferably yet to medically prescribed opiate dependence.

Embodiment 70. Preferably the effects of Embodiments 46 to 69 are opiate use elimination, reduction or minimization.

Embodiment 71. Embodiments 40 to 70 further comprising alternatively obtaining said analytical data in a whole cannabis plant extract being used as said

composition.

Within the context of the present invention are any, a plurality or a single method described herein, preferably those set forth in the section above for selecting compositions of the invention, more preferably those of Embodiment 41 or 56 which further comprise the biometric data as set forth above, More preferably, the application of any of the above recited functional methods to select compositions of claims 41 to 56 of the present invention.

Embodiments of the functional analysis aspect of the invention include, by way of example and not limitation, tests/groups to measure changes in identified outcomes as a result of opiate use vs. placebo and/or drug vs. drug currently used to reduce opiate use.

Example 1

A sample comprising 1 ml of a liquid solution made from a whole plant CBD extract with additional CBD crystals and terpene isolates added is prepared in a base oil comprising propylene glycol such that it contains CBD (50mg), B-caryophyllene (4mg) D-Limonene (5mg), A-Pinene (2mg), B-Myrcene (3mg), and Linalool (2mg). The sample contains 52 mg/g CBD, 5 mg/g CBDA and less than 1 mg/g CBDV, CGB, CBGA, CBN, CBC, THC (delta 8 or 9), and THCA. The total CBD and CBDA is 56 mg/g.

The sample is provided to a Human and functional MRI examination is performed. Upon analysis, the data indicate a correlation between the promotion of tobacco smoking cessation and therapy with the sample when evaluated along with voluntary patient survey data indicative of the presence, absence or amount of tobacco smoking.

Example 2

A group of recipients each of which was self-defined as consuming 10 or more commercially available cigarettes daily was divided substantially equally between placebo and treatment arms. Each arm self-administered a CBD or placebo over a two-week period. The treatment arm comprised 400pg of CBD in a solution of propylene glycol for use in inhalation.

Each arm was evaluated by multiple measuring instruments. An fMRI task probing cue reactivity was subjected to a boxcar designed stimulus study including smoking- related stimuli, neutral and fixation using the International Smoking Image Series (ISIS). The study included 8 blocks of each stimulus, 10 stimuli/block. The sequence was smoking, neutral and fixation stimulus for 3 seconds followed by fixation for 1 second. The task was N-1 back task and picture rating at the end. Other measures included urine tests for smoking related factors, a smokerlyzer and a trait questionnaire. The questionnaire included by way of example: Tobacco Craving Questionnaire short-form (TCQ-SF), Motivation ladder, Minnesota

Withdrawal Scale (MNWS), The State-Trait Anxiety Inventory (STAI), The Snaith- Hamilton Pleasure Scale (SHAPS) and Beck Depression Inventory-ll (BDI-II).

Questionnaire measures showed significant reductions in: craving (TCQ-SF)

state anxiety (STAI)

depression (BDI-II)

withdrawal (MNWS)

As well as significant increase in motivation to quit smoking. No significant group differences were encountered. fMRI results included impacts on: right superior frontal gyrus

right medial frontal gyrus left thalamus

right parahippocampal gyrus

left putamen

middle frontal gyrus

fusiform gyrus

middle temporal gyrus

the precentral gyrus

Cannabis

Cannabis is a genus of flowering plant in the family Cannabaceae. The number of species within the genus is disputed. Three species may be recognized, Cannabis sativa, Cannabis indica and Cannabis ruderalis. C. ruderalis may be included within C. sativa; or all three may be treated as subspecies of a single species, C. sativa. Geoffrey William Guy; Brian Anthony Whittle; Philip Robson (2004); The Medicinal Uses of Cannabis and Cannabinoids. Pharmaceutical Press pp. 74, et. alia; ISBN 978-0-85369-517-2; "Classification Report”; United States Department of Agriculture; "Indica, Sativa, Ruderalis - Did We Get It All Wrong?", The Leaf Online; "Species of Cannabis"; GRIN Taxonomy; describe this background information.

The genus is indigenous to central Asia and the Indian subcontinent. A. ElSohly, Mahmoud (2007); Marijuana and the Cannabinoids. Humana Press p.8. ISBN 1 - 58829-456-0, describe this background information. Cannabis has long been used for hemp fiber, for hemp oils, for medicinal purposes, and as a recreational drug. Industrial hemp products are made from cannabis plants selected to produce an abundance of fiber. To satisfy the UN Narcotics Convention, some cannabis strains have been bred to produce minimal levels of tetrahydrocannabinol (THC), the principal psychoactive constituent. Many additional plants have been selectively bred to produce a maximum of THC (cannabinoids), which is obtained by curing the flowers. Various compounds, including hashish and hash oil, are extracted from the plant. Erowid. 2006. Cannabis Basics, describes this background material.

Within naturally occurring and manmade hybrids cannabis contains a vast array of compounds. Three compound classes are of interest within the context of the present invention although other compounds can be present or added to the compositions to optimize the experience of a given recreational consumer and medical or medicinal patient or patient population. Those classes include cannabinoids, terpenes and flavonoids.

There are many ways of growing cannabis some of which are natural, and some are carefully designed by Humans and they will not be recited here. However, one of ordinary skill in the art of cannabis production will typically place a cannabis seed or cutting into a growth media such as soil, manufactured soil designed for cannabis growth or one of many hydroponic growth medias. The cannabis seed or cutting is then provided with water, light and, optionally, a nutrient supplement. At times, the atmosphere and temperature are manipulated to aid in the growth process.

Typically, the humidity, air to carbon dioxide gas ratio and elevated temperature, either by use of a heat source or waste heat produced by artificial light are used. On many occasions ventilation is carefully controlled to maintain the conditions described above within an optimal range to both increase the rate of growth and, optionally, maximize the plant’s production of the compounds which comprise the compositions of the invention. It is possible to control lighting cycles to optimize various growth parameters of the plant.

Given the number of variables and the complex interaction of the variables it is possible to develop highly specific formulas for production of cannabis which lead to a variety of desired plant characteristics. At times these formulae constitute independent inventions. The present invention is applicable to use with such inventive means for growing cannabis as well as any of the variety of conventional methods.

Cannabis sativa is an annual herbaceous plant in the Cannabis genus. It is a member of a small, but diverse family of flowering plants of the Cannabaceae family. It has been cultivated throughout recorded history, used as a source of industrial fiber, seed oil, food, recreation, religious and spiritual moods and medicine. Each part of the plant is harvested differently, depending on the purpose of its use. The species was first classified by Carl Linnaeus in 1753.

Cannabis indica, formally known as Cannabis sativa forma indica, is an annual plant in the Cannabaceae family. A putative species of the genus Cannabis.

Cannabis ruderalis is a low-THC species of Cannabis which is native to Central and Eastern Europe and Russia. It is widely debated as to whether C. ruderalis is a sub species of Cannabis sativa. Many scholars accept Cannabis ruderalis as its own species due to its unique traits and phenotypes which distinguish it from Cannabis indica and Cannabis sativa.

Cannabis Derived Compositions

The present invention requires cannabis in the form of a living plant to be converted into a composition of the invention. The method of conversion typically involves harvesting and, optionally, one of the extraction, fraction, or purification steps described herein. More typically a combination of two or more such steps, more typically yet 2, 3, 4, 5, 6, 7, 8, 9, or 10 individual steps described herein. More typically still a combination of separating the cannabis from the media in which it is grown, drying to reduce the water content, grinding to form a power, extraction and, optionally, a fractionation or purification step is performed.

More typically the process comprises separation of the cannabis from the media in which is grown followed by 2, 3, 4, or 5 steps described above are performed, more typically yet, 2, 3, or 4 steps are performed.

Preferably the cannabis is separated from the media in which it is grown and first dried and then ground. Once in the ground state it is, optionally, sieved and finally the resins of the plant are extracted. These resins comprise the compositions of the invention or additional synthetic or semisynthetic compounds may be added to the resins. Remembering that optional fractionation and purification steps are possible, the compositions of the invention may have compounds removed from the resin. At that point, again optionally, synthetic or semisynthetic compounds may be added to the resin to form the compositions of the invention.

The specific Embodiments set forth below teach a novel method of not only identifying useful compositions but for performing iterative cycles of selection and, optionally, optimization of the compositions of the invention.

Some steps that can optionally be performed to optimize the utility of the

compositions include addition, removal or control of the absolute concentrations of compounds comprising the compositions, direct breeding of cannabis strains, genetic manipulation by methods known in the field of molecular biology such as gene insertion or deletion, lyophilization and the development of polyploid variants by use of compounds such as colicine. Cannabinoids

A cannabinoid is one of a class of diverse chemical compounds that acts on cannabinoid receptors such as CB1 and CB2 in cells that alter neurotransmitter release in the brain. Ligands for these receptor proteins include the

endocannabinoids (produced naturally in the body by animals), the

phytocannabinoids (found in cannabis and some other plants), and synthetic cannabinoids (manufactured artificially as set forth above). The most notable cannabinoid of the phytocannabinoids is tetrahydrocannabinol (THC), the primary psychoactive compound in cannabis. Cannabidiol (CBD) is another cannabinoid that is a major constituent of the plant. There are at least 113 different cannabinoids isolated from cannabis, exhibiting varied effects.

Synthetic cannabinoids and semisynthetic cannabinoids encompass a variety of distinct chemical classes: the classical cannabinoids structurally related to THC, the non-classical cannabinoids (cannabimimetics) including the aminoalkylindoles, 1 ,5- diarylpyrazoles, quinolines, and arylsulfonamides as well as eicosanoids related to endocannabinoids.

Tetrahydrocannabinol (THC) refers to a psychotropic cannabinoid and is the principal psychoactive constituent of cannabis. Its chemical name is (-)-trans-A⁹- tetrahydrocannabinol and the term "THC" is used to refer to isomers as well.

Like most pharmacologically-active secondary metabolites of plants, THC in

Cannabis is assumed to be involved in self-defense, perhaps against herbivores. THC also possesses high UV-B (280-315 nm) absorption properties, which, it has been speculated, could protect the plant from harmful UV radiation exposure.

Cannabidiol (CBD) is one of the active cannabinoids identified in cannabis. It is a major phytocannabinoid, by some accounts making up to 40% of the plant's extract. CBD does not appear to have any intoxicating effects such as those caused by THC in marijuana, but may have effects on anxiety, depression and have an anti- psychotic effect, and have effects on other comorbidities. In some instances, the comorbidities are related to disorders described herein such as pain and post- traumatic stress disorders commonly referred to as“PTSD.”

Cannabinol (CBN) is thought to be a non-psychoactive cannabinoid found only in trace amounts in Cannabis and can be produced via oxidative degradation of THCA and THC. Pharmacologically relevant quantities are formed as a metabolite of tetrahydrocannabinol (THC). CBN acts as a partial agonist at the CB1 receptors, but has a higher affinity to CB2 receptors, however; with lower affinities in comparison to THC. Degraded or oxidized cannabis products, such as low-quality baled cannabis and traditionally produced hashish, are high in CBN, but modern production processes have been alleged to minimize the formation of CBN. Cannabinol has been shown to have analgesic properties. Unlike other cannabinoids, CBN does not stem from cannabigerol (CBG).

Cannabigerol (CBG) is thought to be a non-intoxicating cannabinoid found in the Cannabis genus of plants. CBG is the non-acidic form of cannabigerolic acid

(CBGA), the parent molecule (“mother cannabinoid”) from which many other cannabinoids are obtained.

CBG has been found to act as a high affinity a2-adrenergic receptor agonist, moderate affinity 5-HT1A receptor antagonist, and low affinity CB1 receptor antagonist. It also binds to the CB2 receptor as an antagonist. CBG does not trigger THC-like activity in mice, rats, gerbils and non-human primates, consistent with it being non-intoxicating. Moreover, CBG was without effect up to 80 mg/kg in the mouse tetrad test of cannabimimetic activity (locomotor suppression, catalepsy, hypothermia and analgesia).

Cannabigerolic Acid (CBGA or CBG-A) is the alleged primordial phyto-cannabinoid.

It is the alleged compound in cannabis from which all the plant’s other naturally occurring cannabinoids are formed; without CBGA, the cannabis plant cannot produce its most useful compounds. It remains one of the most under-studied cannabinoids, with most of current research focusing on the purported healing properties of THC and CBD.

Structures of Selected Cannabinoids

Classification of chemical structures is accomplished in many ways. At times the classifications are defined by biological functional properties, biosynthetic pathways, biodegradation pathways, chemical functional properties, chemical naming systems (also commonly referred to as chemical nomenclature, IUPAC conventions and other systematic naming methods) and a variety of computer-controlled naming systems. Of particular interest in understanding the present invention are biosynthetic pathways, biological functional properties and chemical naming conventions. It is not uncommon for a given chemical compound to be named and/or depicted graphically in a variety of ways. In the context of the present invention, the following graphical depictions and accompanying names represent one preferred

embodiment. Other graphical and/or naming representations may exists for the exemplary chemical structures.

An isomer is the graphical and/or naming of a chemical structure or molecule (when meaning the actual physical substance) with the same molecular formula as another molecule, but with a different three-dimensional chemical structure. That is, isomers contain the same number of atoms of each element but have different arrangements of atoms in three-dimensional space. Isomers do not necessarily share similar properties, unless they also have the same functional groups. There are two main forms of isomerism: Structural isomerism (or constitutional isomerism) and stereoisomerism (or spatial isomerism).

In structural isomers, sometimes referred to as constitutional isomers, the atoms and functional groups are joined together in different ways. Structural isomers have different IUPAC names and may or may not belong to the same functional group. This group includes chain isomerism whereby hydrocarbon chains have variable amounts of branching; position isomerism, which deals with the position of a functional group on a chain; and functional group isomerism, in which one functional group is split up into different ones.

For example, two position isomers would be 2-fluoropropane and 1 -fluoropropane.

In skeletal isomers the main carbon chain is different between the two isomers. This type of isomerism is most identifiable in secondary and tertiary alcohol isomers. Tautomers are structural isomers that spontaneously interconvert with each other, even when pure. They have different chemical properties and, as a consequence, distinct reactions characteristic to each form are observed. If the interconversion reaction is fast enough, tautomers cannot be isolated from each other. An example is when they differ by the position of a proton, such as in keto/enol tautomerism, where the proton is alternately on the carbon or oxygen.

In stereoisomers the bond structure is the same, but the geometrical positioning of atoms and functional groups in space differs. This class includes enantiomers which are non-superimposable mirror-images of each other, and diastereomers, which are not. Enantiomers always contain chiral centers and diastereomers often do, but there are some diastereomers that neither are chiral nor contain chiral centers. Another type of isomer, conformational isomers (conformers), may be rotamers, diastereomers, or enantiomers depending on the exact compound. For example, ortho- position-locked biphenyl systems have enantiomers.

E/Z isomers, which have restricted rotation at a double bond, are configurational isomers. They are classified as diastereomers, whether or not they contain any chiral centers. E/Z notation depicts absolute stereochemistry, which is an

unambiguous descriptor based on CIP priorities.

"Cis-trans isomers" are used to describe any molecules with restricted rotation in the molecule. For molecules with C=C double bonds, these descriptors describe relative stereochemistry only based on group bulkiness or principal carbon chain, and so can be ambiguous. This is especially problematic for double bonds that have more than two substituents. An obsolete term for cis-trans isomerism is "geometric isomerism". For alkenes with more than two substituents, E-Z notation is used instead of cis and trans. If possible, E and Z (written in italic type) is also preferred in compounds with two substituents.

Note that, although conformers can be referred to as stereoisomers, they are not stable isomers, since bonds in conformers can easily rotate, thus converting one conformer to another, which can be either diastereomeric or enantiomeric to the original one.

While structural isomers typically have different chemical properties, stereoisomers behave identically in most chemical reactions, except in their reaction with other stereoisomers. Enzymes, however, can distinguish between different enantiomers of a compound, and organisms often prefer one isomer over the other.

Enantiomers differ in the direction of their optical rotation of polarized light and are therefore sometimes described as optical isomers. Flowever, this term is ill-defined and has also been used to describe other stereoisomers as well as enantiomers. Its use is therefore strongly discouraged, and the molecules should instead be described as either enantiomers or diastereomers as appropriate.

Isomerization is the process by which one molecule is transformed into another molecule that has exactly the same atoms, but the atoms are rearranged. In some molecules and under some conditions, isomerization occurs spontaneously. Many isomers are equal or roughly equal in bond energy, and so exist in roughly equal amounts, provided that they can interconvert relatively freely, that is the energy barrier between the two isomers is not too high. When the isomerization occurs intramolecularly, it is considered a rearrangement reaction.

Other types of isomerism exist. Topological isomers called topoisomers are large molecules that wind about and form different-shaped knots or loops. Molecules with topoisomers include catenanes and DNA. Topoisomerase enzymes can knot DNA and thus change its topology. There are also isotopomers or isotopic isomers that have the same numbers of each type of isotopic substitution but in chemically different positions.

Chirality is a geometric property of some molecules and ions. A chiral molecule/ion is non-superimposable on its mirror image. The presence of an asymmetric carbon center is one of several structural features that induce chirality in organic and inorganic molecules.

The mirror images of a chiral molecule/ion are called enantiomers or optical isomers. Individual enantiomers are often designated as either right-handed or left-handed. Chirality is an essential consideration when discussing the stereochemistry in organic and inorganic chemistry. The concept is of great practical importance because most biomolecules and pharmaceuticals are chiral.

One important type of isomerization is the conversion of one enantiomer to its pair. That form is commonly referred to as enantiomeric conversion, epimerization or, when mixtures of enantiomers is formed by isomerization, it can be called

racemization or partial racemization. Chiral molecules and ions are described by various ways of designating their absolute configuration, which codify either the entity's geometry or its ability to rotate plane-polarized light, a common technique in studying chirality.

All of the above description of isomers, stereoisomers, enantiomers, and so forth, along with the isomerizations set forth are contemplated to be within the scope of the present invention. More specifically, in the example structural representations below, isomers as described herein, together with the appropriate graphical and naming systems for each, are considered to fall within the descriptions of the chemical compounds.

Accordingly, in one aspect of the invention, each of the following graphical representations describes exemplary cannabinoids:

Terpene and Terpenoid

Terpenes are a large and diverse class of organic compounds, produced by a variety of plants, particularly conifers, and by some insects such as termites or swallowtail butterflies, which emit terpenes from their osmeteria. They often have a strong odor and may protect the plants that produce them by deterring herbivores and by attracting predators and parasites of herbivores. The difference between terpenes and terpenoids is that terpenes are hydrocarbons, whereas terpenoids contain additional functional groups.

They are the major components of resin, and of turpentine produced from resin. The name "terpene" is derived from the word "turpentine". In addition to their roles as end-products in many organisms, terpenes are major biosynthetic building blocks within nearly every living creature. Steroids, for example, are derivatives of the triterpene squalene.

When terpenes are modified chemically, such as by oxidation or rearrangement of the carbon skeleton, the resulting compounds are generally referred to as

terpenoids. Some authors will use the term terpene to include all terpenoids.

Terpenoids are also known as isoprenoids.

Terpenes and terpenoids are the primary constituents of the essential oils of many types of plants and flowers. Essential oils are used widely as fragrances in perfumery, and in medicine and alternative medicines such as aromatherapy.

Synthetic variations and derivatives of natural terpenes and terpenoids also greatly expand the variety of aromas used in perfumery and flavors used in food additives. Vitamin A is a terpenoid.

Higher amounts of terpenes are released by trees in warmer weather, acting as a natural form of cloud seeding. The clouds reflect sunlight, allowing the forest to regulate its temperature. The aroma and flavor of hops comes, in part, from sesquiterpenes (mainly alpha-humulene and beta-caryophyllene), which affect beer quality. Terpenes are also major constituents of Cannabis sativa plants, which contain at least 120 identified compounds.

The terpenoids, sometimes called isoprenoids, are a large and diverse class of naturally occurring organic chemicals like terpenes, derived from five-carbon isoprene units assembled and modified in thousands of ways. Most are multicyclic structures that differ from one another not only in functional groups but also in their basic carbon skeletons. These lipids can be found in all classes of living things, and are the largest group of natural products. About 60% of known natural products are terpenoids. There are virtually countless manmade synthetic and semisynthetic terpenes.

Plant terpenoids are used extensively for their aromatic qualities and play a role in traditional herbal remedies. Terpenoids contribute to the scent of eucalyptus, the flavors of cinnamon, cloves, and ginger, the yellow color in sunflowers, and the red color in tomatoes. Well-known terpenoids include citral, menthol, camphor, salvinorin A in the plant Salvia divinorum, the cannabinoids found in cannabis, ginkgolide and bilobalide found in Ginkgo biloba, and the curcuminoids found in turmeric and mustard seed. The steroids and sterols in animals are biologically produced from terpenoid precursors. Sometimes terpenoids are added to proteins, e.g., to enhance their attachment to the cell membrane; this is known as isoprenylation.

Any Terpene can be converted to a terpenoid, synthetic terpenoid or semisynthetic terpenoid by an array of known chemical reactions. These conversions have been taught so exhaustively in the art that one of ordinary skill in synthetic organic chemistry or natural products chemistry would have no difficulty choosing the appropriate steps, sequences of steps and purification means necessary to prepare the subject terpenoid, synthetic or semisynthetic terpenoid and no more will be set forth here.

Table 4b - Selected Terpenoids

Beta-caryophyllene, Borneol, 1 ,8-cineole, camphene, Humulene, Limonene, Linalool, Myrcene, Nerolidol, Pulegone, and Terpinolene.

Flavonoids

Flavonoids (or bioflavonoids) (from the Latin word flavus meaning yellow, their color in nature) are a class of plant and fungus secondary metabolites.

Chemically, flavonoids have the general structure of a 15-carbon skeleton, which consists of two phenyl rings (A and B) and heterocyclic ring (C). This carbon structure can be abbreviated C6-C3-C6. According to the IUPAC nomenclature, they can be classified into: flavonoids or bioflavonoids, isoflavonoids, derived from 3-phenylchromen-4-one (3- phenyl-1 ,4-benzopyrone) structure, and neoflavonoids, derived from 4- phenylcoumarine (4-phenyl-1 ,2-benzopyrone) structure.

The three flavonoid classes above are all ketone-containing compounds, and as such, are anthoxanthins (flavones and flavonols). This class was the first to be termed bioflavonoids. The terms flavonoid and bioflavonoid have also been more loosely used to describe non-ketone polyhydroxy polyphenol compounds which are more specifically termed flavanoids. The three cycle or heterocycles in the flavonoid backbone are generally called ring A, B and C. Ring A usually shows a phloroglucinol substitution pattern.

Flavonoids are widely distributed in plants, fulfilling many functions. Flavonoids are the most important plant pigments for flower coloration, producing yellow or red/blue pigmentation in petals designed to attract pollinator animals. In higher plants, flavonoids are involved in UV filtration, symbiotic nitrogen fixation and floral pigmentation. They may also act as chemical messengers, physiological regulators, and cell cycle inhibitors. Flavonoids secreted by the root of their host plant help Rhizobia in the infection stage of their symbiotic relationship with legumes like peas, beans, clover, and soy. Rhizobia living in soil can sense the flavonoids and triggers the secretion of Nod factors, which in turn are recognized by the host plant and can lead to root hair deformation and several cellular responses such as ion fluxes and the formation of a root nodule. In addition, some flavonoids have inhibitory activity against organisms that cause plant diseases, e.g. Fusarium oxysporum.

Isoflavones use the 3-phenylchromen-4-one skeleton (with no hydroxyl group substitution on carbon at position 2). Examples include: Genistein, Daidzein, Glycitein, Isoflavanes, Isoflavandiols, Isoflavenes, Coumestans, and Pterocarpans.

Table 4c - Selected Flavonoids

Apigenin, beta-sitosterol, cannaflavin A, kaempferol, luteolin, orientin, and quercetin.

Dosage Forms

Suitable dosages of the compositions for use in the methods of the present disclosure will depend upon many factors including, for example, age and weight of an individual, at least one precise event requiring professional consultation, severity of an event, specific composition to be used, nature of a composition, route of administration and combinations thereof. Ultimately, a suitable dosage can be readily determined by one skilled in the art such as, for example, a physician, a veterinarian, a scientist, and other medical and research professionals. For example, one skilled in the art can begin with a low dosage that can be increased until reaching the desired treatment outcome or result. Alternatively, one skilled in the art can begin with a high dosage that can be decreased until reaching a minimum dosage needed to achieve the desired treatment outcome or result. In some embodiments, the compositions of the present disclosure can be administered to a subset of individuals in need thereof as a therapeutic composition. As used herein, an "individual in need" refers to an individual at risk for or having a medical need such as those described herein. Additionally, an "individual in need" is also used herein to refer to an individual at risk for or diagnosed by a medical professional as having a condition described herein. As such, in some embodiments, the methods disclosed herein are directed to a subset of the general population such that, in these embodiments, not all the general population may benefit from the methods. Based on the foregoing, because some of the method embodiments of the present disclosure are directed to specific subsets or subclasses of identified individuals (that is, the subset or subclass of individuals "in need" of assistance in addressing one or more specific conditions noted herein), not all individuals will fall within the subset or subclass of individuals as described herein. Generally, the individual in need is a human. The individual in need can also be, for example, an animal such as a companion animal or a research animal such as, for example, a non-human primate, a mouse, a rat, a rabbit, a cow, a pig, and other types of research animals known to those skilled in the art.

A dosage form is that object delivered to a subject Human or non-Human organism for testing, placebo, recreational, therapeutic or other use. Widely varying types are set forth below. Countless dosage forms exist. One primary reference describing dosage forms is Remington: The Science and Practice of Pharmacy, 21 st ed., ISBN- 13 978-0781746731 (“Remington”). One of ordinary skill in the pharmaceutical and pharmacological arts are aware of a wide variety of dosage forms and more examples and references need not be set forth here.

Suitable amounts of the active agent(s) for use in the dosage forms of the present disclosure will depend upon many factors including, for example, age and weight of an individual, specific active agent(s) to be used, nature of a composition, whether the composition is intended for direct administration or is a concentrate, and combinations thereof. Ultimately, a suitable amount can be readily determined by one skilled in the art. For example, one skilled in the art can begin with a low amount that can be increased until reaching the desired result or effect.

Alternatively, one skilled in the art can begin with a high dosage that can be decreased until reaching a minimum dosage needed to achieve the desired result or effect. As with dosage forms, countless methods of delivery exist. For the purposes of the present invention, delivery includes the provision and use of a dosage form containing a composition of the invention so that about 10%, 20%, 30%, 40%, 50%, 60%, 70%, or 80%, more preferably, about 90%, and more preferably yet, about 95% of the composition of the invention reaches a biological system or material of the subject Human or non-Human such that it is available for biological interaction with said subject.

Dosage forms of the invention comprise bioactive substances selected

independently or in combination from cannabinoids, terpenoids and flavonoids.

Such substances are lipophilic and typically have low solubility in hydrophilic biocompatible matrix materials. One method for obtaining desirable dosage forms comprising lipophilic substances and hydrophilic biocompatible matrix substances is to encapsulate or disperse lipophilic substances in the hydrophilic matrix using additives or modifiers which provide an environment for stable oil-in-water emulsions, micelles, liposomes or other complex phase equilibrium modified compositions. Many of these techniques, modifiers and additives are described herein.

An exemplary method of preparing a stable oil-in-water dosage form is to use a nanoemulsion to encapsulate lipophilic bioactive compounds in a carrier oil. The carrier oil is, optionally, food grade, not adversely affect product quality (such as appearance, taste, texture, or stability), protect from chemical degradation during storage and distribution, and increase bioavailability following ingestion. Carrier oils help stabilize emulsions from Ostwald ripening, a destabilization mechanism of nanoemulsions. This problem arises due to the increased solubility of dispersed phase in a hydrophilic.

Carrier oils can have an effect the physicochemical stability of nanoemulsions in the gastrointestinal tract (Gl Tract). The rate and extent of lipid digestion is higher for MCT emulsions than for LCT emulsions, which is attributed to differences in the water dispersibility of the medium and long chain fatty acids formed during lipolysis. The total bioavailability of active components after digestion can be higher for LCT emulsions than for MCT emulsions.

Long-chain triglycerides (LCT) contain fatty acids of 12-20 carbon atoms, and can form mixed micelles with a hydrophobic core large enough to accommodate active substances such as THC and other cannabinoids, terpenoids and flavonoids. Medium-chain triglycerides (MCT) contain fatty acids of 12-20 carbon atoms and can form mixed micelles with smaller hydrophobic.

Emulsions can be prepared in concentrated form and later diluted several hundred times in sugar/acid solutions prior to consumption to produce finished dosage forms in either carbonated or non-carbonated biocompatible matrix systems. Selection of an emulsifier can affect the shelf-life and physicochemical properties of the emulsion. Emulsions stabilized by surfactants or other types of stabilizing agents

phospholipids, amphiphilic proteins, or polysaccharides, have been developed to provide controlled release, improved entrapment efficiency, and protection from degradation.

Other suitable types of modifiers and additives include natural emulsifiers, oils, thickening agents, minerals, acids, bases, vitamins, flavors, colorants and other processing, storage, distribution, transport, and use conditions such as

ultrasonication, nitrogen dosing, packaging, and sterilization

Emulsions can be prepared several ways such as mechanical processes which employs shear force to break large emulsion droplets into smaller ones, high- pressure homogenization (HPH, including microfluidization) and high-amplitude ultrasonic processing, and ultrasound-assisted emulsification

Small droplet sizes lead to transparent emulsions. Droplet sizes about 100, 90, 80, 70, 60, 50 or 40 nm are desirable. Preferably the droplet sizes for transparent emulsions are in the range of 40 to 60 nm, more preferably they are 45 to 55 nm, more preferably yet, 50 nm.

Nutritional additives and modifiers comprise substances useful to the consumer of the oral dosage form for maintenance of normal body health. Preferably nutritional additives comprise essential nutrients including vitamins, dietary minerals amino acids and fatty acids vitamin A, vitamin B1 , vitamin B2, vitamin B3, vitamin B5, vitamin B6, vitamin B7, vitamin B9, vitamin B12, vitamin C, vitamin D, vitamin E, vitamin K calcium, phosphorus, potassium, sulfur, sodium, chlorine, magnesium, iron, cobalt, copper, zinc, molybdenum, iodine, selenium, manganese, nickel, chromium, fluorine, boron, strontium histidine, isoleucine, leucine, lysine, methionine, cysteine, phenylalanine, tyrosine, threonine, tryptophan, valine, alpha-linoleic acid, and linoleic acid. Optional additives and modifiers comprise one or more of acids, bases, acidity regulators, alcohol, anticaking agents, antifoaming agents, antioxidants, bulking agents, coagulation agents, food coloring, color retention agents, emulsifiers, flavor enhancers, flour treatment agents, gelling agents, glazing agents, humectants, leavening agents, tracer gases, preservatives, stabilizers, sweeteners, tenderizers, and thickeners.

One class of common additive or modifier useful in oral dosage forms of the invention is the group of substances referred to as phospholipids. Phospholipids are made up of two fatty acid tails and a phosphate group head. Fatty acids are long chains mostly made up of hydrogen and carbon, while phosphate groups consist of a phosphorus molecule with four oxygen molecules attached. These two components of the phospholipid are connected via a third molecule, glycerol.

Phospholipids can act as emulsifiers, enabling oils to form a colloid with water.

Phospholipids are one of the components of lecithin which is found in egg-yolks, as well as being extracted from soy beans, and is used as a food additive in many products, and can be purchased as a dietary supplement. Lysolecithins are typically used for water-oil emulsions like margarine, due to their higher HLB ratio.

Dosage forms of this type commonly use phospholipid additives or modifiers to solubilize one or more hydrophobic components of the cannabis or cannabis derived composition. The methods of solubilization are describe herein. In this embodiment, phospholipids are typically derived from natural sources such as a naturally occurring oils from a plant such as coconut, safflower and sunflower. These phospholipids can include secondary products obtained therefrom such as lecithin from sunflower oil. In these embodiments the phospholipid or derivative therefrom is present in about 0.01 -10 weight or volume percent. More typically, 0.01 , 0.1 , 1 or 10 weight or volume percent, more typically yet 0.1 to 1 weight or volume percent.

In the same fashion as phospholipids, triglycerides are a typical additive or modifier of the oral dosage forms of the invention. Triglycerides are chemically tri esters of fatty acids and glycerol. Triglycerides are formed by combining glycerol with three fatty acid molecules. Alcohols have a hydroxyl (HO-) group. Organic acids have a carboxyl (-COOH) group. Alcohols and organic acids join to form esters. The glycerol molecule has three hydroxyl (HO-) groups. Each fatty acid has a carboxyl group (-COOH). In triglycerides, the hydroxyl groups of the glycerol join the carboxyl groups of the fatty acid to form ester bonds:

The three fatty acids (RC0₂H, R'C0₂H, R"C0₂H in the above equation) are usually different, but many kinds of triglycerides are known. The chain lengths of the fatty acids in naturally occurring triglycerides vary, but most contain 16, 18, or 20 carbon atoms. Natural fatty acids found in plants and animals are typically composed of only even numbers of carbon atoms, reflecting the pathway for their biosynthesis from the two-carbon building-block acetyl CoA. Bacteria, however, possess the ability to synthesize odd- and branched-chain fatty acids. As a result, ruminant animal fat contains odd-numbered fatty acids, such as 15, due to the action of bacteria in the rumen. Many fatty acids are unsaturated, some are polyunsaturated (e.g., those derived from linoleic acid).

Most natural fats contain a complex mixture of individual triglycerides. Because of this, they melt over a broad range of temperatures. Cocoa butter is unusual in that it is composed of only a few triglycerides, derived from palmitic, oleic, and stearic acids in the 1 -, 2-, and 3-positions of glycerol, respectively.

In embodiments wherein triglycerides are used as additives or modifiers of the oral dosage form, they are present in about 0.01 -10 weight or volume percent. More typically, 0.01 , 0.1 , 1 or 10 weight or volume percent, more typically yet 0.1 to 1 weight or volume percent.

Natural phospholipid derivatives include egg PC (Egg lecithin), egg PG, soy PC, hydrogenated soy PC, and sphingomyelin as natural phospholipids. Synthetic phospholipid derivatives include phosphatidic acid (DMPA, DPPA, DSPA), phosphatidylcholine (DDPC, DLPC, DMPC, DPPC, DSPC, DOPC, POPC, DEPC), phosphatidylglycerol (DMPG, DPPG, DSPG, POPG), phosphatidylethanolamine (DMPE, DPPE, DSPE DOPE), phosphatidylserine (DOPS), PEG phospholipid (mPEG-phospholipid, polyglycerin-phospholipid, functionalized-phospholipid, and terminal activated-phospholipid).

Phospholipids can form cell, micelle and liposomal membranes as well as other self- organizing multi-molecular structures because the phosphate group head is hydrophilic (water-loving) while the fatty acid tails are hydrophobic (water-hating). They automatically arrange themselves in a certain pattern in water or other polar environment because of these properties, and form membranes. To form

membranes, phospholipids line up next to each other with their heads on the outside of the polar medium and their tails on the inside, thus forming an inner and outer surface. A second layer of phospholipids also forms with heads facing the inside of the structure and tails facing away. In this way, a double layer is formed with phosphate group heads on the outside, and fatty acid tails on the inside. This double layer, called a lipid bilayer, forms the main part of the membrane or other similar structure.

Methods of Making the Compositions of the Invention

Extraction in natural products chemistry is a separation process comprising the separation of a substance from a matrix of natural materials and includes liquid-liquid extraction, solid phase extraction and what is commonly referred to as super-critical extraction. The distribution of any given compound or composition (hereinafter desired material) between two phases is an equilibrium condition described by partition theory. This is based on exactly how the desired material moves from a first solution, typically water or other material capable of dissolving a desired material with a first solubility of the desired material, into second material, typically an organic or other immiscible layer having a second solubility of the desired material layer. Super-critical (supercritical) extraction involves entirely different phenomenon and will be described below.

In the context of the present invention, the desired material may be a composition of the invention, a subset of compounds which are components of the composition of the invention, or a single compound which is a component of the composition of the invention. Preferably, the desired material is a composition described herein substantially free of impurities other than solvent or other extraction reagents, more preferably it is about 10%, 20%, 30%, 40%, 50%, 60%, 70%, or 80% free of said impurities, more preferably it is about 90% free of said impurities, more preferably yet, the desired material is about 95% free of impurities other than solvents or other extraction reagents.

There exist several types of extraction, including liquid-liquid extraction, solid-phase extraction, solid-phase microextraction, Soxhlet extraction, fizzy extraction and super-critical CO2 (supercritical carbon dioxide) extraction.

Extractions often use two immiscible phases to separate a solute such as the desired material from one phase into the other. Typical laboratory extractions are of organic compounds such as the desired material out of an aqueous phase and into an organic phase. Preferred extractant systems arranged in order of their typical preferability include ethyl acetate < acetone < ethanol < methanol < acetone: water (7:3) < ethanol: water (8:2) < methanol: water (8:2) < water, etc., in increasing order of polarity according to the Hildebrand solubility parameter. The extract can be put back to dried or other form using a centrifugal evaporator or a freeze-drier.

Extraction of compositions of the invention are prepared by butane extraction or super-critical CO2 (supercritical carbon dioxide) extraction of cannabis whole plant derived material, preferably, harvested, dried and ground cannabis.

Modern more technical techniques include supercritical carbon dioxide extraction (super-critical CO2), ultrasonic extraction, heat reflux extraction, mechanochemical- assisted extraction, microwave-assisted extraction, instant controlled pressure drop extraction (DIC), and perstraction.

In the context of the present invention, perstraction is the separation technique developed from liquid-liquid extraction. Due to the presence of the membrane a wider selection of extractants can be used, this can include the use of miscible solutions, for example the recovery of ammonia from waste water using sulphuric acid. Perstraction as it relates to the extraction of organic molecules of molecular weights in compliance with the“Robert’s rules” is a developing field and the present invention contemplates the use of the basic principles pf perstraction whether by conventional or highly evolved methods.

This process is analogous to pervaporation in some ways. But the permeate is in liquid phase. Perstraction technique eliminates the problem of phase dispersion and separation altogether.

A basic perstraction is called the single perstraction or membrane perstraction. An advantage is minimizing toxic damage to microorganisms or enzymes.

Nevertheless, perstraction includes problems like expensive membranes, clogging and fouling of membranes. Such methods are advantageous in complex natural products extraction because, based on the availability of suitable membranes, it provides a technique essentially free of high temperatures or complex and potentially destructive liquid phases.

Perstraction has been combined with the ABE (acetone butanol ethanol)

fermentation for butanol production. Butanol is toxic to the fermentation, therefore perstraction can be applied to remove the butanol from the vicinity of the bacteria as soon as it is produced. Liquid-liquid extraction (LLE) was combined with the ABE fermentation for in situ product recovery, but the extractants with the highest affinity for butanol tend to be toxic to the bacteria. The application of LLE would also require the extractant to be sterilized prior to contact with the fermentation broth.

Perstraction can overcome these problems due to a membrane separating the fermentation broth from the extractant. One utility of this method in the context of the present invention for the extraction of desired materials from complex biosynthetic systems, thus leading to commercially practical preparation of cannabis biosynthetic materials.

An example of the extraction of a composition from natural material is boiling tea leaves in water extracts the tannins, theobromine, and caffeine out of the leaves and into the water. Solid-liquid extractions at laboratory scales can use Soxhlet extractors (such as oil from olive cake). Similar methods are applicable to cannabis, in either whole plant synthetic or biosynthetic systems.

In another example, a hydrophobic antibiotic called geldanamycin was separated from media by the capsular perstraction. Outer particle diameter varied from about 500 to 750 pm. Alginate formed the shell of the capsule and its thickness varied from about 30 to 90 pm. Dibutyl sebacate or oleic acid as the liquid core extracted geldanamycin well. The bigger agitation and thinner capsule membrane appear to responsible for the faster transfer rate observed.

Geldanamycin was back-extracted from the capsules. Dibutyl sebacate capsules were disposable because the liquid core came out from the capsules in the back- extraction. On the contrary oleic acid remained in the capsules during the back- extraction when an extractant was saturated with oleic acid. Nevertheless, the presence of oleic acid in the back-extraction solution demanded more purification steps such as precipitation, centrifugation and filtration. Oleic acid was removed because it prevents crystallization of geldanamycin. Therefore, geldanamycin was crystallized and the product was highly purified.

Enzymes can be immobilized to the capsule membrane. In this case the capsules external diameter was about 500 pm and internal diameter was about 300 pm. The product of enzyme-catalyzed reaction can be concentrated to capsules and the end- product inhibition was low. Enzyme recycling could be performed by back-extracting the product. The technique has also been applied to the hydrolysis of penicillin G. One of ordinary skill in the art of natural products extraction and isolation could devise many more methods of extracting said desired materials and no further description need be provided here.

Among the technologies available for the extraction of cannabis to obtain cannabis and cannabis derived desired materials is the use supercritical CO2 (SC-C02, supercritical carbon dioxide) to perform the solubilization of desired material from raw or processed cannabis. In this context, processed cannabis refers to harvested, dried and ground cannabis or any method of processing which provides a similar material. Carbon dioxide (CO2) is non-flammable, relatively inert, abundant and inexpensive when used in the extraction process. Furthermore, the use of CO2 is acceptable in the food industry and Generally Recognized As Safe (GRAS).

Additionally, the waste plant material can be easily recycled. From an ecological point of view, the alternative process is also more sustainable as it consumes less energy and generates less waste. Since waxes are co-extracted with constituents when using SC-C02, a further purification step is needed to obtain an extract pure enough to be used in dosage forms. This can be easily achieved by adding a winterization step, for example by freezing the extract to precipitate the waxes followed by filtration to separate the cannabinoids from the waxes. The purity of the final extract after winterization is around 70, 80, or 90% at optimal conditions, more typically between 75and 90%, more typically, about 75-90%, more typically yet, about 75%. Under controlled conditions SC-CO2 can result in fractionation of constituents with different molecular weights. Fractionation of this type is useful to separate psychotropic (TFIC) and non-psychotropic (CBD) cannabinoids in dosage forms.

Fractionation is a separation process in which a certain quantity of a of any given compound or composition (hereinafter desired material) a desired material, solid, liquid, enzymes, suspension, or isotope, is divided during a phase transition, into many smaller quantities (fractions) in which the desired material varies according to a gradient. Fractions are collected based on differences in a specific property of the individual components. A common trait in fractionations is the need to find an optimum between the number of fractions collected and the desired purity in each fraction. Fractionation makes it possible to isolate multiple components in a mixture in a single run. This property sets it apart from other separation techniques.

In the context of the present invention, the desired material may be a composition of the invention, a subset of compounds which are components of the composition of the invention, or a single compound which is a component of the composition of the invention. Preferably, the desired material is a composition described herein substantially free of impurities other than solvent of other reagents used in the fractionation, more preferably it is about 10%, 20%, 30%, 40%, 50%, 60%, 70%, or 80% free of said impurities, more preferably it is at about 90% free of said impurities, more preferably yet, the desired material is about 95% free of impurities other than solvents or other reagents used in the fractionation.

Fractionation is widely employed in many branches of science and technology.

Mixtures of liquids and gases are separated by fractional distillation by difference in boiling point for example. Fractionation of components also takes place in column chromatography by a difference in affinity between stationary phase and the mobile phase for example. In fractional crystallization and fractional freezing, chemical substances are fractionated based on difference in solubility at a given temperature for example. In cell fractionation, cell components are separated by difference in mass for example.

In pharmacognosy, a typical protocol to isolate a pure desired material from natural origin is bioassay-guided fractionation, meaning step-by-step separation of extracted components based on differences in their physicochemical properties, and assessing the biological activity, followed by next round of separation and assaying.

Purification in a chemical context is the physical separation of a desired material from foreign or contaminating substances. Pure results of a successful purification process are termed isolate. The following list of chemical purification methods should not be considered exhaustive and is provided by way of example:

Affinity purification is used to purify proteins by retaining them on a column through their affinity to antibodies, enzymes or receptors which have been immobilized on the column.

Filtration is a mechanical method to separate solids from liquids or gases by passing the feed stream through a porous sheet such as a cloth or membrane, which retains the solids and allows the liquid to pass through.

Centrifugation is a process in which light particles are revolved at high speed with the help of an electric motor so that the fine particles which do not settle at bottom would settle down. Evaporation is used to remove volatile liquids from non-volatile solutes which cannot be done through filtration due to the small size of the substances.

Liquid-liquid extraction removes an impurity or recovers a desired product by dissolving the crude material in a solvent in which other components of the feed material are soluble.

Crystallization separates a product from a liquid feed stream, often in extremely pure form, by cooling the feed stream or adding precipitants which lower the solubility of the desired product so that it forms crystals. The pure solid crystals are then separated from the remaining liquor by filtration or centrifugation.

Recrystallization: In analytical and synthetic chemistry work, purchased reagents of doubtful purity may be recrystallized, e.g. dissolved in a very pure solvent, and then crystallized, and the crystals recovered, to improve and/or verify their purity.

Adsorption removes a soluble impurity from a feed stream by trapping it on the surface of a solid material such as activated carbon which forms strong non-covalent chemical bonds with the impurity. Chromatography employs adsorption and desorption on a packed bed of a solid to purify multiple components of a single feed stream.

Many common methods of purification include distillation, widely used in petroleum refining and in purification of ethanol separates volatile liquids based on their relative volatilities; water purification combines many methods to produce potable or drinking water; downstream processing refers to purification of chemicals, pharmaceuticals and food ingredients produced by fermentation or synthesized by plant and animal tissues, for example antibiotics, citric acid, vitamin E, and insulin; electrolysis refers to the breakdown of substances using an electric current. This removes impurities in a substance that an electric current is run through; sublimation is the process of changing of any substance (usually on heating) from a solid to a gas (or from gas to a solid) without passing through liquid phase; and bioleaching is the extraction of desired materials from their matrix of biological material using living organisms.

There are also many other methods for obtaining fractions of desired material such as adsorption, adhesion of atoms, ions or molecules of gas, liquid, or dissolved solids to a surface; capillary electrophoresis; centrifugation and cyclonic separation, separates based on density differences; chromatography separates dissolved substances by different interaction with (i.e. , travel through) a material; crystallization; decantation; demister (vapor), removes liquid droplets from gas streams; distillation, used for mixtures of liquids with different boiling points; drying, removes liquid from a solid by vaporization; electrophoresis, separates organic molecules based on their different interaction with a gel under an electric potential (i.e., different travel); electrostatic separation, works on the principle of corona discharge, where two plates are placed close together and high voltage is applied. This high voltage is used to separate the ionized particles; elutriation; evaporation; leaching; field flow fractionation; flotation; dissolved air flotation, removes suspended solids non-selectively from slurry by bubbles that are generated by air coming out of solution; froth flotation, recovers valuable, hydrophobic solids by attachment to air bubbles generated by mechanical agitation of an air-slurry mixture, which float, and are recovered; flocculation, separates a solid from a liquid in a colloid, by use of a flocculant, which promotes the solid clumping into floes; filtration - Mesh, bag and paper filters are used to remove large particulates suspended in fluids (e.g., fly ash) while membrane processes including microfiltration, ultrafiltration, nanofiltration, reverse osmosis, dialysis (biochemistry) utilizing synthetic membranes, separates micrometer-sized or smaller species; fractional freezing; oil-water separation, gravimetrically separates suspended oil droplets from waste water in for example oil refineries, petrochemical and chemical plants, natural gas processing plants and similar industries; magnetic separation; precipitation; recrystallization; scrubbing, separation of particulates (solids) or gases from a gas stream using liquid;

sedimentation, separates using vocal density pressure differences; gravity separation; sieving; stripping; sublimation; vapor-liquid separation, separates by gravity, based on the Souders-Brown equation; winnowing; zone refining.

One of ordinary skill in the art of natural products extraction and isolation could devise many more methods of fractionating said desired materials and no further need be described here.

Once various fractions of desired material have been obtained by any method such as any of the above described fractionation and purification methods, any number of the fractions can be recombined. The recombination can be by simple mixing or by various mechanical.

In one embodiment of the invention, a composition of the invention, a subset of compounds which are components of the composition of the invention, or a single compound which is a component of the composition of the invention, is one or more fractions being recombined. In one embodiment of the invention, a composition of the invention, a subset of compounds which are components of the composition of the invention, or a single compound which is a component of the composition of the invention, is one or more fractions being recombined and another is a synthetic or semisynthetic material such as a synthetic or semisynthetic natural product. In this context, synthetic and semisynthetic means a natural product which has been treated as the terpene as described above. Biosynthetic materials are a preferable desired material of the invention and are used to prepare compositions of the invention by any of the recombination methods described herein. Suitable materials with which the biosynthetic materials are combined are any cannabis related compositions described herein as well as synthetic, semisynthetic or other biosynthetic feed stocks.

In a preferred embodiment of the invention two or more fractions, a subset of compounds which are components of the composition of the invention, or a single compound which is a component of the composition described herein are

recombined to form a composition of the invention.

A Nutraceutical is a pharmaceutical-grade and standardized nutrient as defined as follows. In the US, "nutraceuticals" do not exist as a regulatory category; they are regulated as dietary supplements and food additives by the FDA under the authority of the Federal Food, Drug, and Cosmetic Act or in part under the FDA Botanical Drug Substance (BDS) Development Guidance.

Under Canadian law, a nutraceutical can either be marketed as a food or as a drug; the terms "nutraceutical" and "functional food" have no legal distinction, referring to "a product isolated or purified from foods that is generally sold in medicinal forms not usually associated with food and is demonstrated to have a physiological benefit or provide protection against chronic disease."

The term "nutraceutical" is not defined by US law. Depending on its ingredients and the claims with which it is marketed, a product is regulated as a drug, dietary supplement, food ingredient, or food.

In the global market, there are significant product quality issues regarding products in this classification. Nutraceuticals from the international market may claim to use organic or exotic ingredients, yet the lack of regulation may compromise the safety and effectiveness of products. Companies looking to create a wide profit margin may create unregulated products overseas with low-quality or ineffective ingredients. It is within the scope of the present invention to provide oral dosage forms comprising cannabis or cannabis derived materials which are well controlled for quality and accurately labeled as required by law and regulation on a jurisdiction by jurisdiction basis. A preferred embodiment of this aspect of the invention is a cannabis or cannabis derived composition in a dosage form which comprises natural materials, is free of unwanted materials and is fully compliant with all applicable laws and regulations in the jurisdictions into which it is provided. Such a form is preferably transparent, having particle sizes of about 100 nm, preferably 90-30 nm, more preferably in the range of 70-30 nm, more preferably yet, 40-60 nm, most preferably particle sizes of 40-60 nm, has an acceptable time for physiological effect of the psychoactive substances and contains only natural products obtained by the methods of the invention.

A dietary supplement is a product that contains nutrients derived from food products that are concentrated in liquid or capsule form. In the US, the Dietary Supplement Health and Education Act (DSHEA) of 1994 defined the term: A dietary supplement as a product taken by mouth that contains a "dietary ingredient" intended to supplement the diet. The "dietary ingredients" in these products may include:

vitamins, minerals, herbs or other botanicals, amino acids, and substances such as enzymes, organ tissues, glandular, and metabolites. Dietary supplements can also be extracts or concentrates, and may be found in many forms such as tablets, capsules, softgels, gelcaps, liquids, or powders. It is within the scope of the present invention to provide dosage forms which comprise cannabis or cannabis derived compositions in addition to dietary supplements.

Dietary supplements do not have to be approved by the U.S. Food and Drug

Administration (FDA) before marketing, but companies must register their

manufacturing facilities with the FDA. With a few well-defined exceptions, dietary supplements may only be marketed to support the structure or function of the body, and may not claim to treat a disease or condition, and must include a label that says: These statements have not been evaluated by the Food and Drug Administration. This product is not intended to diagnose, treat, cure, or prevent any disease.

Functional foods are fortified or enriched during processing and then marketed as providing some benefit to consumers. Sometimes, additional complementary nutrients are added, such as vitamin D to milk.

Health Canada defines functional foods as“ordinary food that has components or ingredients added to give it a specific medical or physiological benefit, other than a purely nutritional effect.” In Japan, all functional foods must meet three established requirements: foods should be (1 ) present in their naturally occurring form, rather than a capsule, tablet, or powder; (2) consumed in the diet as often as daily; and (3) should regulate a biological process in hopes of preventing or controlling disease.

Health claims on food labels and in food marketing are claims by manufacturers of food products that their food will reduce the risk of developing a disease or condition. For example, it is claimed by the manufacturers of oat cereals that oat bran can reduce cholesterol, which will lower the chances of developing serious heart conditions.

In the United States, these claims, usually referred to as "qualified health claims", are regulated by the Food and Drug Administration (FDA) in the public interest.

The rule in place before 2003 required "significant scientific consensus" before a claim could be made, applying characterization of a hierarchy of degrees of certainty:

A: "There is significant scientific agreement for [the claim]."

B: "Although there is some scientific evidence supporting [the claim], the evidence is not conclusive."

C: "Some scientific evidence suggests [the claim]. However, the FDA has

determined that this evidence is limited and not conclusive."

D: "Very limited and preliminary scientific research suggests [the claim]. The FDA concludes that there is little scientific evidence supporting this claim."

In the United Kingdom, the law requires that any health claim on food labels must be true and not misleading. Food producers may optionally use the (Discontinued in 2010) Joint Health Claims Initiative to determine whether their claims are likely to be legally sustainable.

In early 2005 the European PASSCLAIM project (Process for the Assessment of Scientific Support for Claims on Foods), sponsored by the European Union and coordinated by ILSI-Europe, ended. The aim of this project was to develop criteria for the scientific substantiation of claims on foods. Several hundreds of scientists from academia, research institutes, government and industry have contributed to the project. The final consensus paper, comprising the final set of criteria, has been published in June 2005 in the European Journal of Nutrition.

The packaging and labeling of food is subject to regulation in most

regions/jurisdictions, both to prevent false advertising and to promote food safety.

In the context of the present invention the various terms surrounding the use of compositions of the invention such as Nutraceutical, Dietary Supplement, or

Functional Food, means that a portion of the Nutraceutical, Dietary Supplement, or Functional Food contains at about 10%, 20%, 30%, 40%, or 50% of a composition of the invention, preferably about 40%, 50% or 60% of a composition of the invention, more preferably yet, about 50% of a composition of the invention. Alternatively, lower amounts of these materials are desirable and dosage forms comprising about 50, 40, 30, 20, 15, 12, 11 , 10, 9, 8, 7, 6, 5, 4, 3, 2, and 1 % of such materials are contemplated. In this low amount embodiment, it is preferred that about 11 %, more preferably 10%, more preferably 5%, more preferably yet, about 1 % of these substances are contemplated.

When such a Nutraceutical, Dietary Supplement, and Functional Food, containing a composition of the invention, the Nutraceutical, Dietary Supplement, or Functional Food delivers to the Human or Non-Human subject an amount of the composition described herein to provide treatment, relief, improvement, stabilization, or other demonstrable benefit to said subject of the condition intended or otherwise indicated for said composition of the invention.

Preferably the Nutraceutical, Dietary Supplement, or Functional Food containing a composition described herein provides to said subject treatment, relief, improvement, stabilization, or other demonstrable benefit to said subject of the condition intended or otherwise indicated for said composition of the invention.

The vast literature relating to the formulation, preparation, packaging and labeling of the Nutraceutical, Dietary Supplement, or Functional Food containing a composition described herein is well known to one of ordinary skill in the arts of Nutraceutical, Dietary Supplement, or Functional Food formulation, preparation, packaging or labeling and will not be recited here. Psvchoactive Substance

Psychoactive and like terms: A psychoactive or psychotropic substance is a chemical substance that acts primarily upon the central nervous system where it alters brain function, resulting in temporary changes in perception, mood,

consciousness and behavior.

These substances may be used recreationally to purposefully alter one's

consciousness (such as coffee, alcohol or cannabis), as entheogens for spiritual purposes (such as the mescaline-containing peyote cactus or psilocybin-containing mushrooms), and as medication (such as the use of narcotics in controlling pain, stimulants to treat narcolepsy and attention disorders, as well as anti-depressants and anti-psychotics for treating neurological and psychiatric illnesses).

Many of these substances (especially the stimulants and depressants) can be habit- forming, causing chemical dependency and may lead to substance abuse.

Conversely, others (namely the psychedelics) can, in certain circumstances, help to treat and even cure such addictions.

A psychoactive drug, psychopharmaceutical, or psychotropic is a chemical substance that changes brain function and results in alterations in perception, mood, consciousness or behavior. These substances may be used medically;

recreationally; to purposefully improve performance or alter one's consciousness; as entheogens; for ritual, spiritual, or shamanic purposes; or for research. Some categories of psychoactive drugs, which have therapeutic value, are prescribed by physicians and other healthcare practitioners. Examples include anesthetics, analgesics, anticonvulsant and antiparkinsonian drugs as well as medications used to treat neuropsychiatric disorders, such as antidepressants, anxiolytics,

antipsychotics, and stimulant medications. Some psychoactive substances may be used in the detoxification and rehabilitation programs for persons dependent on or addicted to other psychoactive drugs.

Psychoactive substances often bring about subjective (although these may be objectively observed) changes in consciousness and mood that the user may find rewarding and pleasant (e.g., euphoria or a sense of relaxation) or advantageous (e.g. increased alertness) and are thus reinforcing. Substances which are both rewarding and positively reinforcing have the potential to induce a state of addiction - compulsive drug use despite negative consequences. In addition, sustained use of some substances may produce physical or psychological dependence or both, associated with somatic or psychological-emotional withdrawal states respectively. Drug rehabilitation attempts to reduce addiction, through a combination of

psychotherapy, support groups, and other psychoactive substances. Conversely, certain psychoactive drugs may be so unpleasant that the person will never use the substance again. This is especially true of certain deliriants (e.g. Jimson weed), powerful dissociatives (e.g. Salvia divinorum), and classic psychedelics (e.g. LSD, psilocybin), in the form of a "bad trip."

Psychoactive drug misuse, dependence and addiction have resulted in legal measures and moral debate. Governmental controls on manufacture, supply and prescription attempt to reduce problematic medical drug use. Ethical concerns have also been raised about over-use of these drugs clinically, and about their marketing by manufacturers. Popular campaigns to allow certain recreational drug use (e.g. cannabis) are also ongoing.

Within the context of the present invention, psychoactive substances and the like can be either desired, undesired, or unimportant constituents of the compositions herein described. It is possible a psychoactive substance or the like can have a beneficial impact on the utility of the compositions in treating disorders such as disorders described herein.

It is also possible that psychoactive substance or the like can create unwanted side effects of treating disorders such as causing euphoria, anxiety, or intoxication during treatment of the disorder described herein.

In a preferred embodiment of the invention, the compositions are free of

psychoactive substances and the like which interfere with the treatment of disorders such as the disorders described herein.

In a preferred embodiment of the invention, the compositions contain psychoactive substances and the like which do not interfere with the treatment of disorders such as the disorders described herein.

In another preferred embodiment of the invention the compositions contain psychoactive substances or the like which benefit the consumer of nutraceuticals, dietary supplements, and Functional Foods by aiding in the treatment of disorders such as the disorders described herein. In another preferred embodiment of the invention the compositions do not contain psychoactive substances or the like which interfere with the consumer of

nutraceuticals, dietary supplements, and functional foods by interfering in the treatment of disorders such as the disorders described herein.

In another preferred embodiment of the invention the compositions contain

psychoactive substances or the like.

The present invention is directed toward compositions, methods of making, delivery and therapeutic use for treatment of disorders described herein. The compositions comprise compounds found in cannabis and, optionally, synthetic, semisynthetic or biosynthetic compounds as described herein. The history of attempted therapeutic use of cannabis and products derived from cannabis is as old as that of many natural products. A key difference between the history of attempted therapeutic use of cannabis and virtually all other natural products is its high concentrations of psychoactive compounds in its natural state.

Because of the presence of psychoactive compounds, cannabis and products derived therefrom are illegal in most of the world and virtually the entire developed world. The legal status of the plant and its products has forced research and development activities out of the academic, industrial and governmental systems. Accordingly, such research and development has been largely, if not completely, underground, not subject to the rigors of the funding or peer review processes in anyway.

Selected Embodiments of the Invention

Embodiment 1 of the invention comprises a method of treating cannabis plant material with one or more of the following steps,

A. manipulating the presence, absence or amount of one or more compound present in the cannabis plant material,

B. transforming one or more compound present in the cannabis plant material into one or more different compound,

C. altering physical properties of the cannabis plant material or composition of this embodiment, and

D. adding one or more compound not present in the cannabis plant material; to form a composition of the invention.

Embodiment 2 of the invention is directed to a composition obtained by method 1 of the invention.

Embodiment 3 of the invention comprises a method of treating cannabis plant material with one or more of the following steps,

B. transforming one or more compound present in the cannabis plant material into one or more different compound, and

D. adding one or more compound not present in the cannabis plant material; to form an intermediate composition of the invention; and which further comprises altering physical properties of the intermediate composition to form a composition of the invention.

Embodiment 4 of the invention is directed to a composition obtained by method 3 of the invention.

Another embodiment of the invention is directed to providing compositions of embodiment 2 or 4 in a delivery system.

Another embodiment of the invention is directed to embodiment 1 or 3 further comprising providing the composition to a consumer of the composition.

Another embodiment of the invention is directed to embodiment 2 or 4 wherein the composition is suitable for providing to a consumer of the composition.

Another embodiment of the invention is directed to any of the above embodiments wherein 1 , 2, 3, or 4 of steps A, B, C, or D are performed.

Another embodiment of the invention is directed to any of the above embodiments wherein 1 , 2, or 3 of steps A, B, C, or D are performed.

Another embodiment of the invention is directed to any of the above embodiments wherein 1 , or 2 of steps A, B, C, or D are performed. Another embodiment of the invention is directed to any of the above embodiments wherein 1 of steps A, B, C, or D are performed.

Another embodiment of the invention is directed to any of the above embodiments wherein step A is performed.

Another embodiment of the invention is directed to any of the above embodiments wherein step B is performed.

Another embodiment of the invention is directed to any of the above embodiments wherein step C is performed.

Another embodiment of the invention is directed to any of the above embodiments wherein step D is performed.

Another embodiment of the invention is directed to any of the above embodiments wherein the cannabis plant material comprises any part of the plant.

Another embodiment of the invention is directed to any of the above embodiments wherein the cannabis plant material comprises root, stem, leaf, pistil, ovary, style, stamen, flower, pollen, oil, extract or kief.

Another embodiment of the invention is directed to any of the above embodiments wherein the cannabis plant material comprises stem, leaf, flower, oil, extract or kief.

Another embodiment of the invention is directed to any of the above embodiments wherein the cannabis plant material comprises stem, leaf or kief.

Another embodiment of the invention is directed to any of the above embodiments wherein the cannabis plant material comprises flower, oil, or extract.

Another embodiment of the invention is directed to any of the above embodiments wherein the cannabis plant material comprises oil, or extract.

Another embodiment of the invention is directed to any of the above embodiments wherein the cannabis plant material comprises oil.

Another embodiment of the invention is directed to any of the above embodiments wherein step A is modifying the presence, absence or amount of one or more substances selected from the group comprising cannabinoids, terpenoids and flavonoids.

Another embodiment of the invention is directed to any of the above embodiments wherein step A is modifying the presence, absence or amount of one or more substances selected from the group comprising cannabinoids.

Another embodiment of the invention is directed to any of the above embodiments wherein step A is modifying the presence, absence or amount of one or more substances selected from the group comprising terpenoids.

Another embodiment of the invention is directed to any of the above embodiments wherein step A is modifying the presence, absence or amount of one or more substances selected from the group comprising flavonoids.

Another embodiment of the invention is directed to any of the above embodiments wherein step B is transforming a compound selected from the group comprising cannabinoids, terpenoids and flavonoids.

Another embodiment of the invention is directed to any of the above embodiments wherein step B is transforming a cannabinoid.

Another embodiment of the invention is directed to any of the above embodiments wherein step B is transforming a terpenoid.

Another embodiment of the invention is directed to any of the above embodiments wherein step B is transforming a flavonoid.

Another embodiment of the invention is directed to any of the above embodiments wherein step C is purification, racemization, enantiomeric inversion, isomerization, denaturization, sterilization, lyophilization, freeze-drying, homogenization, sonication, emulsification, gravimetric separation, aeration, gas infusion or shear force

manipulation.

Another embodiment of the invention is directed to any of the above embodiments wherein step C is purification, denaturization, sterilization, lyophilization, freeze- drying, homogenization, sonication, emulsification, aeration gas infusion. Another embodiment of the invention is directed to any of the above embodiments wherein step C is purification, denaturization, sterilization, lyophilization, freeze- drying, or emulsification.

Another embodiment of the invention is directed to any of the above embodiments wherein the product of step C is classified as a colloid, polymolecule particle, fiber, thin film, porous solid, gel, foam, sol, micelle, aerosol, suspension, solid particles emulsion, liquid crystal, froth, dust, haze, fog, mist, drizzle, smoke, xerogel, or aerogel.

Another embodiment of the invention is directed to any of the above embodiments wherein the product of step C is classified as a monodisperse; heterodisperse, paucidisperse or polydisperse colloid.

Another embodiment of the invention is directed to any of the above embodiments wherein the product of step C contains an electrolyte, polyelectrolyte, polycation, polyanion, polyacid, polybase, polysalt or polyampholyte.

Another embodiment of the invention is directed to any of the above embodiments wherein the product of step C contains an electrolyte.

Another embodiment of the invention is directed to any of the above embodiments wherein step D is adding a compound selected from the group comprising naturally occurring, synthetic or semisynthetic cannabinoids, terpenoids and flavonoids.

Another embodiment of the invention is directed to any of the above embodiments wherein step D is adding a compound selected from the group comprising naturally occurring, synthetic or semisynthetic cannabinoids.

Another embodiment of the invention is directed to any of the above embodiments wherein step D is adding a compound selected from the group comprising naturally occurring, synthetic or semisynthetic terpenoids.

Another embodiment of the invention is directed to any of the above embodiments wherein step D is adding a compound selected from the group comprising naturally occurring, synthetic or semisynthetic flavonoids. Another embodiment of the invention is directed to any of the above embodiments wherein step D is adding a compound selected from the group comprising biosynthetic cannabinoids, terpenoids and flavonoids.

Another embodiment of the invention is directed to any of the above embodiments wherein step D is adding a compound selected from the group comprising biosynthetic cannabinoids.

Another embodiment of the invention is directed to any of the above embodiments wherein step D is adding a compound selected from the group comprising biosynthetic terpenoids.

Another embodiment of the invention is directed to any of the above embodiments wherein step D is adding a compound selected from the group comprising biosynthetic flavonoids.

Another embodiment of the invention is directed to any of the above embodiments wherein step D is adding a compound selected from the group comprising additives and modifiers as set forth herein.

Embodiment 100 of the invention is directed to any of the above embodiments wherein a composition of the invention is provided in a device for delivery of the composition to a consumer comprising; a container suitable for holding a maximum amount of the composition; a provisioning mechanism for providing a dose of the composition to the consumer; and a metering system transporting the composition to the provisioning mechanism; such that the amount of composition delivered to the consumer is controlled by the metering system.

Another embodiment of the invention is directed to embodiment 100 wherein the dose delivered to the consumer is less than the maximum amount held in the container. Another embodiment of the invention is directed to embodiment 100 wherein the dose delivered to the consumer is less than or equal to the maximum amount permitted by law, regulation or medical judgment in the jurisdiction wherein the consumer resides.

Another embodiment of the invention is directed to embodiment 100 wherein the dose delivered to the consumer is controlled by the consumer.

Another embodiment of the invention is directed to embodiment 100 wherein the dose delivered to the consumer is not controlled by the consumer.

Embodiment 200 of the invention is directed to any of the above embodiments wherein a composition of the invention is provided in a device for delivery of the composition to a consumer comprising; a container suitable for holding a maximum amount of the composition; a mechanism for opening the container and allowing delivery of the composition to the consumer; and a label; such that the amount of composition held by the container is described by the label.

Another embodiment of the invention is directed to embodiment 200 wherein the maximum amount of the composition is less than or equal to the maximum amount permitted by law, regulation or medical judgment in the jurisdiction wherein the consumer resides.

Embodiment 300 of the invention is directed to any embodiment 100, 200 or those dependent thereon, wherein a unit dose amount of the composition delivered to the consumer is controlled such that the consumer can not consume more than a specified amount during a specified time.

Another embodiment of the invention is embodiment 300 wherein the maximum amount held by the container is the same as the unit dose amount.

Another embodiment of the invention is embodiment 300 wherein the maximum amount held by the container is more than the unit dose amount. Another embodiment of the invention is embodiment 300 wherein the maximum amount held by the container is more than the unit dose amount and the provisioning mechanism limits the amount available for consumption over a specified time period to the unit dose amount.

Another embodiment of the invention is embodiment 300 wherein the maximum amount held by the container is more than the unit dose amount and the provisioning mechanism limits the amount available for consumption over a specified time period to the unit dose amount and the unit dose amount is described by the label.

Another embodiment of the invention is embodiment 300 wherein the maximum amount held by the container is more than the unit dose amount and the provisioning mechanism limits the amount available for consumption over a specified time period to the unit dose amount and the unit dose amount is less than or equal to the maximum amount permitted by law, regulation or medical judgment in the jurisdiction wherein the consumer resides.

Exemplary Dosage Forms of the Compositions of the Invention

1. The present invention comprises a composition described herein in a dosage form known by one of ordinary skill in the arts of pharmaceutical or pharmacological practice as described in Remington: The Science and Practice of Pharmacy, 21 st ed., ISBN-13 978-0781746731 , which is incorporated by reference herein in its entirety and with specificity.

2. The present invention comprises a composition described herein in a sublingual dosage form, known by one of ordinary skill in the arts of pharmaceutical or pharmacological practice as described in Remington: The Science and Practice of Pharmacy, 21st ed., ISBN-13 978-0781746731 , which is incorporated by reference herein in its entirety and with specificity.

3. The present invention comprises a composition described herein in a transdermal dosage form, known by one of ordinary skill in the arts of pharmaceutical or pharmacological practice as described in Remington: The Science and Practice of Pharmacy, 21st ed., ISBN-13 978-0781746731 , which is incorporated by reference herein in its entirety and with specificity. 4. The present invention comprises a composition described herein in a topical cream dosage form, known by one of ordinary skill in the arts of pharmaceutical or pharmacological practice as described in Remington: The Science and Practice of Pharmacy, 21st ed., ISBN-13 978-0781746731 , which is incorporated by reference herein in its entirety and with specificity.

5. The present invention comprises a composition described herein in a topical gel dosage form, known by one of ordinary skill in the arts of pharmaceutical or pharmacological practice as described in Remington: The Science and Practice of Pharmacy, 21st ed., ISBN-13 978-0781746731 , which is incorporated by reference herein in its entirety and with specificity.

6. The present invention comprises a composition described herein in an oral spray dosage form, known by one of ordinary skill in the arts of pharmaceutical or pharmacological practice as described in Remington: The Science and Practice of Pharmacy, 21 st ed., ISBN-13 978-0781746731 , which is incorporated by reference herein in its entirety and with specificity.

7. The present invention comprises a composition described herein in a nasal spray dosage form, known by one of ordinary skill in the arts of pharmaceutical or pharmacological practice as described in Remington: The Science and Practice of Pharmacy, 21st ed., ISBN-13 978-0781746731 , which is incorporated by reference herein in its entirety and with specificity.

8. The present invention comprises a composition described herein in an ophthalmic dosage form, known by one of ordinary skill in the arts of pharmaceutical or pharmacological practice as described in Remington: The Science and Practice of Pharmacy, 21st ed., ISBN-13 978-0781746731 , which is incorporated by reference herein in its entirety and with specificity.

9. The present invention comprises a composition described herein in a suppository dosage form, known by one of ordinary skill in the arts of pharmaceutical or pharmacological practice as described in Remington: The Science and Practice of Pharmacy, 21st ed., ISBN-13 978-0781746731 , which is incorporated by reference herein in its entirety and with specificity.

21. The present invention comprises a composition described herein in an abuse deterrent immediate release biphasic matrix solid dosage form that releases a composition described herein at a desired rate for quick onset of action when a single unit or prescribed units of the dosage form are orally administered but exhibits a reduced rate of release when more than the prescribed number of units, are administered. When an abuser, with the objective of achieving a high blood concentration of a composition described herein uses multiple units of the dosage forms through multiple modes of abuse such as extraction or ingestion, they encounter resistance of the dosage form to release high amounts of a composition described herein and provide high blood concentration. Such abuse deterrent immediate release biphasic matrix solid dosage forms are disclosed in US 9,642,811 B2, May 9, 2017, the contents of which is incorporated by reference herein in its entirety and with specificity.

22. The present invention comprises a composition described herein in an abuse deterrent immediate release coated reservoir solid dosage form that releases a composition described herein at a desired rate for quick onset of action when a single unit or prescribed units of the dosage form are orally administered but exhibits a reduced rate of release when more than the prescribed number of units, are administered. Such abuse deterrent immediate release coated reservoir solid dosage forms are disclosed in US 9,616,029 B2, April 17, 2017, the contents of which is incorporated by reference herein in its entirety and with specificity.

23. The present invention comprises a composition described herein in a dosage form for transmucosal administration. Said dosage form further comprising one or more active lipophilic compounds which are components of the compositions of the invention, a polymeric matrix formed by two or more water-soluble polymers and a rapid dissolution agent. At least one of the water-soluble polymers is an amphiphilic polymer and at least one is either a hydrophilic polymer or an amphiphilic polymer with a hydrophobic-hydrophilic balance different from the first amphiphilic polymer. In addition, the polymeric matrix is not crosslinked, and no covalent interaction occurs between the two or more polymers and between the polymers and said lipophilic active compound or compounds, which is interwoven with the aforesaid polymeric matrix. Such dosage forms, methods and devices are disclosed in US

2017/0119660 A1 , May 4, 2017, and WO 2017/072774 A1 , May 4, 2017, the contents of which are herein incorporated in their entirety by reference thereto with specificity.

24. The present invention comprises a composition described herein in a dosage form contained within devices and methods for preparing, managing, and/or administering metered doses of a composition described herein for vaporized administration. In some embodiments, dose cartridges comprising at least one composition described herein include a heating element integrated into the cartridge in close contact with said composition. In some embodiments, cartridge-mounted doses are stored in a magazine, optionally in carousel form, before use. Transport of a cartridge from a magazine to an electrically operated vaporizing chamber which activates the heating element is provided by a mechanical pickup means. Such devices and methods are disclosed in US 2017/0119979 A1 , May 4, 2017, the contents of which is incorporated by reference herein in its entirety and with specificity.

25. The present invention comprises a composition described herein in an inhaler dosage form and device for pulmonary delivery of at least one composition described herein from a drug dose cartridge to an inhaling user, comprising: a first conduit for conducting a carrier airflow to a proximal opening of a mouthpiece for use by the user; a holder configured to position the dose cartridge within the carrier airflow; and a second conduit for conducting a shunting airflow to the mouthpiece without passing through the dose cartridge position. In some embodiments, a controller connected to a valve controls a rate of carrier airflow, for example by controlling the shunting airflow, based on a sensor indication of airflow rate and a target airflow profile. Such inhaler devices, without a composition of the invention, are disclosed in US

2017/0119981 A1 , May 4, 2017, and WO 2017/0106153 A1 April 20, 2017, the contents of which are incorporated by reference herein in their entirety and with specificity.

26. The present invention comprises a composition described herein in a dosage form further comprising mucus penetrating particles (MPPs) include one or more core polymers, one or more compositions of the invention; and one or more surface modifying agents. The surface modifying agents coat the surface of the particle in a sufficient density to enhance the diffusion of the modified nanoparticles throughout the mucosa, relative to equivalent nanoparticles that are not surface modified.

Nanoparticles can be sufficiently densely coated with poly (ethylene glycol) (PEG) with a molecular weight of from 10 kD to 40 kD or greater coated with a surface density from about 0.1 to about 100 molecules/100 nm2, preferably from about 0.5 to about 50 molecules/100 nm2, more preferably from about 0.9 to about 45

molecules/100 nm2. Such mucus penetrating particles are disclosed in WO

2017/075565 A1 , May 4, 2017, the contents of which is incorporated by reference herein in its entirety and with specificity.

27. The present invention comprises a composition described herein in an ingestible dosage form further comprising drug delivery device configured for wireless communication with other ingestible drug delivery devices which further comprise a compound of the invention. Such devices are disclosed in US 2017/0106178 A1 , April 20, 2017, EP 3151906 A1 , April 12, 2017, US 2015/343144 A1 , December 3, 2015, US 9662392 B2, May 30, 2017, WO 2015/187289 A1 , December 10, 2015 the contents of which are incorporated by reference herein in their entirety and with specificity.

28. The present invention comprises a composition described herein in a dosage form further comprising an inhaler-delivery-device-packaged homogenate of solid heterogeneous- lipid particulates carrying a composition of the invention, wherein the solid heterogeneous-lipid particles comprise: one (or more) lipid(s) whose melting point(s) is (are) substantially above room temperature; in combination with, one (or more) lipid(s) whose melting point(s) is (are) substantially less than room

temperature. Such inhaler-delivery-device-packages are disclosed in WO

2017/054071 A1 April 6, 2017, the contents of which is incorporated by reference herein in its entirety and with specificity.

29. The present invention comprises a composition described herein in a dosage form further comprising programmable molecular imprinted polymers (MIPs) that have modified binding site kinetics for target imprintable entities (TIEs) that operate to control the adsorption, binding, release and equilibrium distribution of related materials into and out of the MIPs, which are useful for the controlled adsorption, controlled release and control of concentrations of such materials in media including gases, liquids, fluids, biological systems, solutions and other environments. When a collective plurality of the MIPs with modified binding site kinetics are combined, the resulting MIP systems can be tailored to exhibit pseudo zero- and first-order kinetics, as well as higher kinetic profiles, and when further combined with time-delay functionality, can be tailored to exhibit delayed uptake and release, ramped uptake and release of materials, step functions, polynomial, geometric, exponential and other unique kinetic profiles of material exchange between the MIPs and a fluid media that are not readily achievable by other means. The present invention further comprising the use of a composition of Tabel as said material and/or materials.

Such Programmable molecular imprinted polymers and associated technologies are disclosed in US 2017/0050157 A1 , February 23, 2017, the contents of which is incorporated by reference herein in its entirety and with specificity.

30. The present invention comprises a composition described herein in a dosage form further comprising phospholipid nanoparticle compositions of a composition described herein formed from phospholipids and simpler lipids in an unfired sequential process that encapsulate a high concentration of cannabinoids, and create standardized precision-metered dosage forms of a composition of the invention; yielding an increase cannabinoid transport across hydrophobic mucosa; increase the bioavailability of the cannabinoid 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 to 12- fold, preferably 4-fold to 10-fold, more preferably 2-fold to 8-fold, decrease the dose of cannabinoids reduced amount of cannabinoids needed to illicit the same therapeutic effect compared to raw and non-encapsulated cannabinoids; where the nanoparticle dynamic structure reduces the adverse effects of cannabinoids; and enable safe more efficacious cannabinoid therapy. Such nanoparticles are disclosed in US 2017/0000744 A1 , January 5, 2017, the contents of which is incorporated by reference herein in its entirety and with specificity.

31. The present invention comprises a composition described herein in a dosage form further comprising a device and method comprising receiving, in a mixing chamber, a first amount of a first composition described herein from a first container, receiving, in the mixing chamber, a second amount of a second composition described herein from a second container, mixing the first amount of the first composition and the second amount of the second composition to create a mixed composition, vaporizing the mixed composition to create a vapor, and expelling the vapor through an exhaust port for inhalation by a user. Such methods and devices are disclosed in US 2016/03255055 A1 , November 10, 2016, the contents of which is incorporated by reference herein in its entirety and with specificity.

32. The present invention comprises a composition described herein in a sublingual dosage form further comprising a composition of the invention, and a dispenser for delivering at least one pharmacologically active cannabinoid from the composition described herein contained inside the dispenser into the sublingual cavity of a subject when the dispenser is placed within the subject's sublingual cavity with the composition described herein contained therein. Also disclosed are a method and apparatus for preparing the sublingual dosage form, and compositions and kits comprising the sublingual dosage form. Such dosage forms, methods and devices are disclosed in US 2016/0296464 A1 , October 13, 2016, the contents of which is incorporated by reference herein in its entirety and with specificity.

33. The present invention comprises a composition described herein in a dosage form which further comprises a honey-cannabinoid therapeutic compositions and methods of us and making. A therapeutic composition containing a composition described herein providing therapeutic effects to at least some patients includes honey; at least one cannabinoid; and optionally, at least two non-cannabinoid cannabis compounds, hydrogen peroxide, at least one food-approved antioxidant, glucose oxidase, and/or catalase, and water; where the composition is

homogeneous; has oxidative power low enough to keep tetrahydrocannabinol oxidation at a rate of about 90%, 80%, 70%, 60%, 50%, 40%, 30%, 20%, 19%, 18%, 17%, 16%, preferably 15%, more preferable 10% per month; contains hydrogen peroxide at a concentration low enough to keep tetrahydrocannabinol oxidation at a rate of about 90%, 80%, 70%, 60%, 50%, 40%, 30%, 20%, 19%, 18%, 17%, 16%, preferably 15%, more preferable 10% per month; contains at least one food- approved antioxidant at a concentration low enough to keep THC oxidation at a rate of about 90%, 80%, 70%, 60%, 50%, 40%, 30%, 20%, 19%, 18%, 17%, 16%, preferably 15%, more preferable 10% per month; contains glucose oxidase at a concentration low enough to keep tetrahydrocannabinol oxidation at a rate of about 90%, 80%, 70%, 60%, 50%, 40%, 30%, 20%, 19%, 18%, 17%, 16%, preferably 15%, more preferable 10% per month; and/or contains catalase at a concentration high enough to keep tetrahydrocannabinol oxidation at a rate of about 90%, 80%, 70%, 60%, 50%, 40%, 30%, 20%, 19%, 18%, 17%, 16%, preferably 15%, more preferable 10% per month. A partial teaching of this embodiment of the invention is contained in WO 2017072704 A1 , May 4, 2017, the contents of which is herein incorporated in its entirety by reference thereto with specificity.

34. The present invention comprises a composition described herein in a dosage form which further comprises granules made up of about 20, 30, 40, 50, 60, 70, 80, 90, or 99 wt. %, preferably, about 40-95 wt. %, more preferably 50, 60, 70 or 80 wt. %, more preferable yet, 50, 60, 70, or 80 wt. % of lactose particles and 1 -80 wt. %, preferably, 10, 20, 30, 40, 50, 60, 70, 80 wt. %, more preferably yet, 50, 60, 70, or 80 wt. %, more preferably still, about 50 to 75 wt. % of a binding component that holds together the lactose particles within the granules. Said granules have a mass weighted average diameter of 50-500 pm and said binding component is a solid dispersion or a solid solution of 10-75 wt. % of a cannabinoid in 25-80 wt. % of a lipophilic matrix. The lipophilic matrix contains at least 80 wt. % sucrose fatty acid mono-ester, the fatty acid residue being selected from C8-C18 fatty acids. Said granulate can be processed into oral dosage units in the form of tablets for oral delivery the invention further provides a method for the manufacture of the granulate. Such granular dosage forms, methods and devices are disclosed in US 9555019 B2, January 31 , 2017, the contents of which is herein incorporated in its entirety by reference thereto with specificity.

35. The present invention comprises a composition described herein in a dosage form which further comprises a medicament delivery device having an oral tubular section for placement in the mouth of a user and a nasal tubular section for placement in the naris of a user. A medicament located in a corrugated, or flexible, section joining the oral tubular section and the nasal tubular section is dispersed into the nasal cavity of the user by blowing into the oral tubular section. A pinch valve or a one-way valve is used to prevent the user from accidentally inhaling the

medicament. The medicament delivery device may also be used as a pulmonary delivery device into the mouth of a user. Such dosage forms, methods and devices are disclosed in WO 2017136825 A1 , August 10, 2017, the contents of which is herein incorporated in its entirety by reference thereto with specificity.

36. The present invention comprises a composition described herein in a dosage form which further comprises gel formulations of a composition of the invention for intranasal administration and treatment methods for using the lower dosage strength pernasal. Such dosage forms, methods and devices are disclosed in WO

2014083432 A2, June 5, 2014, the contents of which is herein incorporated in its entirety by reference thereto with specificity.

37. The present invention comprises a composition described herein in a dosage form which further comprises intranasal bio- adhesive gels for providing sustained intranasal delivery of a composition of the invention and intranasal treatment methods for safely providing sustained release of said compositions. The present invention relates to improved and sustained intranasal gel formulations of

compositions described herein. The present invention also relates to a system for dispensing intranasally a precise dosage amount of such gels in smaller volumes at an optimal anatomical location within each nostril, so that an effective amount of said composition is deposited within each nostril at the optimal anatomical location. The present invention is also concerned with a novel titration method to determine the appropriate daily treatment regimen, i.e. , a BID or TID treatment regimen, to administer the intranasal compositions. The present invention is also concerned with novel titrations method to determine the appropriate daily treatment regimen, i.e., a QD, BID or TID treatment regimen, to administer the intranasal compositions of the present. Such dosage forms, methods and devices are disclosed in WO2014080282 A2, May 30, 2014, the contents of which is herein incorporated in its entirety by reference thereto with specificity.

38. The present invention comprises a composition described herein in a dosage form which further comprises pernasal compositions of the invention in bio-adhesive gel formulations for intranasal administration for providing sustained intranasal delivery of said compositions. The present invention is also concerned with a novel titration method to determine the appropriate daily treatment regimen, i.e. , a BID or TID treatment regimen, to administer the intranasal gels of the present. Such dosage forms, methods and devices are disclosed in WO2014080283 A2, May 30, 2014, WO 2012156820 A1 , November 22, 2012, and WO 2012156821 A1 ,

November 22, 2012, the contents of which is herein incorporated in its entirety by reference thereto with specificity.

39. The present invention comprises a composition described herein in a dosage form which further comprises sublingual film formulations of a composition of the invention and methods of use, including by way of example and not limitation, restless leg syndrome, sexual dysfunction, and depressive disorders therewith.

Such dosage forms, methods and devices are disclosed in WO 2012083269 A1 ,

June 21 , 2012, and WO 2010144817 A1 , December 16, 2010 the contents of which is herein incorporated in its entirety by reference thereto with specificity.

40. The present invention comprises a composition described herein in a dosage form which further comprises compositions and thin films containing an encapsulated composition of the invention, as well as methods of manufacturing and using the same. Such dosage forms, methods and devices are disclosed in WO2015184317 A1 , December 3, 2015, the contents of which is herein incorporated in its entirety by reference thereto with specificity.

41. The present invention comprises a composition described herein in a dosage form which further comprises a method of preparing a thin film, the method comprising: (a) contacting a lipid, emulsifier, and solvent to provide a uniform first mixture; (b) contacting an active ingredient of the present invention and the uniform first mixture to provide a thickened second mixture; (c) contacting a binder and the thickened second mixture to provide a slurry; and (d) hot extruding, casting, and condensing the slurry to provide the thin film; or cooling, shearing, mixing, casting, and condensing the slurry to provide the thin film. . Such dosage forms, methods and devices are disclosed in WO2014183054 A1 , November 13, 2014, the contents of which is herein incorporated in its entirety by reference thereto with specificity.

42. The present invention comprises a composition described herein in a dosage form which further comprises a composition for applying to skin comprising one or more compositions of the invention contained in a plurality of hydrophobic carriers dispersed throughout a hydrogel, a skin permeation enhancer for enhancing the permeation of the said compositions of the invention into skin, and an emulsifier.

The amount of hydrogel is sufficient to allow the hydrogel to dry to as a substantially continuous film over and in contact with the skin to which it is applied. Related method and apparatus aspects are also described. Such dosage forms, methods and devices are disclosed in WO 2013039994 A2, March 21 , 2013, the contents of which is herein incorporated in its entirety by reference thereto with specificity.

43. The present invention comprises a composition described herein in a dosage form which further comprises compositions and methods for the increasing the quantity of lipids secreted from glandular dysfunction and disorders resulting therefrom. Such dosage forms, methods and devices are disclosed in WO

2017055924 A3, July 6, 2017, WO 2017055924 A2, April 6, 2017, the contents of which is herein incorporated in its entirety by reference thereto with specificity.

44. The present invention comprises a composition described herein in a dosage form which further comprises compositions and methods for the treatment of glandular dysfunction. Said compositions and methods comprise keratolytic agents, such as salicylic acid, selenium disulfide, or the like. Topical administration of said compositions to the eyelid margin or surrounding areas provides therapeutic benefit to patients suffering from glandular dysfunction or other associated medical aliments. Such dosage forms, methods and devices are disclosed in WO 2016063130 A1 ,

April 28, 2016, the contents of which is herein incorporated in its entirety by reference thereto with specificity.

45. The present invention comprises a composition described herein in a dosage form which further comprises liposomes with an entrapped amphipathic weak base and alkyl or aryl sulfonate are described as well as methods of making and using these liposomes. Such dosage forms, methods and devices are disclosed in WO 2013114377 A1 , August 8, 2013, the contents of which is herein incorporated in its entirety by reference thereto with specificity.

46. The present invention comprises a composition described herein in a dosage form which further comprises a functional food and a method of producing same are provide. The functional food is produced by mixing a composition of the present invention with a lipid solvent including a bioactive agent of the present invention with a semi-solid or liquid food base carrier until formation of an emulsion that includes solid lipid particles loaded with the bioactive agent of the invention. Such dosage forms, methods and devices are disclosed in WO 2012023142 A3, May 31 , 2012, and WO 2012023142 A2, February 23, 2012, the contents of which is herein incorporated in its entirety by reference thereto with specificity. 47. The present invention comprises a composition described herein in a dosage form which further comprises a topical pharmaceutical or cosmetic composition, and uses thereof in treating a disease or condition of the hair follicle. The compositions of this invention are emulsions of an oil-in-polyol with a mean particle size of below one micron, and further comprising at least one oil, one polyol, one stabilizer and a composition of the present invention. Such dosage forms, methods and devices are disclosed in WO 2011095970 A1 , August 11 , 2011 the contents of which is herein incorporated in its entirety by reference thereto with specificity.

48. The present invention comprises a composition described herein in a dosage form which further comprises foamable compositions that are capable of producing a sensation or sensation modifying effect upon application on a body surface. More particularly the invention relates to a composition that provides to a subject at least one sensation for a sustained period following application to the skin. The

composition includes (a) at least one composition of the invention, sensation or sensation modifying agent, comprising one or more of a cooling agent, a warming agent, a relaxing or soothing agent, and a stimulating or refreshing agent; (b) a foamable carrier; and (c) a propellant having a concentration about 3% to about 45% by weight of the total composition. The composition is stored in an aerosol container and upon release expands to form a non-crackling short term stable foam. Such dosage forms, methods and devices are disclosed in WO 2009087578 A3, June 10, 2010, WO 2009069006 A3, November 12, 2009, WO 2009098595 A3, November 12, 2009, WO 2009098595 A2, August 13, 2009, WO 2009087578 A2, July 16,

2009, WO 2008110872 A3, June 25, 2009, WO 2008152444 A3, June 18, 2009, and WO 2009069006 A2, June 4, 2009, the contents of which is herein incorporated in its entirety by reference thereto with specificity.

49. The present invention comprises a composition described herein in a dosage form which further comprises a stable non-alcoholic foamable pharmaceutical emulsion composition includes an unctuous emollient, at a concentration of about 0.5% to about 49% by weight; at least one multi-active agent; at a concentration of about 0.5% to about 15% by weight; water; an effective amount of a composition described herein having a degree of solubility in the emulsion composition; and at least one liquefied or compressed gas propellant at a concentration of about 3% to about 25% by weight of the total composition; wherein the unctuous emollient comprises a petrolatum alone or in combination with other unctuous agents; wherein the multi active agent is selected from the group consisting of (a) two or more complex emulgators wherein there is a difference of about 4 or more units between the HLB values of two of the emulgators or there is a significant difference in the chemical nature or structure of two of the emulgators; (b) a surfactant and a foam adjuvant or co surfactant, wherein the surfactant has a HLB close to the required HLB of the oil phase; (c) a surfactant and a liquid wax, wherein the surfactant has a HLB close to the required HLB of the oil phase; (d) a surfactant and a polymeric agent other than starch or a modified starch ester, wherein the surfactant has a HLB close to the required HLB of the oil phase; (e) a polymeric agent and a foam adjuvant or co surfactant, which can cooperate to stabilize the emulsion; (f) a single surfactant without a long polymeric side chain that is composed of a mixture of esters having a HLB close to the required HLB of the oil phase; combinations of any of the above, and wherein the composition is substantially flowable is stored in an pressurized container and upon release expands to form a breakable foam. Such dosage forms, methods and devices are disclosed in WO 2009007785 A3, June 4, 2009, the contents of which is herein incorporated in its entirety by reference thereto with specificity.

50. The present invention comprises a composition described herein in a dosage form which further comprises a colored or colorable topical composition, comprising: a) a foamable base composition comprising, 1 ) a flowable carrier composition; 2) a color agent; wherein the color agent is effective to impart, increase, decrease or otherwise affect color of a foam produced from the foamable composition and wherein the color agent is one or more agents selected from the group consisting of a colored active agent, a colored indicator, a colored excipient, a pigment, a dye, a colorant and a coloring agent; b) a propellant at a concentration of about 3% to about 25% by weight of the total composition; wherein the base composition has a first color; and wherein the foam comprising the colored or colorable topical composition has a second color upon dispensing from an aerosol container, and wherein the first color and the second color are visually different. There is also described a method of changing color, a method of administration, a use as a diagnostic and a kit. Such dosage forms, methods and devices are disclosed in WO 2008032212 A3, April 23, 2009, the contents of which is herein incorporated in its entirety by reference thereto with specificity.

51. The present invention comprises a composition described herein in a dosage form which further comprises a stable non-alcoholic foamable pharmaceutical emulsion composition includes an unctuous emollient, at a concentration of about 0.5% to about 49% by weight; at least one multi-active agent; at a concentration of about 0.5% to about 15% by weight; water; an effective amount of a composition of the invention having a degree of solubility in the emulsion composition; and at least one liquefied or compressed gas propellant at a concentration of about 3% to about 25% by weight of the total composition; wherein the unctuous emollient comprises a petrolatum alone or in combination with other unctuous agents; wherein the multi active agent is selected from the group consisting of (a) two or more complex emulgators wherein there is a difference of about 4 or more units between the HLB values of two of the emulgators or there is a significant difference in the chemical nature or structure of two of the emulgators; (b) a surfactant and a foam adjuvant or co surfactant, wherein the surfactant has a HLB close to the required HLB of the oil phase; (c) a surfactant and a liquid wax, wherein the surfactant has a HLB close to the required HLB of the oil phase; (d) a surfactant and a polymeric agent other than starch or a modified starch ester, wherein the surfactant has a HLB close to the required HLB of the oil phase; (e) a polymeric agent and a foam adjuvant or co surfactant, which can cooperate to stabilize the emulsion; (f) a single surfactant without a long polymeric side chain that is composed of a mixture of esters having a HLB close to the required HLB of the oil phase; combinations of any of the above, and wherein the composition is substantially flowable is stored in an pressurized container and upon release expands to form a breakable foam. Such dosage forms, methods and devices are disclosed in WO 2009007785 A2, January 15, 2009, the contents of which is herein incorporated in its entirety by reference thereto with specificity.

52. The present invention comprises a composition described herein in a dosage form which further comprises a waterless composition and foam as a vehicle in which the composition of the invention, when added is stable or stabilized by or its destabilization is impeded by the presence of a modulating agent. The composition of the invention and foam, includes: a waterless solvent, a modulating agent and one or more active compositions of the invention. The present invention also relates to a method of treatment administering the waterless composition and foam. Such dosage forms, methods and devices are disclosed in W02008152444 A2, December 18, 2008, the contents of which is herein incorporated in its entirety by reference thereto with specificity.

53. The present invention comprises a composition described herein in a dosage form which further comprises a hygroscopic composition of the invention includes at least one hygroscopic substance at a concentration sufficient to provide an Aw value of at least 0.9 and an anti-infective agent. A foamable pharmaceutical carrier includes about 50% to about 98% of a polar solvent selected from the group consisting of a polyol and PEG; 0% to about 48% of a secondary polar solvent;

about 0.2% to about 5% by weight of a surface-active agent; about 0.01 % to about 5% by weight of at least one polymeric agent; and a liquefied or compressed gas propellant at a concentration of about 3% to about 25% by weight of the total composition. Such dosage forms, methods and devices are disclosed in WO

2007054818 A3, October 23, 2008, the contents of which is herein incorporated in its entirety by reference thereto with specificity.

54. The present invention comprises a composition described herein in a dosage form which further comprises a foamable pharmaceutical carrier comprising a composition of the invention; a stabilizer selected from the group consisting of at least one surface-active agent; at least one polymeric agent and mixtures thereof; a solvent selected from the group consisting of water, a hydrophilic solvent, a hydrophobic solvent, a potent solvent, a polar solvent, a silicone, an emollient, and mixtures thereof, wherein the benefit agent, stabilizer and solvent are selected to provide a composition that is substantially resistant to aging and to phase separation and or can substantially stabilize other active ingredients. The invention further relates to a foamable composition further containing a liquefied hydrocarbon gas propellant. Such dosage forms, methods and devices are disclosed in WO

2008038147 A3, October 16, 2008, the contents of which is herein incorporated in its entirety by reference thereto with specificity.

55. The present invention comprises a composition described herein in a dosage form which further comprises a foamable therapeutic composition comprising: (a) a therapeutically effective concentration of at least one composition of the invention; and (b) a foamable carrier comprising: i. about 50% to about 98% of a solvent selected from the group consisting of water; a hydrophilic solvent; a hydrophobic solvent; a potent solvent; a polar solvent, a silicone, an emollient, and mixtures thereof; ii. 0% to about 48% of a secondary solvent selected from the group consisting of water; a hydrophilic solvent; a hydrophobic solvent; a potent solvent; a polar solvent, a silicone, an emollient, a co-solvent, a penetration enhancer and mixtures thereof; iii. a surface-active agent; iv. about 0% to about 5% by weight of at least one polymeric agent; and v. a liquefied or compressed gas propellant at a concentration of about 3% to about 25% by weight of the total composition; wherein the composition is housed in a container and is substantially flowable, and which upon release expands to form a breakable foam; and wherein the foamable carrier is selected to generate a foam of good to excellent quality. The invention further provides a method of treating, alleviating or preventing a disorder of mammalian subject, comprising administering such a composition to an afflicted target site.

Such dosage forms, methods and devices are disclosed in WO 2008110872 A2, September 18, 2008, the contents of which is herein incorporated in its entirety by reference thereto with specificity.

Claims

Claims:

1. A cannabis or cannabis derived composition comprising consistently

controlling the presence, absence or amount of psychoactive compounds in a composition for promoting cessation of chemical dependence, preferably smoking dependence.

2. The composition of Claim 1 comprising consistent quantities of cannabinoids.

3. The composition of Claim 1 comprising consistent quantities of terpenoids.

4. The composition of Claim 1 comprising consistent quantities of flavonoids.

5. The composition of any of Claims 1 to 4 comprising consistent quantities of cannabinoids, terpenoids and flavonoids, each selected independently.

6. The composition of any of Claims 1 to 4 comprising quantities of cannabinoids and terpenoids, each selected independently.

7. The composition of any of Claims 1 to 4 comprising consistent quantities of cannabinoids and flavonoids, each selected independently.

8. The composition of any of Claims 1 to 4 comprising consistent quantities of terpenoids and flavonoids, each selected independently.

9. The composition of any of Claims 1 to 4 comprising consistent quantities of cannabinoids, terpenoids and flavonoids, each selected independently.

10. The compositions of Claims 1 to 9 above wherein the composition is

optimized for use in the treatment of chemical dependence, preferably nicotine dependence.

11. Methods of use, manufacture, and kits of Claims 1 to 10 and iterative methods of finding entourage effects for treating chemical dependence, preferably nicotine dependence, based on the compositions of Claims 1 to 10.

12. A cannabis containing composition for promoting cessation of chemical dependence, preferably nicotine dependence, comprising consistent controlling the presence, absence or amount of psychoactive compounds.

13. The composition of Claim 12 wherein the active compound is a psychoactive compound.

14. The composition of Claims 12 or 13 comprising consistent quantities of

cannabinoids.

15. The composition of Claims 12 or 13 comprising consistent quantities of

terpenoids.

16. The composition of Claims 12 or 13 comprising consistent quantities of

flavonoids.

17. The composition of any of Claims 12 to 16 comprising consistent quantities of cannabinoids, terpenoids and flavonoids, each selected independently.

18. The composition of any of Claims 12 to 16 comprising quantities of

cannabinoids and terpenoids, each selected independently.

19. The composition of any of Claims 12 to 16 comprising consistent quantities of cannabinoids and flavonoids, each selected independently.

20. The composition of any of Claims 12 to 16 comprising consistent quantities of terpenoids and flavonoids, each selected independently.

21. The composition of any of Claims 12 to 16 comprising consistent quantities of cannabinoids, terpenoids and flavonoids, each selected independently.

22. The compositions of Claims 12 to 21 above wherein the composition is

23. Methods of use, manufacture, and kits of Claims 12 to 22 and iterative

methods of finding entourage effects for treating chemical dependence, preferably nicotine dependence, based on the compositions of Claims 12 to 22.

24. A method of suppressing cue associated craving in a process of promoting smoking cessation comprising the use of any of the compositions, methods or kits of Claims 1 -23 wherein said method is independent of heritable

differences in nicotine metabolism.