A cannabinoid is one of a class of diverse chemical compounds that acts on cannabinoid . Tetrahydrocannabinol. Tetrahydrocannabinol (THC) is the primary psychoactive component of the Cannabis plant. . This is because they are fat-soluble, lipophilic molecules that accumulate in fatty tissues. Research shows the. Apr 19, They are considered to be liposoluble molecules classified Like many other components of cannabis, CBN is rejected by water, as it is only. Jul 3, Cannabinoids (CBD, THC, etc.) are hydrophobic (water-hating) oily substances and, as such, not water-soluble. They can, however, be.
components Cannabinoids are liposoluble
In one embodiment milling refers Milling refers wet grinding carried out using methods as a roller ointment mill, tumbling ball mill, vibratory ball mill, a planetary ball mill, a centrifugal fluid mill, an agitating beads mill, a flow conduit beads mill, an annular gap beads mill, and wet jet mill. In one embodiment milling refers to dry grinding by compression or by friction, using methods as a jet mill, a hammer mill, a shearing mill, a roller mill, a shock shearing mill, a ball mill, and a tumbling mill.
In one embodiment milling refers to wet processes for preventing the condensation of the nanoparticles so formed, and obtaining highly dispersed nanoparticles. Cannabis-based medications exert their effects mainly through the activation of cannabinoid receptors CB1 and CB2. They have antispastic, analgesic, antiemetic, neuroprotective and anti-inflammatory actions. Emerging clinical applications for cannabinoid therapies include Alzheimer Disease, Amyotrophic Lateral Sclerosis ALS , chronic pain, Diabetes Mellitus, dystonia, epilepsy, fibromyalgia, gastrointestinal disorders,.
Once extracted, cannabinoid blends can be separated into individual components using wiped film vacuum distillation or other distillation techniques. The relative amount of each principal phytocannabinoid in cannabis extract varies according to the cannabinoid profile and levels of the particular plants and methodology of extraction.
High purity cannabinoids are obtained by purification from a natural source or via synthetic means. The relative amount of CBD in hempseed extract varies according to CBD content of the hemp plants and methodology of extraction.
The Endocannabinoid System regulates numerous. Endocannabinoid System can produce impairments of various processes including. The Endocannabinoid System has been shown to be involved in different pathologies including Alzheimer disease, Multiple Sclerosis, Parkinson disease, chronic inflammation, chronic pain, cancer, nausea, vomiting, obesity, epilepsy, glaucoma, asthma and mood disorders.
CB2 receptors are almost exclusively found in the immune system, with the greatest density in the spleen. CB2 receptors appear to be responsible for the anti-inflammatory and possible other therapeutic effects of cannabis. Cannabinoids bind reversibly and stereo- selectively to the cannabinoid receptors. The affinity of an individual cannabinoid to each receptor determines the effect of that cannabinoid.
Cannabinoids that bind more selectively to certain receptors are more desirable for medical usage. These receptors are embedded in the cell membrane where they are coupled to G- proteins. The binding of the cannabinoid ligand to the receptor leads to a signaling cascade that either decreases or increases the activity of a particular enzyme to raise a receptor response above basal activity They target proteins that are usually transcription factors, proteins that bind DNA and promote the expression of certain genes within the cell that alter cellular.
Behavioral effects of cannabinoids may occur through other receptors or a synergic action of CB receptors with these other receptors. They act on specific neurotransmitters in respect to certain memory regions of the brain.
Glutamate, dopamine and acetylcholine are three neurotransmitter systems that are thought to play in the adverse memory effects of cannabinoids. Additionally, dopamine is often investigated for its possible role in working memory within the prefrontal cortex. Other research has observed decreased levels of hippocampus acetylcholine from cannabinoids producing adverse effects on behavioral tasks.
The membranes define a cellular boundary and provide a basic platform for tight regulation of many biological processes, including material transport, signal transduction, trafficking, pathogenic pathways, intercellular organization and response to the extracellular matrix. Furthermore, cannabinoids exhibit a slow clearance from the body. They alter the functions of various membrane proteins which participate in signal transduction, the function of the lipid part of cell membranes and the role of essential fatty acids.
The fluidity or flexibility of membranes is dependent on the degree of unsaturation of the fatty acids forming the membrane. As the degree of unsaturation increases, the cell membrane becomes more flexible and fluid. It is thought that the various adverse effects associated with the chronic use of cannabinoids, including increased tolerance to cannabinoids over time, result from the interaction of cannabinoids with cell membranes.
Their poor solubility and low dissolution rate in the aqueous gastrointestinal fluids and significant first-pass liver metabolism result in low oral cannabinoid bioavailability. Rather the composition is being swallowed and passing into the GI tract for absorption and the THC is undergoing gastric degradation first pass liver metabolism before reaching the systemic circulation.
The surface area can be determined through the control of the particle size. Therefore, the bioavailability of cannabinoids can be improved by reduction in their particle size that increases surface area and encapsulating them in the lipid nanoparticle delivery system of this invention.
The phospholipid lipid nanoparticles encapsulations of cannabinoids in this disclosure improve, increase cannabinoid bioavailability, cannabinoid receptor binding, reduce the required dosages for therapeutic activity and decrease the occurrence of adverse effects from cannabinoid administration.
Studies show solubility and dissolution improvement of the synthetic cannabinoid CB 13 l-Naphthalenyl[4- pentyloxy -l-naphthalenyl]methanone loaded into PLGA polymer nanoparticles were shown. Other studies have used cyclodextrin complexes to improve cannabinoid bioavailability. Polymer nanoparticles are recognized to contain toxic monomers and solvents that form toxic degradation products.
From the past studies of polymeric nanoparticles exhibiting cytotoxic effects, the safety profile of current polymer carriers of cannabinoids is not encouraging or not reported extensively so as to conclude that they are a safe carrier for cannabinoids. By contrast, the cytotoxicity of lipid nanoparticles can be minimal or absent, due to their better physiological acceptability when compared to polymeric nanoparticles.
These effects occur because reduced particle size exponentially increasing the surface area for biological interactions and increased ability of the nanoparticle to cross biological membranes and excipients to alter metabolism. The various combinations of polymers, surfactants, emulsifiers and excipients used the different techniques described in the literature for producing nanostructured carriers of cannabinoids can produce adverse effects, including toxicity and inflammation.
There is inadequate testing of many of these ingredients for safety in nanocarriers and these techniques of manufacturing nanoparticles to conclude they are safe for commercial drug applications. The lipid matrix degradation occurs mostly by lipases whereas only non-enzymatic hydrolytic processes degrade a minor part.
Lipid carriers prepared with several lipids and emulsifying agents have shown low toxicity in humans. There are many commercially available surfactants. They have different properties and the same surfactant may have a wide range of applications.
The pharmaceutical surfactants lecithin; phosphadylcholine fractions, poloxamer, sodium cholate and polysorbate 80 are well tolerated and non-toxic in nanoparticles. They are unlikely to induce allergic reactions, hypersensitivity or cytokine production. The method of manufacturing a lipid nanoparticle can risk contamination. Methods like solvent evaporation and emulsification; emulsification-solvent diffusion technique and micro emulsion technique can produce nanoparticles with toxic solvent residues left over from product production or high levels of surfactants and other excipients that cause toxicity.
Intraoral Sublingual Delivery of Nanoparticle Cannabinoids  The absorption of the lipid nanoparticle drugs through the sublingual route is 3 to. Sublingual administration of a cannabinoid avoids contact with the GI tract and avoids barrier functions of the GI tract and the first passage of the drug in the liver where some of the cannabinoid is metabolized to inactivity.
Several formulation approaches for cutaneous administration of cannabinoids have proposed in conventional pharmaceutical forms and vehicle preparations, including topical patches creams, salves and ointments. Studies found transdermal delivery achieved a sustained and steadier action than inhalation or oral administration of the cannabinoid THC. Compared to other biological membranes, the nasal mucosa is a rather porous and thin endothelial basal membrane.
It also has a rapid blood flow, with a highly vascularized epithelial layer and a vast absorption area with microvilli in epithelial cells. The passage of drugs across the nasal mucosa occurs in three ways: Smaller sized lipid nanoparticle compositions are recognized for direct nose-to-brain drug delivery of lipophilic drugs via intransal administration. The highest concentration of nanoparticles delivered through the nose ends up in the olfactory bulb, medulla, and brainstem at the entry point of the trigeminal nerves.
However, widespread delivery to the striatum and cortex also occurs. This phospholipid lipid nanoparticle carrier system is used for the delivery of cannabinoids into mammals.
In one embodiment, the disclosure teaches a method of assembly for producing lipid nanoparticle carrier compositions of cannabinoids in standardized and precision-metered dosages. At least one cannabinoid is incorporated into the process, effective for administration to mammals.
This method of assembly allows for commercial production. The nanoparticles are stable phospholipid nanoparticle compositional structures with a particle size distribution from about 50 to nm.
The assembly can be scaled for commercial production and scalable to commercially available size production. The nanoparticles are stable phospholipid nanoparticle compositional structures that provide standardized precision-metered dosages of cannabinoids for methods of delivery that include oral, intraoral, intranasal and transdermal administration. The nanoparticles are stable phospholipid nanoparticle compositional structures that provide standardized precision-metered dosages of cannabinoids as viscoelastic gels for methods of delivery that include oral, intraoral, intranasal and transdermal administration.
The disclosure further teaches a product, by the process disclosed above, for transdermal administration across dermal and epidermal barriers. The disclosure further teaches a product, by the process disclosed above, for administration across the gastrointestinal GI tract mucosal barrier.
The disclosure further teaches a product, by the process disclosed above for administration across the nasal mucosal barrier. Suitable formulation methods include spray drying of lyophilization of lipid structured nanoparticle dispersions with suitable excipients followed by incorporation of a dry powder into a tablet, or pellet. Another method is granulating phospholipid nanoparticles liquid dispersions with excipients and binders into powders for compression into tablets or pellets for sublingual and buccal delivery.
Phospholipid nanoparticles may be incorporated into lozenges, lollipops, gum, gels and films for intra-oral delivery. The disclosure teaches standardized precision-metered dosage forms of cannabinoids for different routes of delivery. The disclosure teaches increasing cannabinoid transport across hydrophobic mucosa; increasing the bioavailability of the cannabinoid delivered; decreasing the dose of cannabinoids needed to illicit the same therapeutic effect compared to raw and non- encapsulated cannabinoids.
Most polymers have not been tested as nanoparticles at this time to recommend them safe for human use. For example, both synthetic and natural polymers may act upon the complement system. Natural polymers can lead to lead to cellular and humoral immune responses from being recognized as foreign substances. PEG is a hydrophilic biocompatible and non-biodegradable nanoparticle biomaterial. PEG is degraded by oxidative degradation under biologically relevant conditions. The generation of reactive oxygen species ROS may have biological consequences.
PEG has the propensity to induce blood clotting and clumping of cells. Lipid nanoparticles are known for their high degree of biocompatibility, controlled release, efficient targeting, stability, natural biodegradability and high therapeutic index to their payload. The preferred cannabinoid lipid nanoparticle carrier assemblies of this disclosure are NanoSpheres NS. SLN have a mean particle size in the nanometer range.
SLN combine the advantages of emulsions, liposomes and polymeric nanoparticles. The solid matrix can protect incorporated active ingredients against chemical degradation and provide the highest flexibilities in the modulation of the drug release profiles. SLN provide controlled release, efficient targeting, and stability. SLN are particulates structurally related to polymeric nanoparticles.
However, in contrast to polymeric systems, SLN can be composed of biocompatible lipids that are physiologically well tolerated when administered in vivo and may also be prepared without organic solvents. NLC have a mean particle size in the nanometer range. NLC a controlled nanostructuring of the lipid matrix is performed due to the mixture of solid and liquid lipids, in order to increase drug- loading and prevent its expulsion. In addition, the NLC nanostructured lipid matrix gives more flexibility in modulation of drug release.
NLC are composed of a lipid matrix of cannabinoids with a nanostructure that improves cannabinoid loading and firmly retains the cannabinoids during storage.
NanoSpheres are synthesized from biocompatible, and biodegradable essential phospholipids, lipids, and excipients in a unified sequential process. NanoSpheres in this disclosure are characterized by an outer phospholipid membrane and adjustable viscoelastic lipid gel core containing cannabinoids.
NanoSpheres have a mean particle size in the nanometer range. The fluidity and viscoelastic properties of the NanoSpheres phospholipid membrane and core's properties favorably influences properties such as cannabinoid transport across cell membranes, binding to receptor sites and signal transduction.
Nanospheres present numerous advantages over other carrier formulas. They are biocompatible, biodegradable and can easily be produced by the versatile and up-scalable unified sequential assembly process of this disclosure. SLN have limited controllability. Crystallization of their lipid core generally leads to separation of encapsulated agents from their lipid core and expulsion causing a high burst release. This enables a better encapsulation ratio and control over release kinetics.
They're comprised of an amorphous viscoelastic internal core and external membrane for characteristics of long-term stability and a desirable high-encapsulation, localization and release behavior of their cannabinoid payloads. In lipid nanoparticles they can either be can be distributed homogenously throughout the entire nanoparticle's matrix or more likely be distributed in relatively different amounts in different regions of the nanoparticles.
They improve the integrity of the cell membrane and up-regulates the fluidity of the cell membrane. Preferred phospholipids in lipid nanoparticles of this disclosure should be biocompatible, GRAS listed and non-toxic as nanoparticles.
The preferred simpler lipids in this disclosure are medium chained triglycerides, hemp seed oil, safflower oil and sesame oil. Preferred simpler lipids used in forming phospholipid nanoparticles of this disclosure should biocompatible, GRAS listed and non-toxic as nanoparticles.
Preferably, the weight ratio is from about 2: Preferably, the weight ratio is from about 3: They're a surface active group of amphiphilic molecules which are manufactured by chemical processes or purified from natural sources or processes. These can be anionic, cationic, nonionic, and zwitterionic. Surfactants that should not be used in assembly of nanoparticle compositions of this disclosure include ionic, synthetic, and polymer surfactants recognized as toxic and irritants.
The phospholipids present in liquid lecithin phosphatidylcholine. Their surface-active simultaneous hydrophilic and hydrophobic properties enable lecithin to make stable blends of biomaterials that otherwise do not mix. Lecithins can provide fast, complete wetting of powders into aqueous systems.
They are non-ionic liquids used as surfactants for dispersing hydrophobic particles in aqueous solutions ion the assembly of lipid nanoparticles of this disclosure. Polysorbate 80 is a polyethylene sorbitol ester, also known as Tween 80, sorbitan monooleate, polyoxyethylenesorbitan monooleate is used for emulsifying and dispersing substances. Polysorbate 20 is a polyoxyethylene sorbitol ester member of the polysorbate family used as emulsifying agents for the preparation of stable oil-in-water emulsions.
They include lecithins such as Alcolec S, Alcolec BS and Alcolec XTRA-A, polysorbates such as Polysorbate 80 and Polysorbate 20, monoglycerides, diglycerides, triglycerides, glyceryl monoleate, polysorbates polaxamers and other non-toxic ionic and ionic surfactants that are known to the art. Surfactants may be selected to provide coatings and functional groups on the nanoparticle membrane and alter the membrane surface charge for greater transport of cannabinoids across cell membranes, binding to receptor sites and signal transduction.
These lipids include fatty acids such stearic acid, palmitic acid, belenic acid, myrisitic acid and oleic acid; free fatty acid alcohols such as stearyl alcohol, cetyl alcohol, myristyl alcohol, lauryl alcohol; triglycerides such as trimyristin, tripalmitin, trilaurin; waxes such as bees wax, cetyl palmitate, carnuba wax, cannabis wax extract; mono, di and triglycerides mixtures such as Suppocire NC, witepsol bases, glyceryl monostearate, glyceryl behenate, palmitostearate, and softisan; and others such as cacao butter, castor oil, anhydrous milk fat, and hydrogenated palm oil.
Preferred surfactants in nanoparticles of this disclosure should be biocompatible, biodegradable GRAS listed and non-toxic as nanoparticles. Suitable carrier fluids and solvents include water, sterile saline, glycerides glycerine, and ethanol, sorbitol, lipids, fatty acids, glycine, and silicone oils; and their dispersions emulsions, suspensions, mixtures, self- assembly and other methods of incorporation in the assembly of nanoparticles.
Suitable carrier fluids and solvents should be GRAS listed, biocompatible, biodegradable and non-toxic as nanoparticles. Plus, preservatives should be selected that do not induce changes in barrier functions, do not induce toxic and allergic effects, do not induce adverse effects to the nanoparticles, and do not induce adverse effects to the transported cannabinoids. Some of the preservatives for consideration in use include tocopherols, ascorbyl palmitate, sorbates, parabens, optiphen, thimersal, benzoic acid, benzalkonium chloride, benzehtkonium chloride polyquaternium- 1 , ethyl lauroyl arginate, and rosemary oleoresin, Jeecide and Optiphen.
Preferred preservatives in phospholipid nanoparticles of this disclosure should be. Preferred preservatives should not interfere with the delivery of the cannabinoids. Nanoparticles with 50 nm show the most efficiency of uptake. These results in greater cannabinoid bioactivity in therapy and fewer adverse effects compared to administration of raw and non-encapsulated cannabinoids. The sweeteners used may be natural sweeteners or artificial sweeteners.
Natural sweeteners include Stevia extract Steviol Glycosides, xylitol, sucrose, fructose,. Examples of artificial sweeteners include sucralose, aspartame, acesulfame K, neohesperidine, dihydrochalcone, thaumatin, saccharin and saccharin salts.
Preferred sweeteners for this disclosure should be sucralose, Acesulfame K and natural sweeteners such such as steviol glycosides, xylitol, erythritol and thaumatin. Preferred sweeteners in nanoparticles of this disclosure should be biocompatible, GRAS listed and nontoxic as nanoparticles.
The flavors used may be natural sweeteners or artificial sweeteners. Examples of flavoring agents useful in the compositions of the invention include fruit e. Typically the sweetener content will be about 0. The actual increase amount depends on the molecular characteristics of the cannabinoid, the encapsulation characteristics into phospholipid nanoparticles, the structural characteristic of the phospholipid nanoparticles, the method and vehicles of administration and metabolic difference between users.
The dose reduction can range from a 2-fold reduction in mg dose to an 8-fold reduction in mg dose. Preferably, the range is from about a 2-fold reduction to about an 8-fold reduction in mg cannabinoid dose. These techniques can be performed in this sequential order or may be performed sequentially in alternate orders. They represent an alternative class of vehicles to liposomes, emulsions, aqueous solutions, vaporizing, smoking, transdermal patches, chewing gums, edible food forms and solid formed tablets and capsules to for cannabinoid therapy.
The preferred method is a. Methods suitable for administering a composition to the nasal cavity will be well known by the person of ordinary skill in the art.
Any suitable method may be used. The preferred method of administration is the use of a pump device. The liquid nanosphere gel is administered under the tongue for transport directly into the blood stream. Sublingual drug solutes are rapidly absorbed into the reticulated vein, which lies underneath the oral mucosa, and transported through the facial veins, internal jugular vein, andbraciocephalic vein and then drained in to systemic circulation.
Procedure for a In sequence, pre-nanoparticle blend is ground through a product mill for particle size reduction, at 10, RPM for 10 minutes with an Ultra-Turrax.
Next, 20 mg of potassium sorbate preservative, mg of flavor oil and 50 mg of steviol glycoside sweetener is thoroughly dispersed into the composition.
Composition is administered to the sublingual mucosa by a precision liquid pump device bottle that delivers mcl per pump. Each pump dose contains 30mg of CBD and 1. Heat this vessel to C. Next, discharge mg of water heated to C into the vessel from a separate heated vessel.
Stir this vessel containing pre-nanoparticle blend for 5 minutes. In sequence, pre-nanoparticle blend is ground through a product mill for particle size reduction, homogenate at 10, RPM for 10 minutes with a Ultra- Turrax homogenizer under cooling, and processed in an ultrasonification system for 40 minutes with watts of power in a flow through chamber under cooling to form the phospholipid nanoparticle cannabinoid composition.
Discharge mg of ethanol into a vessel containing the blend stirring at RPM. Next discharge mg of Xanthum gum into a vessel containing the blend stirring at RPM. Follow by discharging 33mg of potassium sorbate preservative in the vessel and stir for 5 minutes.
The NanoSphere Gel composition is administered topically to skin by precision liquid pump device bottle that delivers mcl per pump. Each pump contains 50 mg of CPD and 2. Procedure for a 1: This has been demonstrated by Marcellino and colleagues when the CB1R antagonist rimonabant and the specific A2AR antagonist MSX-3 blocked the inhibitory effect of CB1 agonist on D2-like receptor agonist induced hyperlocomotion in rats [ Marcellino et al. Receptor heteromers provide better understanding of how these different neurotransmitter systems interact with each other.
The authors propose that it is likely that functional CB1—A2A—D2 receptor heteromers can be found in the dendritic spines of GABAergic enkephalinergic neurons, where they are highly coexpressed, and their analysis provides new information on the role of endocannabinoids in striatal function, which can be considered as retrograde signals that inhibit neurotransmitter release.
Further evidence for the existence of D2 and CB1Rs in ventral striatum is provided by electron microscopy analysis, which confirms the relevance to the rewarding and euphoric, as well as motor effects produced by cannabis, by enhancing dopamine levels particularly in the nucleus accumbens [ Pickel et al. The authors point out that there is a bidirectional cross antagonism which involves the antagonists of either receptor to block the other.
In more recent years, three other novel receptor candidates, GPR18, GPR19 and GPR55, have been discovered, as well as non-CB1Rs and non-CB2Rs, but knowledge on these systems is incomplete and the discussion on whether or not they meet the criteria to qualify as receptors or channels is ongoing [ Mackie and Stella, ; Pertwee et al.
The involvement of the particular neural regions and the neurotransmitter systems here is significant due to the fact that the very same brain areas and neurotransmitter systems are also implicated in psychoses, particularly in schizophrenia [ van Os and Kapur, ; Smieskova et al. Available evidence indicates that we do not yet have a complete understanding of the varied functions of the endocannabinoid system, which is widely distributed both in the brain and in the peripheral system and most glands and organs in the body.
Even though our knowledge on the role of the endocannabinoid system is still evolving, the available evidence indicates that this system has multiple regulatory roles in neuronal, vascular, metabolic, immune and reproductory systems. As mentioned previously, the on-demand regulatory role on other neurotransmitter systems clearly affect functions such as cognition, memory, motor movements and pain perception [ Howlett et al.
The cannabis plant has two main subspecies, Cannabis indica and Cannabis sativa , and they can be differentiated by their different physical characteristics. Indica -dominant strains are short plants with broad, dark green leaves and have higher cannabidiol content than the sativa plants in which THC content is higher. Sativa- dominant strains are usually taller and have thin leaves with a pale green colour. Due to its higher THC content, C. It is a complex plant with about chemical entities, of which more than 60 are cannabinoid compounds [ Dewey, ].
In the plant, cannabinoids are synthesized and accumulated as cannabinoid acids, but when the herbal product is dried, stored and heated, the acids decarboxylize gradually into their proper forms, such as CBD or dTHC [ De Meijer et al. Originally it was thought that CBD was the metabolic parent to dTHC, but it was later found that its biosynthesis occurs according to a genetically determined ratio [ Russo and Guy, ].
Even though the chemical structures of all four compounds are similar, their pharmacological effects can be very different. The most researched compounds of the plant are dTHC and CBD and therefore we will mainly focus on these two compounds and their differences.
Natural compounds of the cannabis plant are also referred to as phytocannabinoids of which dTHC is the main psychoactive ingredient and has been widely researched both in animals and humans. It characteristically produces, in a dose-dependent manner, hypoactivity, hypothermia, spatial and verbal short-term memory impairment [Hayakawa et al.
However, the second major compound, CBD, does not affect locomotor activity, body temperature or memory on its own. The available research indicates that the main two compounds, dTHC and CBD, whilst having similar effects in certain domains, also have almost opposite effects to one another in other aspects [ Carlini et al.
Table 1 summarizes the varying effects of these two compounds. Effects of tetrahydrocannabinol and cannabidiol, adapted and updated from Russo and Guy . In fact the different and opposing effects of the main two compounds of the plant were noticed in some early studies. In a double-blind study with 40 healthy volunteers, Karniol and colleagues orally administered dTHC and CBD and the mixtures of the two together, whilst pulse rate, time production tasks and psychological reactions were measured [ Karniol et al.
Whilst dTHC alone increased pulse rate, disturbed time tasks and induced strong psychological reactions in the subjects, CBD alone provoked no such effects. CBD also decreased the anxiety component of dTHC effects in such a way that the subjects reported more pleasurable effects. Most recently there have been a number of drug challenge studies with sound methodologies examining the effects of both of these compounds.
Our group carried out a number of double-blind, pseudo-randomized studies on healthy volunteers who had previous minimal exposure to cannabis. All participants were administered 10 mg of dTHC, mg of CBD and placebo flour in three different functional magnetic resonance imaging sessions while performing a response inhibition task, a verbal memory task, an emotional task viewing fearful faces and an auditory and visual sensory processing task. The overall concluding results showed that dTHC and CBD had different behavioural effects and also, at times, opposing brain activation in various regions [ Borgwardt et al.
DTHC caused transient psychotic symptoms and increased the levels of anxiety, intoxication and sedation, whilst CBD had no significant effect on behaviour or these parameters. In relation to the imaging data, during the response inhibition task, relative to placebo, dTHC attenuated the engagement of brain regions that normally mediate response inhibition, whilst CBD modulated activity in regions not implicated with this task [ Borgwardt et al.
During the verbal learning and retrieval of word pair tasks, dTHC modulated activity in mediotemporal and ventrostriatal regions, whilst CBD had no such effect [ Bhattacharyya et al. During an emotional processing task dTHC and CBD had clearly distinct effects on the neural, electrodermal and symptomatic response to fearful faces [ Fusar-Poli et al. Our results suggest that the effects of CBD on activation in limbic and paralimbic regions may contribute to its ability to reduce autonomic arousal and subjective anxiety, whereas the anxiogenic effects of dTHC may be related to effects in other brain regions.
During the auditory task, again these two compounds had opposite effects in the superior temporal cortex when subjects listened to speech and in the occipital cortex during visual processing [ Winton-Brown et al. Our group also assessed whether pretreatment with CBD could prevent the acute psychotic symptoms induced by dTHC when six healthy volunteers were administered dTHC intravenously on two occasions, after placebo or CBD pretreatment [ Bhattacharyya et al.
Both animal and human studies indicate that CBD has anxiolytic properties. In fact in a recent double-blind study carried out on patients with generalized social anxiety disorder, it was found that relative to placebo, CBD significantly reduced subjective anxiety and its effect was related to its activity on limbic and paralimbic areas as shown by single photon emission computed tomography [ Crippa et al. CBD has also been proposed to have antipsychotic effects and is considered a potential antipsychotic medicine, particularly due its relatively low side-effect profile [ Zuardi et al.
Another interesting compound of the plant, dtetrahydrocannabivarin dTHCV , a novel CB1R antagonist, also exerts potentially useful actions in the treatment of epilepsy and obesity [ Pertwee, ; Izzo et al. A review of this compound, along with dTHC and CBD by Pertwee suggests that plant extractions of d - 9-THCV produces its antiobesity effects more by increasing energy expenditure than by reducing food intake [ Pertwee, ].
The author also points out that a medicine such as dTHCV, by simultaneously blocking CB1Rs and activating CB2Rs, may have potential for the management of disorders such as chronic liver disease and obesity, particularly when these are associated with inflammation.
However, the CBD content was found to be extremely low in more recent times. More recently, a meta-analysis to assess the potency of cannabis from to was carried out. From 21 case series covering a number of countries, a recent and consistent worldwide increase in cannabis potency was reported [ Cascini et al.
These findings suggest that current trends for preferring higher THC content variants carry significant health risks, particularly to those who are susceptible to its harmful effects. Indeed, Morgan and colleagues carried out a study on current users, which included 66 daily and 54 recreational users, whose hair analyses revealed their THC and CBD amounts. The study found that higher THC levels in hair in daily users were associated with increased depression and anxiety, as well as poorer prose recall and source memory [ Morgan et al.
However, higher CBD in hair was associated with lower psychosis-like symptoms and better recognition memory. In relation to people with psychosis, health risks are even higher with stronger variants of the plant. In a recent study of people with a first episode of psychosis, it was found that patients used higher-potency cannabis for longer durations and greater frequency compared with a healthy control group [ Di Forti et al.
As the stronger variants have been taking over the street market, there has been a surge of interest in studying the links between cannabis use and mental health problems. The first to draw attention to such a link was a number of epidemiological studies and reviews, which pointed towards an association between the use of cannabis and the increased risk of developing a psychotic illness, in a dose-dependent manner [ Zammit et al.
A psychotic outcome is not the only diagnostic category which has been associated with cannabis use. Symptoms of depression and anxiety commonly coexist with cannabis use and lead to diagnostic dilemmas [ Nunes et al. Cannabis use can induce such symptoms, as well as be used secondary to a primary depressive illness [ Dakwar et al. As the majority of the studies have had psychotic illness as an outcome, in this section we will mainly be focusing on this diagnostic category.
This is important as the strong THC variants of cannabis use have been increasing steeply, as have concerns on cannabis-related health risks, particularly for young people [ Hall and Degenhardt, ; Potter et al.
Recent epidemiological studies point towards a link between the use of cannabis and the development of a psychotic illness [ Zammit et al.
Further evidence comes from a systematic review of longitudinal and population-based studies which show that cannabis use significantly increases the risk of development of a psychotic illness in a dose-dependent manner [ Moore et al. The clinical picture of transient psychosis can be indistinguishable from a frank acute psychosis with delusions and hallucinations, except for its short duration.
Evidently there is considerable variation in the effects of cannabis on individuals. The biological basis of this variable sensitivity is yet unclear. There have been a number of studies exploring which groups are more vulnerable to developing a psychotic outcome as a result of cannabis use [ van Os et al. Findings so far indicate that the effect of cannabis use is much stronger in those with any predisposition for psychosis at baseline than in those without [ Henquet et al.
Indeed, individuals with a predisposition to psychosis indicated by a positive family history of psychosis have been found to be particularly sensitive to the effects of cannabis [ McGuire et al.
Another indicator for a higher psychosis risk is the presence of subclinical psychotic features and again such individuals have been affected by a higher risk of developing a psychotic illness [ Henquet et al. Furthermore those who are at ultra high risk for psychosis have been reported to be more sensitive to the psychotogenic effects of cannabis compared with users in the general population [ Peters et al.
Because of the reported links between the schizotypal personality and schizophrenia, this type of personality disorder has come under scrutiny in examining the role of cannabis in producing psychotic symptoms.
Indeed, it has been shown that people scoring high in schizotypy who use cannabis are more likely to have psychosis-like experiences at the time of use, together with unpleasant side effects [ Barkus et al.
This study has been replicated and it has been confirmed that those with schizotypal personality disorder carry a higher risk of experiencing psychotic symptoms with cannabis use [ Stirling et al. Most recently, another study has provided further support for a strong association between early cannabis use and the development of schizophrenia spectrum disorder symptoms [ Anglin et al.
The reported vulnerability factors mentioned here imply a strong genetic predisposition and there have been a number of studies looking particularly to specific genes which have been implicated in psychoses.
The first such study was carried out by Caspi and colleagues [ Caspi et al. In this longitudinal study, a specific susceptibility gene which has been linked to schizophrenia and bipolar disorder, catechol-O-methyltransferase COMT , was examined in a representative birth cohort followed to adulthood.
The study found that carriers of the COMT valine allele were most likely to exhibit psychotic symptoms and to develop schizophreniform disorder if they used cannabis before the age of However, the number of people carrying this allele was small in this study. Using a case-only design of people with schizophrenia, Zammit and colleagues re-examined this association but their findings did not support the different effects of cannabis use on schizophrenia according to variation in COMT [ Zammit et al.
More recently, van Winkel and colleagues looked at the effects of recent cannabis use whilst examining single nucleotide polymorphisms in 42 candidate genes in patients with psychosis and their unaffected siblings [ van Winkel et al. The authors found that genetic variation in serine-threonine protein kinase AKT1 may mediate both short- and long-term effects on psychosis expression associated with cannabis use. Further support for the possible involvement of the AKT1 gene comes from our study with healthy volunteers.
This study found that, during the encoding and recall conditions of the verbal memory task, the induction of psychotic symptoms by dTHC was correlated with the attenuated striatal and midbrain activation only in those who were G homozygotes of AKT1 and carriers of the 9-repeat allele dopamine transporter DAT1 [ Bhattacharyya et al.
Apart from schizotypal personality, the vulnerability factors to the psychotogenic effects of cannabis require replication.
It is clear that further work needs to be carried out to explore the biological mechanisms which determine the vulnerability towards a psychotic outcome.
During the last decade, endocannabinoid research has been one of the fastest growing fields in psychopharmacology, opening ways to discover new medicines for a wide variety of health problems, ranging from metabolic disorders, to glaucoma and schizophrenia.
The distribution of the endocannabinoid system in the brain is interesting as the very same brain areas are also implicated in psychoses, particularly in schizophrenia. Furthermore, complex and intricate involvement of this system with other neurotransmitters such as dopamine, GABA and glutamatergic systems may have implications for the development of a psychotic illness.
Naturally, due to the recent and constant increase in the availability of higher THC content variants of cannabis around the world, there have been increasing concerns about the health risks, particularly for young people. However, cannabis affects people differently and therefore it is important to understand what makes someone more at risk and how they differ compared with those who do not develop psychotic illness.
Here we have provided an overview of the available information on the risk factors which may make an individual more at risk, such as predisposition to psychosis, schizotypal personality and certain susceptibility genes. Finding groups who are vulnerable is particularly important so that they can be targeted for early preventative and therapeutic interventions. Such a search would also lead to the discovery of the biochemical mechanisms involved in cannabis and endocannabinoid research and ultimately to a better understanding of how the brain and the body functions.
Thanks to Ethan Russo and Geoffrey W. Guy for providing the inspiration for Table 1. Also thanks to Dr Sanem Atakan for her help with the editing of the first draft. This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.
Conflict of interest statement: The author declare no conflicts of interest in preparing this article. National Center for Biotechnology Information , U. Journal List Ther Adv Psychopharmacol v. Author information Copyright and License information Disclaimer.
This article has been cited by other articles in PMC. Abstract Cannabis is a complex plant, with major compounds such as deltatetrahydrocannabinol and cannabidiol, which have opposing effects. Cannabis, deltatetrahydrocannabinol, cannabidiol, tetrahydrocannabivarin, endocannabinoids, individual sensitivity to cannabis. Introduction Cannabis is a complex plant with over chemical entities of which more than 60 of them are cannabinoid compounds, some of them with opposing effects.
Brief history of the biochemistry of the cannabis plant Even though cannabis has been used and cultivated by mankind for at least years [ Li, ] our current knowledge on its pharmacological properties is based on studies which have taken place only since the end of the nineteenth century.
Chemical Components of Cannabis
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