WO2014100231A1 - Use of cannabinoids and terpenes for treatment of organophosphate and carbamate toxicity - Google Patents

Abstract

Pharmaceutical compositions in which isolated cannabinoid receptor modulators are optionally combined with terpene blends in a pharmaceutically acceptable carrier. Methods for treating or preventing a disease, disorder, dysfunction or condition caused by exposure to an organophosphate or carbamate acetylcholineesterase inhibitor with the inventive compositions are also disclosed.

Description

USE OF CANNABI OIDS AND TERPENES FOR TREATMENT O F ORGANOPHOSPHATE AND CARBAMATE ΤΟΧΚ3ΤΫ

CROSS REFERENCE TO RELATED APPLICATIONS

Tins application claims priority to U.S. Provisional Application Serial No. 61/738.782, filed December 18, 2012, the disclosure of which is incorporated herein by reference.

FIELD OF THE, INVENTION

The present invention discloses the novel uses of cannabinoid system modulators and terpenes in treatment of the symptoms and signs of antichoiinestera.se toxicity associated with organophospkate ("OP") and/or carbamate exposure. More particularly, the present invention relates to compositions containing cannabinoid receptor agonists and derivatives thereof, including partial agonists and modifiers of cannabinoid metabolism and terpenes for prevention and treatment of acute and chronic OP toxicity and acute and chronic carbamate toxicity. BACKGROUND OF THE: INVENTION

Orgaiiopliospliates are compounds having the general chemical formula:

0(S)

R1— P- 2

X

wherein Rl and R2 are alkyl-, alkoxy-, alkyltbio- or aink!o groups and X is an acyl residue or leaving group whe the OP phosphorolates acetylcholinesterase (AChE). The R groups are generally esters, amides, or thiol derivatives of phosphoric, phosphonic, or phosphinic acids. In an OP, the O or (S) has a double bond with the central P. If the S is present the compound is a phosphorothioate but is still called aa OP because of its mechanisms of action. Phosphorothioates must be biotransfoi ned to an oxon, wit an O replacing the S, to become an OP. An example of such includes the biotransformation of parathion to paraoxon. Without the replacement of the S with an O, there is no inhibition of AChE. OP inhibition of AChE is initially reversible but may become irreversible based on binding time.

Carbamates are carbamic acid derivatives and reversibly inhibit AChE having the general formula: 0^:

^RV%-^R

Carbamate insecticides include aldiearb (Ternik), carbofuran (Furadan), carbartk (Sevin), methyl ciubomate, ethienoearb, and others. Carbamate esters are also caused methanes. OPs typically came a more severe and difficult to treat cholinergi crisis because OPs are capable of irreversibly inhibiting AChE.

OP and carbamate compounds are typically used as insecticides, pesticides, petroleum additives, and p etrochemicals . Deadly OPs and carbamates have also been developed for use as chemical warfare nerve agents by conventional armies, military special forces, desperate regimes, and or terrorists. Sarin, a highly potent OP. was used by Sadam Hussain's Republic of Iraq against Kurdish civilians in Halabja and other villages in March 1988 killing at least 3200 people and injuring many more people. (These attacks also involved two other OPs, Vx and tabim and mustard gas). The 1995 Tokyo subway attacks by a "religious "cult" used the same OP injuring many civilians. The use of Sarin more than once recently in the Syrian conflict lead to many casualties alarming the international community about the risks to the stability of the region.

Monocrotophos was the OP insecticide responsible for killing 23 school children in India who ate contaminated food, in a widely publicized incident. At least 750,000 cases of OP poisoning occur every year. Mortality and morbidity is higher in poorer countries where OP and carbamate pesticides, some of which are banned in developed countries, are inexpensive and accessible. They are estimated to cause around 300,000 fatalities a year. See Balali-Mood et al, "Recent Advances in the Treatment of Organophosphorous Poisonings" ban J Med Sci. 2012 .Time; 37(2); 74-91. Pharmacologically, OPs behave as anticholinesterase agents inhibiting the acetylcholinesterases (AChEs) enzymes and other esterases resulting in increased cholinergic tone, hi summary, OP and carbamate pesticides cause hundreds of thousands of deaths each year and many more injuries.

AChE is a serine protease in the carboxylestera.se family of enzymes with EC number 3.1.1.7. Mammals have a single AChE gene: however, AChE diversity in humans results from location, other molecular associations such as with membrane components, as well as from alternative mR A splicing and posftranslational associations or structural and catalytic subunits. Inhibition of ACliE prevents the breaking down of the neurotransmitter ACh thereby increasing both ilie level and duration of actio of this neurotransmitter. ACh is a neurofransiidtter that coatributes to nerve conduction following its release in the central nervous system (CNS) as well as autonomic ganglia at sympathetic preganglionic synapses, at parasympathetic postganglionic synapses, and at neuromuscular junctions.

At the skeletal neuromuscular junction the ACh receptor is nicotinic. In the autonomic nervous system the ACh receptor is muscarinic. Both muscarinic and nicotinic ACh receptors are foraid in the ceniial and peripheral nervous system. AChE catalyzes the hydrolysis of the acetylcholine into choline and acetic, acid. Such a reaction is necessary to allow a cholinergic neuron to return to its resting state after activation to restore normal muscle and neurological activities. AChEs are very efficien t with each functional enzyme capable of hydrolyzing at least 5000 ACh hydrolytic reactions per second. DFP or diisopropylflur ophosphaie is an OP developed in 1941. DFP bears structural similarity or homology with the nerve agent sarin. DFP has activity similar to sarin, although DFP is less potent. DFP is commonly used as a research OP proxy for sarin. See generally Goodman & Gillman, The Pharmacological Basis of Therapeutics 10th edition. 2001, Chapter 7 and Handbook of Toxicology of Chemical Warfare Agents, edited by Ramesh Gupta, 2009, especially chapters 6, 7, 32, 33, 42, 43, 61, 63, and 64.

The effects of chronic and acute exposure to OP and carbamates have been extensively documented in the literature. When OPs or carbamates are used as insecticides the prolonged exposure and inhalation of such compounds could lead to multiple ophthalmic and neuromuscular symptoms. OPs are also used as warfare nerve agents, ("nerve gas") and acute exposure to them by any route of exposure can be fatal. Carbamates may also be used in war or in terrorist attacks. Even if not fatal, exposure may lead to temporary incapacitation as well as permanent cognitive deficits, depression and other neitropsychiatric disorders. Current treatment after acute injury does not seem to prevent the emergence of "Organophosphate induced delayed neuropathy," an axoripathy. In any event OP and carbamate casualties require medical intervention and decontamination. Nerve agents, also called gasses regardless of physical state, are classified by die US military and into two types of agents, the G- and the V-class agents. G-agents such as tabun ( G A ) and sarin (GB) were originally synthesized by a German group during the 1930s and except for tabun (GA ethyl N„ N- dimethylphophorainidocyanitkte) .include ftuorinated compounds of orgaiiophosphate, such as sarin (GB; 2-fluoro- methylphophoryloxypropane), soman (GD; 3-fmoro- methyl-phosphoryioxy-2, 2-dirnethyl- butane), and cyciosarin (GF; fluoro-methyl- phophoryloxycyciohexane). G agents are volatile liquids at room temperature with a slightly higher density than water. Their primary route of entry is via the respiratory tract and mucous membranes such as the eye. Because of their high volatility G agents are considered non persistent nerve agents. Toxic exposures are most likely to be via eye, mouth, nose, and especially involve the respiratory tract unless filtered and/or neutralized by an improvised or purposely built gas mask. G agents in liquid form may penetrate skin and as well as volatilize presenting significant respiratory hazards. The respiratory tract tissues, primarily the air sacs or alveoli, provide a large surface area, about 100 square meters. Hie skin surface area in about 1.73 square meters. Loss of consciousness is expected in < one minute with death expected in < 15 minutes following 2 deep breaths of highly concentrated G class vapors. Since G agents and some OP pesticides are colorless, tasteless, and virtually odorless, they may also be accidently ingested into the GI tract or ingested via deliberate contamination of food and drinking liquids.

V-agents were initially synthesized after Work! War li by scientists from the United Kingdom. The V agents are sulfur containing organophosphate compounds including VE (S-2-diethylarnino ethyl O-ethyletliylphophonothioaie). VG (2 diethoxyphosphorylsiilfanyl- Ν,Ν-dieihylethanaiiiiiie), VM (2-ethoxy-methylphosphoryl suifaiiyl-N, -oiethylethanaiiiine },, VR or RVX (Russian VX; N,N-diethy-2-methyl-2- memylpropoxy phosphoiyl sirlfanyleihanainiiie) and VX (S-2 drisopropylarnrno O- eihyimethylphosphonotliioaie). The V-agents, oily liquids at room temperature that very slowly release gas due to their low volatilities, are both more toxic, as well as longer persisting in the environment than the G-agents. Their primary, but not the sole route of entry, is via skin contact. A single drop of VX the size of this dot (.) unless rapidly decontanrinated or removed, may be fatal within 30 tninutes if placed on intact thin moist skin, faster if on a wound, and within 120 minutes if on dry thick skin. The human LD 50 for VX is 10 mg.

Toxicity associated with OP compounds mainly results from excessive cholinergic stimulation through inhibition of AChE. The resulting hypercholinergie tone crisis may also cause other neuronal hyperexciiation, e.g. ghiiamate release and depletion of high energy phosphates leading to cellular damage and physiological exhaustion. Nerve agents react rapidly with a serine hydroxyl group in the active site of AChE to form a phosphate or phosphonate ester. Phosphorylated AChE is not able to functionally hydrolyze AC . Functional ACh regenerates very slowly. Thus, the enzyme will remain inhibited until new enzyme is generated, or until an enzyme re-activator (oxime) is used, as long as receptor aging or irreversible binding from molecular rearrangements of the AChE from the effect of the OP has yet not occmied.

As depicted in the schematic above, AChE represented by the Enzyme, contains serine in the active (esteratic) site. Following the binding of DFP to this site the AChE is inactivated. This uiactivaiiou of AChE may be hydrolyzed siowiy and spontaneously or rapidly reversed or restored with an oxime (and perhaps other chemicals). However, the binding or inhibition can eventually become permanent (irreversible or aged).

The symptoms of OP and carbamate toxicit are receptor and body site specific. Nerve agents antagonize muscarinic receptors to cause miosis, ocular ciliary or pupillary constrictor muscle spasm and eye pain, glandular hypersecretion (salivary. bronchial, iaerirnal/tear glands), bronchoeonstiiction, vomiting, diarrhea, urinary mid fecal mcoaiinence, and bradycardia.

Nerve agents act on nicotinic receptors to cause sweating, hypertension, tachycardia, and on skeletal muscle, they cause initial fasiculations, twitching, tremors, spreading areas of spasm, and defasciculation from exhaustion followed by weakness and flaccid par alysis.

Nerve agents also antagonize cholinergic receptors to produce irritability, giddiness, fatigue, lethargy, amnesia, ataxia, seizures, coma, respiratory depression, and paralysis. Nerve agents independently cause cardiac tachycardia and hypertension via stimulation of the adrenal medulla. Exposure to low concentrations of nerve agent vapor further produce immediate ocular symptoms, includin rliinorrhea (from nasolacrimal duct drainage), and in some patients, even dyspnea. These ocular effects are secondary to the localized absorption of vapor across the outermost layers of the eye, causing lacrimal gland stimulation (tearing), pupillary sphincter contraction (miosis), and ciliary body spasm (ocular pain).

As the exposure increases, dyspnea and gastrointestinal symptoms ensue. Intoxication signs and symptoms and treatment of patients exhibiting OP or carbamate toxicity is similar. Retrospective data review series involving OP and carbamate toxicity are frequently combined. See for example the 46 patient 5 year review from Jordan, a country where OP and carbamate agricultural insecticides are widely used. These chemicals are also used as agents in suicides and to injure enemies. See AM Saadeh et al, "Cardiac manifestations of acute carbamate and organophosphate poisoning" Heart, 1997: 77:461-464.

It is well documented that exposure to high concentrations of nerve agent vapor causes immediate loss of consciousness, followed shortly by convulsions, flaccid paralysis, and respiratory failure. These generalized effects ar e caused by the rapid absorption of nerve agent vapor across the respiratory tract, producing maximal inhibition of ACliE within seconds to minutes of exposure. Nerve agent vapor exposure, unless aggressively treated and to include decontamination to prevent reexposure to patient and also endanger rescuer, is expected to have significant effects by the time victims present to the emergency care system. Decontaminants include soap and water as well as the more effective expedient dilute chlorine bleach solutions for skin, dilute baking soda (sodium bicarbonate) solutions for eyes, nostrils, hair, ears, mouth, and other delicate tissues and genitourinary mucous membranes, or RSDL. RSDL is Reactive Skin Decontamination Lotion, a specialty pharmaceutical topical product issued to combat soldiers and some first responders. RSDL achieves a much more rapid and effective decontamination than any of the expedients.

The effect of dermal exposure fora liquid nerve agent depends on the matomic site exposed, ambient temperature, and dose of nerve agent. Percutaneous absorption of nerve agent typically results in localized sweating caused by direct nicotinic effect on the skin, followed by muscular fasciculatioiis and weakness as the agent penetrates deeper and a nicotinic effect is exerted on underlying muscle. Following moderate dermal exposures, vomiting and/or diarrhea occur. Vomiting and/or diarrhea soon after exposure are ominous signs. With further absorption, fullblown systemic or remote effects occur. Nerve agents cause death via respiratory failure, which in turn is caused by increased airway resistance (eg bronchospasm). excessive bronchopulmonary secretions, respiratory muscle paralysis, and most importantly, loss of central respiratory drive.

Other studies have shown that nerve gases such as sarin produced delayed and long- term effects on cardiac function such as reduced ejection fraction. Sarin caused left ventricular dilation two months after an asymptomatic dose. This is a marker for dilated cardiomyopathy. Levels of atrial and brain natriuretic peptides in the heart were increased, indicating cardiac remodeling possibly due to volume overload. It has also been reported that prolonged exposure to OP leads to cognitive impairment of central information processing leading eventually to IQ loss. See Davis et ai, Advances in Psychiatric Treatment, 2000; 6: 187-192.

The treatment modalities generally depend on severity of intoxication. In additio to decontamination, there are several treatments for intoxicated patients. More specifically, such treatments include administration of intravenous or intramuscular atropine, at least 2 mg at a time for adults, to counteract muscarinic over-stimulation. and an intravenous or intramuscular oxime, typically pralidoxime or 2-PAM, to reactivate acetyl cholinesterase. For example, the US military uses as front line therapy autoinjectors for IM administration combining 2.1 nig of atropine with 600 mg of 2- ΡΑΜ^'. If fascieiilation or seizures are present, the US military, prior to arrival of a medic, uses as a GABA A anti-seizure agent IM diazepam 10 mg in an autoinjector. Soldiers are given kits containin 3 autoinjectors of the combination atopme pralidoxime and 3 autoinjectors containing diazepam 10 mg. There is no ceilin on -the dose of atropine: additional injections are titrated vs adverse symptoms other tlian miosis every few ruinates as needed, hi oilier countries, armed forces and or emergency protocols use a different oxirne, e.g. obidoxirne or HI6, a different antiiniiscarinie (anticholinergic),, e.g. scopolamine and or other belladonna alkaloids in place of atropine, and a different antiseizure agent e.g. avizafone or midazolam or barbiturates. For some patients the dose of atropine required may exceed 100 mg! hi the absence of OP intoxication an atropine dose of 2 nig will cause severe poisoning and a dose of 100 mg will be fatal. For this reason Israel stopped including atropine with its gas mask kits for civilians after severe adverse reactions to atropine happened in civilians w o injected atropine in response to sirens warning of incoming SCUD missiles during the first Gulf War in 1991.

Supportive and intensive care therapy includes the use of oxygen, IV fluids,

.glucose, and electrolytes (salts) and bicarbonate, to replace the fluids and salts and bicarbonate lost from vomiting, diarrhea, profuse sweating (diaphoresis) and respiratory secretions. In addition titrated IM and IV diazepam to control convulsions, aiiopiiie bxiine, mechanical respiration, and intensive cardiorespiratory and neurological sign monitoring with aggressive treatment of cardiac rhythm disorders and pulmonary edema. Experimental eholinesterase infusions are also being researched as are catalytic scavengers that would split an OP molecule to render it inactive, such as from infusions of FFP or Fresh Frozen Plasma, or from stoichiometric scavenger's to bind an OP and antibodies against OPs . Recent investigations have revealed that intravenous infusion of sodium bicarbonate to produce niikl to moderate aikahnization is effective. Gacyclidine, an antigiutamaiergie compound, was also proved to be beneficial in conjunction with atropine, prahdoxime, and diazepam in nerve agent poisoning. Intravenous magnesium sulfate was reported to decrease hospitalization duration and improved outcomes in patients with organophosphorous poisoning from pesticides. etamine may also be useful if given early. See Balali-Mood et al, Iran J Med Sci. 2012 June: 37(2); 74-91. At present, pyrostignnine bromide 30 ing tablets (PB) every 8 hours seems to be the most common prophylactic. PB is approved for military medical use by the US FDA at this dose and frequency for this indication for soman. G-agent soman ages the AChE in under 2 rniaiiies. Soman is probably the most rapidly aging OP (based on non classified or public domain data). Pre-exposure treatment with PB sequesters some AChE from OP binding and aging. Any subsequent post OP or post carbamate intoxication is more rapidly and more effectively treated with atropine/oxime therapy. Like all medications PB has adverse effects. Adverse reactions to PB include salivation, lacrimation. urination, defecation symptoms and miosis. Prophylactic use of PB has also been linked to the Gulf War Syndrome. Regimens used by trained soldiers acting under rni!itary medical orders in other countries include prophylactic tablets with physostigmine rather than pyridostigmine with or without Trihexyphenidyl, benactyzine, and/or a transdermal patch containing HI-6.

Access to effective prophylaxis and treatment has important implications for military or civilian populations since iow-dose, non-symptomatic exposure to OPs or carbamates may result i long-lasting effects. See Fusek et al. CHIT. Med. Chem. 2009; 16{23):2977-86 and Chapter 63. Prophylactic and Therapeutic Measures in Nerve Agent Poisoning in Handbook of Toxicology of Chemical Warfare Agents, edited by Ramesh Gupta, 2009, and US Prescribing Information for Physostigmine bromide 30 mg for military medical use.

However, since pyridostigmine barely crosses the blood-brain barrier it provides no protection against nerve agent-induced central injury. Pyridostigmine, as written in the FDA approved prescribing information, is ineffective when administered without post-exposure treatment of atropme/2 PAM or similar drags. Also many of the prophylactic and treatment regimens cause cognitive impairment or excessive dryness (e.g. atropine and other antimuscarinics), certainly not desirable in combat situations or hot environments where perspiration also serves as a temperature regulator. Excessive dryness increases the chances of heat exhaustion related disorders including heat stroke.

Therefore, other directions for different types of prophylactic and non- injection, less expensive, and self-administered treatments for those not requiring an intensive care unit for potentially therapy) should be explored. Atropine overdose or misuse risks heat stroke and temporary psychosis. A common mnemonic used to describe the physiologic .manifestations of atropine overdose is: "ho as a hare, blind as a bat (from very dilated pupils and cycloplegia), dry as a bone, red as a beet, and mad as a hatter".-These associations reflect the specific changes of warm, dry skin fioin decreased sweating, blurry vision with hypersensitivity to light, decreased sweating/laeiimation, vasodilation, and central nervous system effects o muscarinic receptors, type 4 and 5. This set of symptoms is known as anticholinergic toxidrorne.

Recently there have been discussions on combination prophylactic therapies including such compounds as carbamates (reversible ACliE inhibitors) and central anticholinergics or NMDA receptor antagonists, benzodiazepines or partial agonists for benzodiazepine receptor, and other central AChE inhibitors. The transdermal route is an alternative way for delivering the prophylactic agent and has also been discussed in the art. Regardless, there is still a need for additional prophylactic or adjunct to existing prophylactic regimens to mitigate drag related adverse events or direct treatments to alleviate undesiied symptoms associated with the OP and carbamate toxicities. There is a need particularly for nontoxic treatment modalities, with favorable therapeutic indices compared with PB, atropine and such respiratory depression-inducing anticonvulsants as midazolam, diazepam, and barbiturates. There is a need for anti OP and carbamate therapy that may be easily self-administered or easily administered by first respoiider medics and paramedics in mass casualty situations or even by lightly injured casualties to each other and to more seriously injured, casualties. In the event of mixed nerve agent/conventional warfare casualties, there is also a need for antidotes to the nerve agents that won't have significant drug/drug interactions with medications used to treat surgical wounds including general anesthesia agents. The present invention addresses such shortcomings.

SUMMARY OF THE INVENTION

The present invention discloses the role of cannabmoids in mitigating OP toxicity via manipulation of the endocarmabiooid (EC) system and other physiological systems. In one embodiment of the present invention discloses a pharmaceutical composition, comprising an isolated eai abinoid receptor modulator, and optionally containin a blend of terpenes in a pharrnaceuticaily acceptable carrier.

Another embodiment of the present invention discloses a pharmaceutical composition former comprising a blend of two or more terpenes selected from the group consisting of linionene, pineiie, myrcene, linaiool, beta eaiyophylene, terpineol and terpinoiene.

In another embodiment of the invention, the teipene blend comprises two or more terpenes selected from the group consisting of linionene, pinene, myrcene, linaiool, beta eaiyophylene.

hi another embodiment of the invention, the weight ra tios of said terpenes is within the in range of about 1-10: about 1-10: about 1-6: and about 1-6: 0.25-3. respectively. hi another embodiment of the invention, the weight ratio of said terpenes is about 4:4:3:3:1 respectively.

In another embodiment of the invention, the weight ratio of said terprenes is about

4:7 3:3 : 1 respectively.

Another embodiment of the present invention discloses a pharmaceutical composition, wherein said cannabinoid receptor modulator agonist is a CB receptor agonist or a modifier selected from the group consisting of phytocaiinabiiioids, tetrahydrocannabinol (THC) (-) trans delta 9 THC, dronabinol, {±)-traiis-3-(lJ-

dibenzo[b,d]pyran-9-one (nabilone), ariandamide, 2-arachidoriCiyl-glycerot (2-AG), N- acyl- phosphatidylethariolaiiMiie-phospholipase D, diacyi glycerol lipase (DAGL), caimabidiol (CBD), abnormal cannabidiol (abn-CBD), iiabiximols, EPIDIOLEX®, rimonabant, (-)-l.l dimemylheptyl analogs of l l-hydi xy-8-ietrahydiocannabinol (HU 210), HU 211, HU 308. ajulemic acid. AM-411, L-759.633, AM-855, VCHSR, nonabme, JWH 133, JWH-171, BML-1 0, A-41988, O-806, 0-2694 and 0-2545, JZL184, JWH-359, CB-13, GW-405,833, JTE-907, URB754, Miibitors of FAAH or fatty acid amide hydrolasel-

(AM- 1241), WI 55,212-2, oilier natural or endogenous endocannabinoid derivatives, and combinations thereof. The pharmaceutical composition of the the present invention are in oral, nasal, topical, ophthalmic, buccal, sublingual, rectal, vaporization-ready, nebulization-ready, nanoparticie formulations, liposomal formulations, vaginal and/or IV or other parenteral form.

The pharmaceutical composition of the the present invention further comprise one or more non-cannabinoid active ingredients selected from the group consisting of a terpene, a benzodiazepine, a belladonna alkaloid, an anticholinesterase an oxinie, and combinations thereof.

In an embodiment of the invention belladonna alkaloid is atropine and anticholinesterase is pyiidostiganiine.

Another embodiment of the invention is directed to a method of treating or preventing a disease, disorder, dysfunction or syndrome caused by exposure to an organopliosphate (OP) or carbamate acetylcholinesterase inhibitor, saqid method comprising administering to a subject exposed to or at risk of exposure to said OP or carbamate in an amount effective to moduolate the cannabinoid receptors of said subject.

In an embodiment of the invention the pharmaceutical composition is for treating disease, disorder, dysfunction or syndrome is selected from the group consisting of muscle disorder, ophtlialrnic dysfunction, metabolic disorders, cardiac, rhythm and contractility dysfunctions, social related disorders, mood disorders, seizures, learning disorders, cognition disorders, memory disorders, respiratory disorders, locomotor activity disorders, movement disorders, immiaie disorders, inflammation, ceil growth, pain or neurodegenerative related syndromes, drug abuse, alcohol abuse, bipolar disorder, cognitive impairment, post traumatic stress disorder (PTSD), Gulf War like syndrome and premature senile dementia.

hi one embodiment of the invention, the muscle disorder is selected from the group consisting of dyskinesia, akinesia, tremor, bradykiiiesia, skeletal muscle rigidity and spasticity.

In one embodiment of the invention the ophmalmie disorder is selected from the group consisting of miosis, ciliary muscle spasm, ophthalmic pain, headache and lacrimaiion disorder.

In another embodiment of the invention the OP is a G or V class nerve agent. In another embodiment of the invention the cannabmoidreeeptor modulator is selected from the group consisting of phvtocannabinoids, tetrahydrocannabiooi (THC) (-) trans delta 9 THC, dronabinol (±)-irans-3-(lJ-dimetliyiheptyl)-6,6a, 7,8.10, lOa- hexahydr Hl-hydiOxy-6-6-dnnethyl- 9H-dibenzo{b_fd]pyraa-9-one (nabiione), anaudamide, 2-aradiidonoyi-giycerol (2-AG , N-acyl- phosphatidylethanolainiHe-phospholipase D, diacyl glycerol lipase (DAGL), cannabidiol (CBD), abnormal cannabidiol (abn-CSD), iiabixiinois, EPIDIOLEX®, rirnonabant dnnethylheptyl analogs of l l-hydroxy-8- tetrahydroeannabinol (HU 210), HU 211, HU 308, ajulemic acid, ΑΜ-4Π, L-759,633, AM-855, VCHSR, nonabine, JWH 133, JWH-171, B L-190, A-41988, O-806, 0-2694 and 0-2545, JZL184, JWH-359, CB-13, GW-405,833, JTE-907, URB754, inhibitors of FAAH or atty acid ainide hydrola.se!- (methylpiperkliii-2-yiniethyl)-3-(2-iodo-5- nitrobenzoyi)indole (ΑΜ-Ϊ241), WIN 55,212-2, oilier natural or endogenous eiidocamiabiiioid derivatives, and combinations thereof.

Another embodiment of the invention provides for adininistermg a non- cannabinoid receptor modulator selected from the group consisting of opioids, gabapemins, pregabaiins, a benzodiazepines, atropines, oxinies, antioxidants, alkalizing agents, teipenes, and NSAIDs.

Another embodiment of the invention provides for administering the composition in oral, nasal, topical, ophthalmic, buccal, sublingual, rectal, vaporization-ready, nebulization-ready, nanoparticle formulations, liposomal ibm lations, vaginal and/or IV or other parenteral form.

Another embodiment of the invention provides for administering the composition prior to exposure to said organophosphate or carbamate and said composition comprises at least one terpene selected from the group consisting of limonene, mycrene, pinene, iinalooL beta caryophyllene, and a cannabinoid selected from the group consisting of THC or CBD, and a mixture of THC, CBD.

Another embodiment of the invention provides for the step of exposing said subject to an OP or carbamate acetylcholinesterase inhibitor as a prophylactic treatment.

Another embodiment of the invention provides for admimstering to a subject atropine and an oxime in an amount effective to prevent adverse effects from said prophylactic exposure to OP or carbamate. Another embodiment of the invention provides for eo-adniinistering pyridostigmine broini.de to a subject.

Another embodiment of the invention provides for administering to said subject after exposure to an OP or a carbamate acetylcholinesterase inhibitor and said composition comprises a blend of CBD and THC i a weight ratio of between about 3 and 400 nig to about 0.0001 and 10 mg, respectively.

Another embodiment of the invention provides for aehiihhstering a blend of two or more teipenes.

In another embodiment of the invention, the terpine blend comprises two or more teipenes selected frorn the group consisting of of linionene. pinene, niyrcene, linalool, beta earyophyiene. teipineoi and terpinolene.

Another embodiment of the invention provides for a method of treating or preventing a disease, disorder, dysfunctio or syiidrome caused by exposure to an organophosphate or carbamate acetylcholinesterase inhibitor, said method comprising administering to a subject exposed to or at risk of exposure to said OP or carbamate, q composition comprising at least two teipmes selected from the group consiting of iimonene, myrcene, linalool, beta earyophyiene, teipineoi, terpinolene, and pmene, in an amount effective to treat or prevent said disease, disorder, dysfunction or syndrome.

Another embodiement provides for a terpine mixture comprises alpha pinene.

Another embodiement provides for a a blend which comprises beta- earyopliylene, Iimonene. myrcene, and linalool.

Another embodiement provides compound having the following stricture:

wherein L is selected from the group consisting of ^x * and ^{¾ »} ; Z = O, S or NR7. R7 = H, alkyl. aryl, -OfL-O, or lower alkoxy; A is aryl, heteroaryl, fused pyran or a fused fetrahydropyran: B is C(=0)-0-R6; R6 is an alkaloid azabicyclo ring snbsti uen; C is H, F, lower alkoxy, C , S(0)iiCH3 where n = 0-2, and Z = O. Another embodiement provides for a compound selected from the

group consisting of:

I another embodiment such compounds may be administered to a subject in need in effective doses corresponding to the therapeutic doses of THC, CBD and or atropine. The composition of the present invention may be used to treat symptoms associated to OP or carbamate exposure. Such symptoms include ocular symptoms, skeletal motor symptoms, respiratory and C S associated symptoms. In another embodiment, the ocular symptoms to be treated include lacrimal gland stimulation (tearing), painful pupillary sphincter contraction (miosis), and ciliary body spasm (ocular pain), hi another embodiment, the respiratory symptoms being treated include dyspnea, bronchospasm, coughing, rhinorrhea, bronchorhea, respiratory distress, sensation of shortness of breath, respiratory failure, pulmonary edema, and air hunger. The gastrointestinal symptoms that ensue after exposure usually include hyper salivation, vomiting, diarrhea and stomach cramps.

In another embodiment, the symptoms being treated include motor symptoms such as fasiculations, dyskinesia, akinesia, tremor, bradykiiiesia, skeletal muscle rigidity. spasticity. In yet another embodiment, the CNS symptoms being treated me iding cognitive brain damage, neuropathy including axonopathy, anxiety, memory impairment, PTSD, and depression.

In at least one aspect of the present invention, the composition of the present claims may be administered either directly or indirectly to the site Of interest by the way of eye drop, eye ointment, oral spray, rectal suppository, intravenously, mtramuscularly, siibcutaneously, intradeiinally, orally in the form of capsules or tablets or diluted oils topical rubs on the skin or mucous membrane or bitccaliy. Alternatively, the formulation may be applied directly to the site of interest such as via nasal application devices to sphenopalatine ganglion and cribriform plate, which is the pathway to the olfactory cranial nerve and brain, as well as the cerebrospinal fluid or by the way of inhalation of vapors for rapid absorption. In the alternative, the formulation may also be introduced as a vapor into a gas mask, bag/valve mask use used in manual resuscitation or assisted breathing, nasal emulation. CPAP or Continuous Positive Airway Pressure or valiants of CPAP such as BiPAP, or via intubation with or without general anesthesia. Other objects, features, benefits and advantages of the present invention will be apparent from this summary and the following descriptions of certain embodiments, and will be readily apparent to those skilled in the art having knowledge of various ehemotherapeutic compounds, methods and/or modes of operation. BRIEF DESCRIPTION OF THE FIGURES

Figure 1A and IB depict the composition of the inventive terpene blends described herein.

DETAILED DESCRIPTION OF THE: INVENTION

Unless defined otherwise, all technical and scientific terms used herein have the same meaning as is commonly imderstood by one of skill in the art to which this invention belongs and shall be imderstood to have the meanings described below. All publications and patents referred to herein are incorporated by reference in their entirety. Unless otherwise specified, a reference to a particular compound includes all such isomeric forms, including racemic and other mixtures thereof. Unless otherwise specified, a reference to a particular compound also includes ionic, salt, solvate (e.g., hydrate), protected forms, prodrugs, and oilier stereoisomers thereof, for example, as discussed herein. It may be convenient or desirable to prepare, purify, and/or handle a corresponding salt of the active compound, for example, a phai naceiiticaily-accepiabie salt Examples of harmaceutically acceptable salts are _.discussed in Beige et al, 1977, "Pb¾inaceiiticalty Acceptable Salts," J. Phaim Sci., Vol. 66, pp. 1-19.

The term "lower aficoxy" is defined as Ci to Cj alkoxy.

The term ''benzodiazepine'^* as used herein pertains to all different short and long acting benzodiazepines including but not limited to prodrugs as well as estazolarn. fiurazepam, temazepam, triazolam, alprazolam, ehiordiazepoxide. clorazepate, diazepam, halazepam, lorazepam, midazolam, oxazepam, piazepam, quazepam, and clonazepam Benzodiazepine antagonists are thus such compounds that antagonize the benzodiazepine activities, especially respiratory depression secondary to benzodiazepine toxicity.

The term "cannabinoid" as used herein pertains to all different cannabmoids have been isolated from the Cannabis sativa plant or synthetically created to have activity invoking the endocannabinoid system. The term cannabinoid includes but are not limited to all classes of cannabmoids from Cannabis derived from cannabigero!-type compounds including (9THC), cannabidiol (CBD). caimabinoi (CBN), and dodeea- E,4E,8Z,10E/Z-tetraenoic-add-isobutylarnides, cannabigerol (CBG), caimabichroniene, caimabieyclolCCBL), cannabivaiin (CBV), tetraiiydiOcaimabivariii (THCV), cannabidivarin (CBDV , cannabichromevaiin (CBCV), cannabigerovarm (CBGV), and cannabigerol mononiethylether (CBGM).

As used herein, the term "composition" is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product winch results, directly or mdirectly. from combination of the specified ingredients in the specified amounts.

The term "organophosphate" as used herein, pertains to compounds that are generally esters, amides, or thiol derivatives of phosphoric, phospfionic, or phosphiiiic acids. Aside from certain limited medical uses, these compounds are typically used as insecticides, pesticides, petroleum additives, and even warfare nerve agents. Organophosphates includes substances such as echofhiophaie, diisopropyl f!uorophosphate (DFP), tabun. GA, GB (sarin), GD, GF, VX, VE, VG, VM, diazinon, maiathion, and parathion. The term "terpenes" or "terpenoids'^' as used herein refers to a class of hydrocarbon occurring volatile molecules that provide a unique smell. Terpenes are derived from, units of isoprene, which has the molecular formula CsHs. The basic molecular formulae of terpenes are multiples of that (Cs¾¾, where n is the number of linked isoprene units. They include but are no limited to limoiiene, beta-caiyc¾ hyllene, myreene, iioalool, pinene, terpineol and terpinolene and any isomeric forms thereof.

The term "treatment" or "therapy" as used herein in the context of treating a condition, pertains generally to treatment and therapy of a human subject, hi which some desired therapeutic effect is achieved. For example, therapy can include the inhibition of the progress of the condition, reduction in the rate of progress, a halt in the rate of progress, amelioration of the condition, absolute or partial prevention of a delayed complication, and cure of the condition. Treatment also includes prophylactic measure; as well as, adjunct treatments to a standard treatment regimen established in the art.

The term "tlierapeutically-effective amount," as used herein, pertains to that amomit of an active compound, or a materiaL composition or dosage from comprising an active compound, which is effective for producing some desired therapeutic effect, commensurate with a reasonable benefit/risk ratio.

It may be convenient or desirable to prepare, purify, and/or handle the active compoimd in the form of a prodrug. The term ''prodrug'^* as used herein, pertains to a compound which, when metabolized, yields the desired active compound or in itself is the active compound. Typically, the prodrug is inactive, or less active than the active compomid, but may provide advantageous handling, administration, or metabolic properties. For example, some prodrugs are ethers or esters of the active compound; during metabolism the ether group is cleaved to yield the active drug. Also, some prodrugs are activated eiizymatically to yield the active compound, or a compoimd which, upon further chemical reaction, yields the active compound. Thus, the methods of treatment of the present invention disclosed herein, the term "administering" shall encompass the treatment of tlie various conditions described with the compound specifically disclosed or with a compound which may not be specifically disclosed, but which converts to the specified compound i vivo after adniinistratkai to the patient. Metabolites of these compounds include active species produced upon introduction of compounds of this invention into the mammalian subject.

Any of the compounds of the present invention may be contemplated for administration to the human subject in the form of a drag, prodrug or even active metabolite.

The camiabinoid and the THC-CBD combinations have been known in the art for treating or preventing a number of diseases or disorders. For example, U.S. Pat. No. 6,630.507 discloses cannabinoids for use as anti-oxidants and neuro-protectants: U.S. Pat. No. 7,105,685 discloses Cannabinoids for the treatment of diseases associated with immune dysfunction, particularly HTV disease and neoplastic disorders; U.S. Pat. No. 7,109.245 discloses Cannabinoids useful as vasoconstrictors; US Patent Publication US 20110257256 discloses THC- CBD composition for use in treating or preventing Cognitive Impairment and Dementia; PCT Publication WO/2009/147439 discloses use of a combination THC and CBD in the manufacture of a medicament for use in the treatment of cancer, in particular the glioma tumor (a brain cancer): PCT Publication WO/2007/1 8094 discloses use of THC-CBD composition for the treatment of neuropathic pain: and US Patent Publication US20100286098 discloses a method of treating tissue injury in a patient with colitis admimstering the THC-CBD combination.

Currently, US Drag Enforcement Administration (DEA) lists cannabis as a Schedule 1 compound which means Cannabis and similarly scheduled cannabinoids have not been shown to have safety and/or accepted medical use. However, different combinations of cannabinoids are still under investigation.

The psychoactive constituent in cannabis, 9THC was isolated in the period 1 63-64 by Prof. Raphael Meehoulam, but the camiabinoid receptors, the CB 1 and the CB2, and the preliminary endogenous cannabinoids, e.x. anandamide and 2- arachidonoyl glycerol were identified only 20 to 25 years later. The camiabinoid system affects both central nervous system (CNS) and peripheral processes. In at least one aspect of the invention, methods of manufacturing a pharmaceutical composition containing a camiabinoid is contemplated including the steps of purifying and/or isolating the camiabinoid recepto agonist and mixing said agonist with a pharmaceutically acceptable carrier. In one aspect of the present invention methods of ameliorating or treating a cannabinoid receptor mediated disease, disorder or syndrome in a human subject are disclosed by such steps as administering to the subject an effective amount of a composition containing cannabinoid receptor modifiers and/or terpenes such as d- iimonene, pinene, rnyreene, linalool, beta caryophylene or a combination thereof.

More particularly, the present invention relates to a method of treating OP or carbamate related toxicity in human patients. In this aspect of the invention, methods are provided for modulating the CB system to reduce functional signs or toxicity following exposure to OP or carbamate. In such a method, patients receive a therapeutically effective amount of EC system modulator for sufficient time to reduce the time of acetylcholine binding to its respective receptors thereby limiting cholinergic signs of toxicity associated with prolong OP exposure.

hi at least one embodiment, the mediated disease, disorder, dysfunction or syndrome being treated is secondary to organophosphate exposure and include appetite disorder (such as loss of appetite), muscle disorder, ophthalmic dysfunction, metabolic disorders, cardiac, rhythm and contractility dysfunctions, social related disorders, mood disorders, seizures, substance abuse, learning disorders, cognition disorders, memory disorders, respiratory disorders, locomotor activity disorders, movement disorders, immune disorders, inflammation, cell growth, pain or neurodegenerative related syndromes, substance abuse including alcohol abuse, bipolar disorder, cognitive impairment, post- traumatic stress disorder (PSTD), Gulf War syndrome type disorders and premature senile dementia, hi a preferred embodiment, the instantly described methodology is used as an adjunctive treatment to the standard medical regimen typically used for OP toxicity.

hi another embodiment, the muscle disorders are dyskinesia, akinesia, tremor, bradykmesia, skeletal muscle rigidity and spasticity. In another embodiment the ophthalmic disorders are miosis, ciliary muscle spasm, ophthalmic pain, headache and laerimaiion disorder.

In yet another embodiment, the present invention is directed to methods of antagonizing G and V class nerve agent organophosphate toxicity' via administering to a subject hi need thereof a cannabinoid receptor agonist, its free base, in pharmaceutically acceptable salt form and a pharmaceutically acceptable carrier. Such toxicities include those that lead to permanently cognitive impairment, such as attention deficit disorder, executive f mctioii disorder, loss of coordination particularly when operating hazardous machinery, learning disability, safe driving, delayed axonopatliy.

In a preferred, embodiment, the present invention is directed to a synergistic combination of suitable cannabinoid, terpene and an alkaloid such as atropine. I this embodiment, such combination can be in a water soluble solution, suspension, or otiier suitable delivery system, or in a kit. In another embodiment, any such ingredients may be linked together by the way of a biodegradable linker system releasing individual active ingredients.

In another embodiment, the present invention provides a synergistic combination of a CB receptor agonist, or partial agonist with a secondary pain medication including but not limited to opioids, NSAIDS, and gabapentin, pregabalin, a benzodiazepine, atropine, oxime, antioxidants (e.g. grape seed, blueberry extracts, vitamm E, vitamin C), and suitable alkalizing agents.

The present invention discloses the novel uses of cannabinoid receptor modifiers in the treatment of the symptoms associated with the OP exposure. By the way of example, cannabinoid receptor agonists employed in the present invention include, but are not limited to delta 9THC, CBD, CBN, nabilone, dronabinol, nabixknols, or mixtures thereof. Cannabinoid receptor antagonists include rimonabant.

In mother aspect of the present invention, endogenous ligands of the cannabinoid receptors such as anandamide and 2-AG, and endocannabinoid metabolizers diacylglycerol lipase (DAGL) and degradation of these lipid mediators (fatty acid amide hydrolase (FAAH) and MAGL (monoacylglycerol lipase) are formulated in combination with cannabinoid receptor modifiers such as 9THC, CBD, CBD-V, THC-V, CBN, nabilone, dronabinol, nabiximols, rimonabant. In a more preferred embodiment, the combination comprises at least any two of 2- AG, DAGL, 9THC, CBD, CBN, nabilone, dronabinol, Epidiolex®, nabiximols, and rimonabant. Other minor lipid metabolites different from, but chemically similar to, anandamide and 2-AG are also suitable for the presently described formulations. In at least another embodiment, the invention manipulates the endocannabinoid system, a G-protein-eoupled cannabinoid receptor to treat symptom associated with the OP toxicity. In the brain, endocannahinoid primarily influences neuronal synaptic communication, and affects biological functions, including eating, anxiety, learning and memory, reproduction, metabolism, growth and development, via an array of actions throughout the nervous system. In at least one aspect of the present invention, EC signaling function is targeted to improve the therapeutic benefits of cannabinoids and terpenes in protecting subjects at risk due to carbamate or OP exposure. In another aspect of the present invention the agonists used activate or selectively block one type of cannabinoid receptor more potently than the other type partial agonists or full agonists with differing CB1 and CB2 receptor affinities.

hi another aspect of the present invention is the new discovery of the correlation of desirable properties of CB agonists and supplemental terpenes in alleviating the symptoms of toxic OP or carbamate exposure. In a preferred embodiment such properties include pupillary dilatation or at least a decrease in miosis and recovery to normal size, dry eyes, dry month, muscle relaxation, neuroprotection against oxidative stress, and anxio!ysis. hi other word, those of ordinary skill in the art would appreciate that the undesirable properties of recreationail smoking marijuana causes, i.e. dry eyes, dilated pupils, dry mouth, reduced ability to vomit if one desires to vomit, and difficulty with micturition are shown herein to be serendipitous benefits, desirably prevent, decrease or provide therapeutic effects in the context of OP and carbamate toxicity. Those of ordinary skill in the art can further appreciate that the ideal property sought in cananbinoid therapy is devoid of unwanted psychoactive components, or attempts to minimize them in a risk: be efit assessment, except for perhaps an anxiolytic effect and reduction in memory of being acutely sick from OP or carbamate intoxication.

It is also well established that CB 1 receptors are widespread in the brain which can explain its involvement in multiple memory stages that might require different neural substrates. In this context, several intriguing, reports suggest the presence of CB 1 receptors in astrocytes. See Navarrete M., Araque A. 2010. Endocannabinoids potentiate synaptic transmission through stimulation of astrocytes. See Neuron 68, 113-126) and mitochondria (Benard G., et al. 2012. Mitochondrial CB Ϊ receptors regulate neuronal energy metabolism. N t Neurosci. 15, 558-56), where they can also participate in the control of cognitive processes.

In the brain, eamrabiaoids and eiidocannabinoids modulate a number of intracellular signaling pathways, some critically involved i the deleterious effect of cannabinoids on learning and memory processes. The involvement of the mammalian target of the rapamycm pathway and extracellular signal-regulated kinases, together with their consequent regulation of cellular processes such as protein translation, seem to play a critical role in the amnesic-like effect of cannabinoids. hi at least one embodiment, methods of limiting brain toxicity and cognitive impairment associated with OP exposure are disclosed. In suc methods, cannabinoids are directly and locally administered to brain regions identified to be at risk secondary to OP toxicity. Mode of administration in this aspect of the invention includes suitably designed nasal and/or regional catheters.

In at least one embodiment of the present invention, CB agonists can be administered locally, that is cutaneously, over areas of skin sweating and fasieulations and directly to the site(s) of interest such as via nasal applicators to the sphenopalatine ganglion and cribiform plate or by the way of inhalation for rapid absorption, hi another embodiment, die CB agonists are administered ophthalmicliy and buccally in the form of an isotonic solution, extracts, ointments, inhaler or injectable. In another embodiment, a water soluble delivery system is administered by inhalation via an electric charge e-cigarette or a nebulizer.

In a preferred embodiment, the formulation contains sufficient amount of caimabinoid to competitively inhibit the binding of OP to the ACIrE. hi at least one embodiment the formulation contains 27 mg of 9THC and at least 25 mg of CBD, COG or CADGE in alkyl alcohol. In a more preferred embodiment, the formulation comprises 1-3 mg of (-) delta 9THC and 25 mg CBD, wherein each 100 microliter spray for sublingual deliver}' contains up to 0 05 g alcohol.

In another embodiment, at least a composition containing a terpene mixture is described, hi such embodiment, terpenes may be a combination of limonene: pinene myrcene: linalool: beta caryophylene: terpineol; terpiiiolene in such ratios as 1-10: 1-10; 1-6: 1-6: 0.25-3; 0-10; 0-10. respectively, hi another embodiment, the ratio between such terpenes is 4:4:3:3: 1:0:0. In yet another embodiment, the ratio between such teipenes is respectively 4:7: 3:3:2: 0:0.

In another embodiment,, other ingredients can be used to formulate a stable caiMiabifioid, terpens, alkaloid composition. Such ingredients include but are not limited to Sterile Water, Organic Vegetable Glycerine,, phospholipids, glycerols, polyethylene glycerol, or volatile acid to formulate a Cannabis extiact having a concentration of 15-50 mg of cannabinoids per ml, and 5% alcohol (for preservation), hi another aspect of the invention, the cannabinoids may be present and mixed with Grapeseed Oil with an organic solvent such as alcohol ranging from 0- 5% w/v.

In a more preferred embodiment such formulation can be applied for a maximum of 25 sprays per day with at least a 15 minute gap between sprays, hi another embodiment, such formulation is applied for a total of 15 sprays per week. hi another embodiment, the CB agonist is administered orally. At least one suitable drug is nabilone, a synthetic cannabinoid. Nabilone occurs as a white to off- white polymorphic crystalline powder. In aqueous media, the solubility of nabilone is less than 0.5 rng L, with pH values ranging from 1.2 to 7.0. Chemically, nabilone (±)-irms-3-(Il-diniethylhept 4)- 6,6 a 7,S, 10,10a-hexahydro-l-hydroxy-6-6-dimethyl is similar to the active ingredient found in naturally occurring 9THC. In at least one embodiment, nabilone can be administered orally at doses ranging from 0.005 nig to 200 mg, preferably 1 mg to 100 mg in a tablet, capsule, oral solution, immediate or extended release formulations. In a more preferred embodiment nabilone is administered orally at 0.05 , 0. 5 , 1 , o 2 mg and two to three times a day.

In another aspect of the present invention, those of ordinary skill in the ail would appreciate that the present invention establishes the link between antagonizing specific and general manifestation activities of the chemical war nerve agents of the G and V classes as well as toxicity secondary to OP or carbamate insecticide exposure in humans, hi at least one embodiment, the formulation containing the CB agonist or modulator is administered in the form of an eye drop or ointment, in tins aspect of the invention, the eye drop may be used to prevent or minimize miosis and/or ciliary muscle spasm and/or lacri ation secondary to G and V agent or carbamate exposure.

In another aspect of the invention the CB receptor agonist can be an active metabolite of THC. in another embodiment, the CB agonist or modifier can be administered intranasalty to the sphenopalatine ganglion and cribiform plate regions of the patient with, or without atropine with or without a decongestant or with or without a local anesthetic, in a more preferred, embodiment this mode of admhnsteation is accomplished by a long-acting local anesthetic ingredient. As used herein, the CB modifiers include such compounds that can compete with endocannabhioids or can enhance agonistic activities at such receptor sites.

In another aspect of the invention, the CB receptor agonist is administered via inhalation to mucosal membranes and alveoli of the respiratory tract via the mouth or nose. In this aspect of the invention, the agonist may also be administered via vaporization, or a nebulization via a mask nebulizer, below the temperature of combustion so as to be less irritating to mucosal and alveoli of the respiratory tract via the mouth or nose. In another embodiment, the eannabmoid may be delivered to the alveoli as well as to the sphenopalatine ganglion, olfactory nerve, and cribiform plate.

In yet another embodiment, the camiabinoid formulation is administered by inhalation, via, nose and/or via mouth in the form of a nanomolar formulation or a liposomal formulation that includes added terpenes and/or atropine dry powder via suitable metered dose inhaler, or an electronic nebulizer, designed to deliver therapeutically effective amount of the agonist to the lung. In a more preferred embodiment, the CB receptor agonist is in dry powders or liposomes having particles size diameters ranging from 10 nanometers to 3000 am, preferably ranging from 50 ma to 2000 nrn. In a more preferred embodiment, the liposomes have a wall containing phosphatidylcholine, phosphatidic acid, cholesterol and phosphatidylethanolamine.

In another aspect of the invention, the CB receptor agonist is prepared in the form of a culinary extract in the form of or resembling butter or margarine to be used for baking and cooking. In another embodiment, the product is in a form ready for vaporization such as in an E cigarette, or administration into a gas mask, bag/valve mask or CPAP device, or any form combining cannahinoids with or without added terpenes, but optionally with atropine, an oxinie and/or a benzodiazepine for combination therapy. In a preferred embodiment, the potent anticholinergic drag combination includes a camiabinoid modulator with or without terpenes in combination with atropine, oxinie and a benzodiazepine. In certain embodiments of the present invention a composition containing the CB agonist or a modifier can further contain a pharmaceutically-acceptable carrier component Without limitation, such a composition can comprise a raeeniic mixture of compounds.

In another embodiment .the invention relates to a method for use in treating or preventing ophthalmic pain, muscular spasticity, neuromuscular pain, including neuropathic pain secondary to OP or carbamate toxicity. In a more preferred embodiment the preferred combination product is used as an adjunctive therapy to standard OP or carbamate toxicity medical management.

In at least one aspect of the invention, the inventor discloses formulations containin camiabinoid that are use to alleviate or prevent brain injuries that can be caused by prolonged OP or carbamate exposure causing increased cholinergic tone. It has been shown that within the hippocampus at least, cannabinoids presynaptically inhibit the release of acetylcholine, possibly through the activation of CB 1 receptors located on cholinergic nerve terminals. Direct in vivo inicrodialysis studies in rats also showed cannabinoid-induced decreases in acetylcholine release in the hippocampus through a CB 1 receptor-mediated mechanism, hi at least one aspect of the present invention, the cannabinoid compositions a e used for Preventionfceatment/niitigation of OP or carbamate induced brain injuries.

hi this aspect of the invention, the pharmaceutical composition is in oral, nasal, topical, ophthalmic, buccal, sublingual, rectal, vaginal, vapor, and/or parenteral form.

The above active compounds may also be used as part of an in vitro assay, for example, in order to determine whether a candidate host is likely to benefit from treatment with the compound in question. Any active compound of the present invention may also be used as a standard, for example, in an assay, in order to identify oilier active compounds, other anti- proliferative agents, other antⁱinflammatory agents, etc.

In yet another aspect of the instant invention, the IC50 or the half maximal inhibitory concentration of the candidate compounds were determined to assess drug potency and potential dosing regimens for in vivo use. One of ordinary skill in the art is readily able to ascertain such information using commonly known methodologies. As it has been well described in the art, IC50 represents and measures how much of a paiticular substance/molecule is needed to inhibit some biological process by 50%. In the instant case, the IC5G of the candidate -compounds were determined as the concentration that led to a response of 50% compared to the vehicle control ceils.

As noted herein, the salts of the compounds of this invention refer to non-toxic

"pharmaceutically acceptable salts." Other salts may, however, be useful in the preparation of the compounds according to the invention or of their phaiinaceutically acceptable salts. When the compound's of t e present invention contain a basic group, salts encompassed within the term "pharmaceutically acceptable salts" refer to non-toxic salts which are generally prepared by reacting the free base with a suitable organic or inorganic acid. Representative salts include any such salt known in the art. Where compounds of the present invention cany a acidic moiety, suitable pharmaceutically acceptable salts thereof may include alkali metal salts, e.g., sodium or potassium salts; alkaline earth metal salts, e.g., calcium or magnesium salts; and salts formed with suitable organic ligands, e.g., quaternary ammonium salts.

To treat a human patient an effective amount of one or more compounds of tlie present invention, or a piiamiaceutically-acceptable salt thereof, is administered to the human subject in need so as to promote exposure to or contact of the tissue at risk or the targeted region of the body or nerves, synapses, or neuromuscular junctions, or organ systems including but not limited to the autonomic and central nervous systems. Effective dosage forms, modes of administration and dosage amounts may be determined empirically, and making such determinations is within the skill of tlie art.

It is understood by tlie physician, pharmacists or clinician of ordinary skill in the ait that the dosage amount will vary with the activity of the particula compoimd employed, course and' or progression of the disease state, the route of adim istration, the rate of excretio of the compound, status of the nervous system, renal and hepatic function of the patient, the duration of the treatment, the identity of any other drugs being administered to the subject, age, weight and like factors.

As discussed herein, the cannabinoid compounds of tlie present invention can be administered in such oral dosage forms as tablets, capsules (each of which includes sustained release or timed release formulations), pills, powders, micronized compositions, granules, elixirs, tinctures, suspensions, ointments, vapors, liposomal particles, nanoparticles, syraps and emulsions. Likewise, they may also be adniinistered in intravenous (bolus or .iniusion), intraperitoneal, topical (e.g., dermal epidermal, transdermal, opthaimieaily such as ocular eyedrop, intranasaily, subcutaneous, iniialaiion, mtrarnuseuiar or transdermal (e.g., patch) form, all using forms well known to those of ordinary skill i the pharmaceutical arts. Again, the ordinarily skilled physician, veterinarian or clinician or a clinical pharmacist may readily determine and prescribe the effective amount of the drug required to prevent, counter or arrest the progress of the condition.

Dosages of phytocaimabiiioids eg THC and CBD, or synthetics of the present invention, when used for the indicated effects, will range between about 0.0001 mg per kg of body weight per day (mg kg/day) to about 100 mg/kg/day, preferably 0.001 to 20 mg/kg day, and most preferably 0.01 to 10.0 mg/kg/day. For oral admiiiistiation, iiie compositions are preferably provided in the form of tablets containing 0.01, 0.05, 0.1, 0.5, 1.0, 2,5, 5.0, 10.0, 15.0, 25.0, 50.0, 100 and 500 milligrams of the active ingredient for the symptomatic adjustment of the dosage to the patient to be treated. A medicament typically contains from about 0.01 mg to about 500 mg of the active ingredient, preferably, from about 1 mg to about 100 mg of active ingredientntravenously or via a vapor inhalation, the most preferred doses will range from about 0.01 to about 10 mg kg/niiniite during a constant rate infusion or rate of respiration. Compounds of the present invention may be administered in a single daily dose, or the total daily dosage may be administered in divided doses of two, three or four or six times daily, hi the case of a prodrug construct, those of ordinary skill in the art would appreciate that the clinical outcome follows the same serum concentrations or clinical endpoints as those of THC or CBD.

hi at least one embodiment, the method of treatment includes both prophylactic and active treatment regimens. In at least one such embodiment, the suitable composition contains a blend of CBD to THC having the ratio of CBD: THC in ranges of 10 - 400 mg: 0.0001 - 10 mg. In yet another embodiment, such method includes the step of admiinstering a blend of terpenes optionally including pinene. In a more preferred embodiment, pinene may be added in case there is exposure to oxime. This is because pinene has a beneficial bronchodilaiorory effects to counteract OP or carbamate induced bronchospasm. However, pinene also has an anticholinesterase property. This property would makes pinene more ideal as a prophylactic and less ideal as a post-exposure therapeutic miless an oxime and atropine are admiiiisteted shortly after OP or toxic carbamate exposure. THC also has an anticholinesterase property that makes it useful for prophylaxis only in microgram, quantities. THC is likewise less ideal as a post-exposure therapeutic in other than microgram quantities unless an oxime and atropine are administered shortly after OP or toxic carbamate exposure

In another embodiment, the method is intended for active treatment of emotional and neiirophysiological stresses, mvoluntary eye muscles twitches,, bronchospasm, iasiculaiions. tremors, seizures, headaches, neuropathy and neuropsychiatric disorders including PTSD. In yet another embodiment, prophylactic methods are contemplated to counter OP toxicity. Accordingly, such methods include the step of sniffing a terpene mixture, wherein the terprene mixture contains a terpene blend of l monene, myrcene, hnalool, beta caryophylene, terpineol, terpinolene optional pinene, and mixtures thereof.

As noted herein, the compounds of the present invention may be used in combination with other pain management, anticholinergic agents or other agents winch will enhance the treaiineni regime for the huma subjects. The individual components of such combinations can be administered separately at different times during the course of therapy or concurrently in divided or single combination forms to patients or regions of such patients in need of such therapy. The instant invention is therefore to be miderstood as embracing all such regimes of simultaneous or alternating treatment and the term ^administering'' is to be interpreted accordingly. It will be understood that the scope of combinations of the compounds of this invention with oilier agents useful to treat the targeted cancer condition includes in principle any combination with any pharmaceutical composition useful for treating disorders related to optimal cholinergic and general nervous system functioning.

Pharmaceutical formulations of the present invention include those suitable for oral, nasal, topical (including buccal and sublingual), rectal, vaginal and or parenteral administration. Regardless of the route of administration selected, the active ingredient(s) are formulated into herbal and phamiaceutieally-aeceptable dosage forms by conventional methods known to those of skill in the art.

The amount of the active ingredieni(s) which will be combined with a carrier material to produce a single dosage form will vary depending upon the host being treated, the particular mode of administration and all of the other factors described above. The amount of the active ingredients) which will be combined with a carrier material to produce a single dosage form will generally be that amount of the active ingredients) which is the lowest dose effective to produce a therapeutic effect.

In another aspect of the invention, a cainiabmoid formulation is described to prevent unauthorized diversion of a formulation that contains clinically significant amounts of THC or other CBI agonist with psychoactive properties. As such the formulation agonist with psychoactive activity may have atropine or a similar anticholinergic agent added. The anticholinergic property of atropine, in the absence of OP or carbamate, will cause an uncomfortably dry mouth and dryness at other mucous membranes. Approved medications that contain atropine (or pharmacologically similar" belladonna alkaloids) to piwent diversion of a narcotic or barbiturate, respectively, and/or to aid in intended therapeutic activity include for diarrhea diphenoxylate/atropine and for spastic colon, phenobarbital with hyoscyamine. atropine and scopolamine. Spastic colon is also called IBS, or Irritable Bowel Syndrome. IBS is a symptom-based diagnosis characterized by chronic abnormal pain, discomfort, bloating, and alteration of bowel habits. As a functional GI disorder, IBS as no known organic causes diarrhea or constipation may predominate, or they may alternate (classified as IBS-D, IBS-C or IBS- A. respectively).

Another aspect of the present invention provides compounds having the following structure:

hi such embodiment, L is a linker bridging a cannabinoid moiety to an alkaloid

N

moiety, hi a preferred embodiment, L is *^{■ 1} or ^¾- ^e attached at the designated points, Z = 0, S, NR7, and where R7 = H. alkyl, aryl -OH,-0-Cl -C3 alkyl.

hi a more preferred embodiment, where A is aryl, heteroaryl, fused pyran or fused tetrahydropyran B is C(=0)-0-R6, where R6 is an azabicyclo ling substitueiit (alkaloid), C is H, F, CI-C3 alkoxy, CN, S(0)_aCl¾ where n = 0-2, and Z = O. methods- of preparing such compounds generally follow the conventional methods known in the ait.

In at least one embodiment, where Z is O (a carboxy grou linker), the new cornpoimd lias the formula:

construct.

CBD atropine

Methods of preparing compounds are understood in the art and follow those employing earboxylate, phosphate and amine moieties. Methods of preparing formulations or compositions include the step of bringing the active ingredients) into association with the earner and, optionally, one or more accessory and /or stabilizing or preserving ingredients. In general, the formulations are prepared by uniformly and intimately bringing the active ingredients) into association with liquid carriers, or finely divided solid carriers, or both, and then, if necessary, shaping the product.

Formulations of the invention suitable for oral administration may be in the form of capsules, cachets, pills, tablets, lozenges (using a flavored basis, usually sucrose and acacia or tragacanth), powders, granules, or as a solution or a suspension in an aqueous or nonaqueous liquid, or as an oil-in-water or water-m-oil liquid emulsion, or as an elixir or syrup or tincture, or as pastilles (using an inert base, such as gelatin and glycerin, or sucrose and acacia) and/or as mouth washes and the like, each containing a predetermined amount of the active ingredients). The active ingredients) may also be administered as a bolus, electuary or paste.

In solid dosage forms of the invention for oral administration (capsules, tablets, pills, dragees, powders, granules and the like), the prodrugfs), active ingredients) (in their micronized form) is/are mixed wife one or more phamiaceinically-acceptable carriers, such as sodium citrate or dicaicium phosphate, and or any of the following: (1) fillers or extenders, such as starches, lactose, sucrose, glucose, mannitoL and or silicic acid; (2) binders, such as, for example, carboxymethyl-celhilose, alginates, gelatin, polyvinyl pyrrolidone. sucrose and or acacia; (3) humectants, such as glycerol; (4) disintegrating agents, such as agar- agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate; (5) solution retarding agents, such as paraffin; (6) absorptio accelerators, such as quaternary aninionimii compounds; (7) wetting agents, such as, for example, ceiy alcohol and glycerol monostearate; (8) absorbents, such as kaolin and hentonite clay; (9) lubricants, such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof; and (10) coloring agents, hi the case of capsules, tablets and pills, the pharmaceutical compositions may also comprise buffering agents. Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugars, as well as high molecular weight polyethylene glycols and the like.

A tablet may be made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets may be prepared using a binder (for example, gelatin or hydroxypropyhnethyl cellulose), lubricant, inert diluent, preservative, disintegrani (for example, sodium starch glyeoiate or cross-linked sodium carboxyniethyl cellulose), surface- active or dispersing agent. Molded tablets may be made by molding in a suitable machine a mixture of the powdered active ingredient(s) moistened with an inert liquid diluent.

The tablets, and either solid dosage forms of the pharmaceutical compositions of the present invention, such as dragees, capsules, pills and granules, may optionally be scored or prepared with coatings and shells, such as enteric coatings and other coatings well known in the phaiinaceiitical-formulatiiig art. They may also be formulated so as ίο provide slow or controlled release of the active ingredients) therein using, for example, hydroxypropylmethyl cellulose in. varying proportions to provide the desired Mease profile, other polymer matrices, liposomes and/or microspheres or nanopartkles. They may be sterilized by, for example, filtration through a bacteria- retaining filter. These compositions may also optionally contain opacifying agents and may be of a composition that they release the active ingredients) only, or preferentially, in a certain portion of the gastrointestinal tract, optionally, in a delayed manner. Examples of embedding compositions which can be used include polymeric substances and waxes. The active ingredients) can also be in microencapsulated form.

Liquid dosage for s for oral administration of the active ingiedient(s) include pliarmaceutically-acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. In addition to the active ingredients), the liquid dosage forms may contain inert diluents commonly used in the art, such as, for example, water or other solvents, solubilizing agents and emulsifiers, such as ethyl alcohol, isopropyl alcohol, emylacetate, butyl alcohol, benzyl benzoate, propylene glycol, glycol, oils (in particular, cottonseed, groundnut, com, germ, olive, castor, hempseed, cocoanut, and sesame oils), terpenes or terpenoids, glycerol or glycerol, amy! alcohol, tetrahydromryl polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof.

Besides inert diluents the oral compositions may also include wetting agents, emulsifying and suspending agents, sweetening, flavoring, coloring, perfuming and preservative agents. Suspensions, in addition to the active ingredients), may contain suspending agents as, for example, ethoxylated alcohols, poiyoxyethyiene sorbitol and sorbitan esters, microciystalhiie cellulose, a imimirn meiahydroxide, bentonite, agar- agar and tragaeanth, and mixtures thereof.

Formulations of the pharmaceutical compositions of the invention for rectal or vaginal adininistration may be presented as a suppository, which may be prepared by mixing the active ingredients) with one or more suitable nonirritating excipients or carriers comprising, for example, cocoa butter, polyethylene glycol, wax or salicylate which is solid at room temperature, but liquid at body temperature and, therefore, will melt in the rectam or vaginal cavity and release the active ingredients). Formulations of the present invention which are suitable for vaginal administration also include pessaries, tampons, creams, gels, pastes, {bams or spray formulations containing such carriers as are known in the art to be appropriate.

Dosage forms for the topical, ophthalmic or transdermal administration of the active ingredieat(s) include powders sprays, ointments, pastes, creams, lotions, gels, solutions, patches and inhalants. Theactive mgredieni(s) may be mixed under sterile conditions with phannaceutically-acceptable carrier, and with any buffers, or propellan s which may be required.

The ointments, pastes, creams and gels may contain, in addition to the active ingredient(s). excipients, such as animal and vegetable fats, oils, waxes, paraffins, starch, iragaeanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide, terpenes or terpenoids, or mixtures thereof. Powders and sprays can contain, i addition to the active nigredient{s), excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicates and polyamide powder, or mixtures of these substances. Sprays can additionally contain customary propellants such as chlorofiuorohydiocarboiis and volatile iinsubstituted hydrocarbons, such as butane and propane.

Compoimds of the present invention may be administered in intranasal form via topical use of suitable intranasal vehicles, or via transdermal routes, using those forms of transdermal skin patches well known to those of ordinary skill in the art. A transdermal delivery system provides for continuous ^'administration._, throughout the dosage regimen. Transdermal patches have the added advantage of providing controlled delivery of the active gredient(s) to the body. Such dosage forms can be made by dissolving, dispersing or otherwise incorporating the active ingredienifs) in a proper medium, such as an elastomeric matrix material. Absorption enhancers, such as iontophoresis, can also be used to increase the flux of the active ingredients) across the skin o a mucous membrane or a mucocutaneous junction area. The rate of such flux can be controlled by either providing a rate-controlling membrane or dispersing the active ingredient(s) in a polymer matrix or gel.

The compounds of the present invention can also be administered in the form of liposome delivery systems, such as small unilamellar vesicles, large unilamellar vesicles and multilamellar vesicles. Liposomes can be formed from a variety of phospholipids, such as cholesterol, steaiyiamhies or phosphatidylcholines. Another mode of delivery for the compounds of the present invention may be. delivery via. the use of monoclonal antibodies as individual carriers to which the compound molecules are coupled. The compounds of the present invention may also be coupled with soluble polymers as targetable drag earners. Such polymers can include pol vmylp)HOlidone, yeast derivatives (e.g. ghicans , pyran copolymer, polyhydmxypropyhiiethacrylainide-phenoL polyhydi'oxy-ethylaspartamide- phenol, or polyemyieneoxkie-polylysine substituted with palmitoyl residues. Furthermore, the compounds of the present invention may be coupled to a class of biodegradable polymers useful in achieving controlled release of a drug, for example, polylactic acid, polyglycolic acid, copolymers of polyactie and poiyglycolic acid, polyepsiion caprolactone, polyhydroxy butyric acid, poiyorthoesters, polyaeetais, porydihydropyrans, polycyanoacrylates and crosslinked or amphipathic block copolymers of hydro gels.

Pharmaceutical compositions of this invention suitable for parenteral administraticai comprise the active ingredient(s) in combination with one or more pharmaceutically-acceptable sterile isotonic aqueous or nonaqueous solutions, suspensions or emulsions, or sterile powders which may be reconstituted into sterile injectable solutions or dispersions just prior to use, which may contain antioxidants, buffers, solutes which render the formulation isotonic with the blood of the intended recipient or suspending or thickening agents.

Examples of suitable aqueous and non-aqueous carriers which may be employed in the formulation, hi some cases, in order to prolong the effect of the active ingredient(s), it is desirable to slow the absorption of the drug from subcutaneous or intramuscular injection. This may be accomplished by the use of a liquid suspension of crystalline or amorphous material having poor water solubility. The rate of absorption of the active ingredients) then depends upon its/their rate of dissolution which, in turn, may depend upon crystal size and crystalline form. Alternatively, delayed absorption of pareiiterally-administered active mgredieiit(s) is accomplished by dissolving or suspending the active ingredients ) in an oil vehicle.

Injectable depot forms are made by forming microeneapsiile matrices of the active ingredients) in biodegradable polymers such as polylactide-polyglycolide. Depending on the ratio of the active mgredieiit(s) to polymer, and the nature of the particular polymer employed, the rate of release of the active ingredients) can be controlled. Examples of other biodegradable polymers include poiy(orthoesters) and poly(aijhydrides). Depot injectable fonnulatioiis are also prepared by entrapping the active mgredient{s} in liposomes or microemitlsioii or nanoparticies which are compatible with body tissue. The injectable materials can be sterilized for example, by filtration through, a bacterial-retaining filter.

The formulations may be presented in unit-dose or multi-dose sealed containers, for example, ampoules and vials, or in specialized capsules for vapor or nebulized administration and may be stored in a lyophilized condition requiring only the addition of the sterile liquid carrier, for example water or oil for injection, immediately prior to use. Extemporaneous injection solutions and suspensions maybe prepared from sterile powders, granules and tablets of the type described above.

Unless otherwise specified all starting materials and reagents are of standard commercial or medicinal grade, and are used without further purification, or are readily prepared from such materials by routine methods. Those skilled in the art of clinical therapeutics will recognize that starting materials and reaction conditions may be varied to achieve the desired end product. In at least one embodiment, a kit is described containing differing prophylactic and active treatment regimen for a cannabinoid rescue regimen.

hi this aspect of the invention, the cannabinoid therapy may include a terpeiie blend containing limonene, alpha pinene, myrcene, linalool and beta carylophylene preferably in weight ratios of about 4:7:3:3:2. (See Figure 1). In another embodiment such prophylactic kit contains CBD containing compositions for both inhalation therapy and oral administration, hi another embodiment, the therapy or the teipene blend may contain THC in amounts less than I mg.

hi another aspect of the invention, the cannabinoid rescue regimen is a kit for active treatment, hi addition to the teipene blend and CBD composition, the active treatment kit contains THC: CBD containing compositions in the ratios of 1:10, 1 :12.5, 1 :15. 1 :20, and 1 :40 w w. Such kit may further contain hemp oil, atropine, an oxime, a benzodiazepine, instructions as to the order of treatment and other administration means. In a more preferred embodiment, the THC: CBD composition and terpenes are water soluble. In another preferred embodiment, the atropine/oxime is lipid soluble. The following examples are meant to better define the scope of the present invention.

Example 1

OP toxicity was determined using DFP toxicity. Male and female. albino rats

(total 4 rats) were singly dosed subcutaneously with different amounts of the DFP. Severity of salivation, iacrimation, urination and defecation (SLIJD) signs were measured at dose levels of 0.63, 1.88, 1.25, and 2.5 DFP ing kg. Dose escalation is used if the previous doses used do not, induce sufficient responses to test efficacy of the test aiticle such as abnormal pupil response, SLIJD, arousal, abnormal motor movement, gait and posture.

Example 2

The same protocol as in Example I is conducted in a primate to measure the OP DFP toxicity by monitoring the same parameters to find a dose ievel that would provide clear and measureable evidence of DFP toxicity in a primate.

Example 3

hi order to test the onset of cannabinoid and terpene activities in rats, a combination of THC, CBD, and terpenes were administered to the animals. In accordance with an IRB approved protocol, a first group of rats were administered a terpene blend for 20 seconds of sniffing of the blend. After sniffing of the terpene blend, different combinations of camiabinoids by themselves or in cannabinoid terpene · blends were administered by oral gavage.

At least one of the blend combinations was composed of .D-limonene: alpha pineiie: myrceiie, linalool: beta caryophylene in volumetric ratios of about 4:4:3:3; 1 respectively to make approximately a 30 nig kg dose. The same method may be used to explore other combinations within the scope of the ratios described herein above, such as for example, a terpene blend containing limonene, alpha pineiie, myrcene, linalool and beta carylophylene preferably in weight ratios of about 4 7:3:3:2 as described in Figure 1.

In another experiment the annuals are given THC' at doses of 0.001, 0.01, 0.05. 0.1, 0.5, I and high doses of 2.5 or 3 mg kg. Another group of the animals are given a mixture containing CBD:THC at CBD doses including but not limited to 0.1, 1 , 10, 12.5, 15, 20, 25, 30, 37.5 mg/kg and such THC doses to make up ratios of 10: 1, 12.5:1, or 15:1, 20:1, 25: 1 , 40:1 , 100:1, and 200:1 CBD:THC .respectively.

In another experiment, the arjinsls are given CBD at doses of 0.25, 1, 5, 50, 75, 100, 150, 200 nig'kg and a terpene Mend at a dose of 40 mg kg-120 mg/kg.

In anoiiier experiment the animals are gi ven THC at 2.5 mg kg, CBD at. 15 mg/kg and terpene blend at 40 mgkg. In anoiiier experiment the animals are given an undiluted terpene blend via sniffing for 2 seconds. Then the THC/CBD/terpene blend was administered by oral gavage 2.25 hours prior to subcutaneous administration of DFP.

Observations: Female rats tolerate higher doses of DFP than male rats. Cannabinoid effects such as hyperthermia, abnormal gait and posture seen with both THC and CBD receiving annuals, particularly more prominent at 8 hours than at 4 hours after dosing, showing splayed hind limbs and hunched or crouched body position. Both DFP and cannabinoids cause significant hypothermia in rats, (but not in primates). All animals receiving cannabinoids with and without additional terpenes or just a terpene blend recovered at 24 hours after receiving the test materials. Terpenes by themselves appeared very well tolerated, except the rats did not like the smell of linalool. The degree of hypothermia observed with groups receiving CBD was unexpected, potentially due to questionable integrity of CBD formulation. CBD is expected to attenuate hypothermia associated with THC in rats.

Example 4

Animals were tested for efficacy of the cannabinoid rescue therapy, hi the first study, 4 male and 4 female Spraiige Dawiey rat pups were treated initially with DFP subcutaneously at dose of 1.35 mg/kg for males and 1.9 mg/kg for females. A Cannabinoid mixture was delivered by oral gavage at 2.25 hours prior to the administration of DFP and again 24 hours later. Animals could then sniff terpene blend for 2 seconds immediately prior to gavage and again the terpene alpha pinene for 2 seconds prior to first DFP subcutaneous injection. Similar approach may be taken hi oilier species, however, cannabinoids and terpenes may be administered as vapors or in ways Cither than oral gavage.

An outcome of at least 10%, improvement in toxicity parameters is to be observed in animals, such as primates who received THC, CBD and terpenes prophylacticaliy. Small doses of atropine/oxime will be available as soon as possible after exposure vs. conventional therapy of only a opme/oxime. These improvement changes; are less likely to be seen in rodents due to biological differences in reactions to cannabmoids. Related parameters in other systems would, indicate at least a 10% overall improvement in all other major organ systems impacted by DFP or another OP.

For example animals receiving the treatment regimen would show at least a 10 % less abnormal respiratory rate, hypoxemia, audible wheeze, digital pulse oximetry abnomialities, abnormalities hi FEV1 (forced expiratory volume) at one (1) second and vital capacity as well as any flow volume loop measurable by spirometery. In the alternative, respiratory distress assessments based on pulse oximetry and/or arterial blood gas analysis including C02 retention as compared to non-treatment group. Similarly, animals receiving the cannabinoid rescue regimen will exhibit substantial clinical response to supplemental oxygen in part due to reduced bronchospasm and respiratory hyper secretion (broncho hmorhea) .

emOpsyciiiatric exam will also show at least 10% less disorientation and learning abnomialities or measures of cognitive function at 30 days after moderate to severe OP exposure (following at least a 3 day washout from any significant dose of THC or a CB 1 receptor agonist). Similar results would be observed for parameters indicative of axonopafhy from delayed OP-indueed neuropathy. Other clinical signs related to the severity of PTSD, severity of anxiety, depression are to be monitored in appropriate interval respectively associated with development of abnormal signs in the animal models. Those of ordinary skill in the art can appreciate that a proper approach would implement a washout period after psychoactive cannabinoid adinnnstratioii before any memory assessments or cognitive task assessments could be determined.

Neuromiiscular exam will also provide for at least a 10% decrease in severity of tremors, either abnormal movements, and a 20% decrease hi seizures, in a preferred outcome, at least a 20 % decrease i LD 50 studies is observed in primates in groups that have received prophylactic-airy alpha pinene and low dose THC and CBD where concentrations of CBD to THC follows at least a 20: 1 ratio respectively.

In an alternative regimen, the treatment plans include (a) CBD with or without a terpine blend and optionally (b) atropine or oxime or both following OP exposure.

At least one aspect of the present invention describe improvements that would include at least 10% improvements in hypersalivation and eye pain, clinically significant SLTJD, dryness and other cholinergic adverse effects as compared wit a prophylactic pyridostigmine bromide treatment. It is contemplated that i primates carmabinoid therap results in a more rapid return of pupil size from the miosis induced fay an OP or a carbamate. OP-indueed miosis from G class nerve agent vapors that reach the eye is resistant to treatment with atropine.

hi another observation, neuroprotective effect from cannabinoids as an adjunct to standard therapy will be superior to standard therapy alone 30 days after exposure and when assessed against a stand alone pyridostigmine treatmen

In yet another embodiment, high CBD:THC (> 20:1) ratios, with or without terpenes but if with terpenes then without significant pinene would provide an alternative standard treatment in cases where atropine and an oxime will not be administered in a timely fashion. This approach may be suitable particularly for civilian use.

Although the invention herein has been described with reference to particular embodiments, it is to be understood that these embodiments are merely illustrative of the principles and applications of the present invention. It is therefore to be understood that numerous modifications may be made to the illustrative embodiments and that other arrangements may be devised without departing from the spirit and scope of the present invention as claimed in the appending claims.

All publications, patents, and patent applications cited in tins application are herein incorporated by reference to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated herein fay reference.

Claims

We Claim:

1. A pharmaceutical composition comprising an isolated caanabinoid receptor modulator, and optionally containing a blend of teipenes in a phamiaceutically acceptable carrier.

2. The pharmaceutical composition of claim 1 , comprising a blend of two or more teipenes selected from the group consisting of limonene, pinene, myrcene, linalool, beta caryophyleiie, ieipineol and terpinolene.

3. The composition of claim 2, wherein the terpene blend comprises two or more teipenes selected from the group consisting of limonene, pinene. myrcene, linalool, beta earyopliylene.

4. The composition of claim 3, wherein the weight ratios of said teipenes is within the in range of about 1-10: about 1-10: about 1-6: and about 1-6: 0.25-3, respectively,

5. The composition of claim 4, wherein the weight ratio of said teipenes is about 4:4:3:3:1 respectively.

6. The composition of claim 4, wherein the weight ratio of said terprenes is about 4:7:3:3:1 respecti ely.

7. The pharmaceutical composition of claim 1, wherem sa d eannabmoid r e c e p t o r m o d u l a t o r agonist is a CB receptor agonist or a mo difi er selected from the group consisting of phytoeannabinoids, tetrahydrocannabinol (THC) (-) trans delta 9 THC, dronabinol, {±)-iraiis-3-(lJ-d5meihyibep )-6-6a, 7,8,10, lOa-hexahydro-1- hydroxy-6-6-diniethyI- 9H-dibenzo[b,d]pyran-9-one (nabiloiie), anandannde, 2- arachidonoyl-glycerol (2-AG), N-acyl- pho^hatidylethaiiolamine-phQspiiolipase D, diacyl glycerol lipase (DAGL), cannabidiol (CBD), abnormal carmabidiol (abn-CBD), nabiximols, EPIDIOLEX®, rimonabant, {-)-l,l dimethylheptyi analogs of l l-hydroxy-8- tetrahydrocannabinol (HU 210), HU 211, HU 308, ajulemic acid, AM-411, L- 759,633, AM-855, VCHSR, noiiabine , JWH 1 33 , JWH- 171 , BML- 190, A-41988 , O- 806, 0-2694 and 0-2545 , JZL 1 84. J H-359, CB- 13 , GW-405 ,833 , JTE- 907, U B 754, inhibitors of FAAH or fatty acid amide hydrolasel- (meihylpiperid i-2-ymieihyl)-3-(2-iodo-5-mtrobenzoyl)m^ (AM- 1241), WIN 55 ,21 -2-2 , oilier natural or endogenous endocamiabinoid derivatives, and combinations thereof.

8. The pharmaceutical composition of claim 1, wherein the composition is in oral, nasal, topical, ophthalmic, buccal, sublingual, rectal, vaporization-ready, nebulization- ready, nanopartiele formulations, liposomal formulations, vaginal and/or or other parenteral form.

9. The pharmaceutical composition of claim 1, further comprising one or more non-eannabinoid active ingredients selected from me group consisting of a terpene , a benzo diazepine , a belladonna alkaloid, an anticholinesterase an oxiine. and combinations thereof.

10. The composition of claim 9, wherein said belladonna alkaloid is atropine and said anticholinesterase is pyiidostiganiine.

11. A method o f treating or preventing a disease, disorder, dysfunction or syndrome caused by exposure to an organophosphate (OP) or carbamate acetylcholinesterase inhibitor, saqid method comprising administering to a subject exposed to or at risk of exposure to said OP or carbamate in an amount effective to moduolate the cannabinoid receptors of said subject.

12. The method of claim 11 wher ein the mediated disease, disorder, dysfunction or syndrome is selected from the group consisting of muscle disorder, ophthalmic

dysfunction, metabolic disorders, cardiac, rhythm and contractility dysfunctions, social related disorders, mood disorders, seizures, learning disorder's, cognition disorders, memory disorders, respiratory disorders, locomotor activity disorders, movement disorders, immune disorders, inflammation, cell growth, pain or neurodegenerative related syndromes, drug abuse, alcohol abuse, bipolar" disorder, cognitive impairmen post traumatic stress disorder (PTSD), Gulf War like syndrome and premature senile dementia.

13. The method of claim 12, wherein the muscle disorder is selected from the group consisting of dyskinesia, akinesia, tremor, bradykinesia, skeletal muscle rigidity and spasticity.

14. The method of claim 12, wherein the ophthalmic disorder is selected from the group consisting of miosis, ciliary muscle spasm, ophthalmic pain, headache and lacximation disorder.

15. The method of claim 11 , wherein said OP is a. G or V class nerve agent.

16. The method of claim 11. wherein said cannabmoidreceptor modulator is selected from the group consisting of ph}^ocannabinoids, tetrahydrocannabinol (THC) (- ) trans delta 9 THC, dronabinol, (±)-tians-3-(l,l-dimeihylhq?tyl)-6,6a, 7,8,10, lOa- liexahydrO-l-hydroxy-6-6-dimetliyl- 9H-dibenzo[b,d]pyran-9-one (nabilone), anaiidamide, 2-aracaidonoyl-glyceroi (2- AG), N-acyi- phosphatidyletlianolamine-piiosphoiipase D, diacyl glycerol lipase (DAGL), camiabidiol (CBD), abnormal cannabidiol (abn-CBD), nabiximois, EPIDIOLEX®, rimonabant, f-)-Ll dimethy!heptyl analogs of 1 I-hydroxy-8- tetrahydiOcannabmol (HU 210), HU 21 L HU 308, ajulernic acid, AM-411, L-759,633, AM-S55, VCHSR, nonabine, JWH 1 33 , JWH-171 , BML- 190, A-41 988, O- 806, 0-2694 and 0-2545 , JZL 1 84, JWH-359 , CB- 1 3 , GW-405.833 , JTE- 907, URB754, inhibitors of FAAH or fatty acid amide hydrolasel- (iiieihylpiperkiin-2-yhiiethyl)-3 -(2-iodo-5-mtiObenzoyl)indole (AM- 1241 ), W I N

55 ,2 12-2, other natural or endogenous endocannabinoid derivatives, and combinations thereof,

1 . The method of claims 11 or 15, further comprising administering a non- cannabffioid receptor modulator selected from the group consisting of opioids, gabapenrins, pregabalins, a benzodiazepines, atropines, oxirnes, antioxidants, alkalizing agents, terpenes, and NSAIDs.

18. The method of claim 11 , wherein said composition is administered the composition is in oral, nasal, topical, ophthalmic, buccal, sublingual, rectal,

vaporization-ready, nebiiiizaiion-ready, nanoparticle formulations, liposomal

formulations, vaginal and/or IV or other parenteral form.

19. The method of claim 11, wherein said composition is administered prior to exposure to said organophosphate or carbamate and said composition comprises at least one terpene selected from the group consisting of limonene, mycrene, pineiie, linalool. beta eaiycpliyileiie, and a cannabinoid selected from th group consisting of THC, CBD. and a i ture of^'THC, CBD.

20. The method of claim 19, further comprising the step of exposing said subject to an OP or carbamate acetylcholinesterase inhibitor as a prophylactic treatment

21. The method of claim 20, further comprising administering to said subject atr opine and an oxime in an amount effective to prevent adverse effects from said prophylactic exposure to OP or carbamate.

22. The method of claim 19, further comprising co-administering pyridostigmine bromide to said subject.

23. The method of claim 11, wherein said composition is administered to said subject after exposure to an OP or a carbamate acetylcholinesterase inhibitor and said composition comprises a blend of CBD and THC hi a weight ratio of between about 3 and 400 mg to about 0.0001 and 10 mg, respectively.

24. The method of claim 23, further comprising the step of administering a blend of two or more terpenes.

25. The method of claim 24, wherein said terpiiie blend comprises two or more terpenes selected from the group consisiting of of limonene, pinene, myrcene, iinalool, beta caryophylene, terpineol and terpinolene.

26. A method of treating or preventing a disease, disorder, dysfunction or syndrome caused by exposure to an organophosphate or carbamate aeetyMiolinestera.se inhibitor, said method comprising admmistering to a subject exposed to or at risk of exposure to said OP or carbamate, q composition comprising a least two teipmes selected from the group consiting of limonene. myrcene, Inialool, beta caryophyiene, terpineol, terpmolene. and pinene, in an amount effective to treat or prevent said disease, disorder, dysfunction or syndrome.

27. The method of claim 26, wherein said terpine mixture comprises alpha pinene.

28. The method of claim 26, wherein said blend comprises heta-earyophyiene, limonene, myrce e, and linalool. A compound having the following stucture:

wherein L is selected from th

e group consisting of ; Z = O, S or N ^' R7 = H, aikyl, aryl, -ΟΗ,-Ο, or lower alkoxy; A is aryl, lieteroaiyl, fused pyran or a fused tefrahydropyraii; B is C(=0}-O-R6; R6 is an alkaloid azabieydo ring substituen: C is H, F, lower alkoxy, CN, S 0)_BCH3 w ere 11 = 0-2, and Z = O.

30. The compound of claim 29, selected iom the group consisting of:

and