IS CANNABIS SATIVA, THE MIND ALTERING NIGHTMARE PLANT OF THE WORLD?

Research Paper

Medical Science

E-ISSN No : 2454-9916 | Volume : 7 | Issue : 6 | Jun 2021

IS CANNABIS SATIVA, THE MIND ALTERING NIGHTMARE PLANT OF THE WORLD? 1

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Raghavendra Rao M. V | Tiara calvo | Frank Navarrete | Mahendra. K. Verma | Abrar A Khan | R.K. Kudari | Kumar Ponnusamy7 | Siva Anoop Yella8 | Badam Aruna Kumari9 | Dilip Mathai10 1

Scientist-Emeritus and Director Central Research laboratory, Apollo institute of Medical Sciences and Research, Hyderabad, TS, India.

2 Associate Professor, American University School of Medicine Aruba, Caribbean islands 3 Associate Professor, American University School of Medicine Aruba, Caribbean islands, 4 Assistant Professor, American University School of Medicine Aruba, Caribbean islands, 5 Professor, Dean of Basic sciences, American University School of Medicine Aruba, Caribbean islands 6 Professor Department of Pharmaceutical Analysis, Hindu College of Pharmacy, Guntur, Andhra Pradesh India.

7 Professor of Biochemistry, Avalon University School of Medicine, Curacao, Caribbean islands 8 Senior Resident, Department of Psychiatry, Telangana Institute of Medical Sciences, T S, India.

9 Associate Professor, Department of Respiratory Medicine, ESIC Medical College, Sanathnagar Hyderabad,,T S,India 10 Professor, Department of Medicine, Dean, Apollo Institute of Medical Sciences and Research, Jubilee Hills, Hyderabad, Telangana, India.

ABSTRACT Cannabis Sativa is the hatred weed. Marijuana, is popularly known as pot, weed, ganja, Mary jane nicknames. Marijuana, far-reaching well liked mind-boggling medicaments across the globe. Cannabis Smolder assassinated, but consuming marijuana could stretch out the growth of cancer. This is used as hallucinogenic materials by man from times immemorial. Due to its known ability to induce euphoria and relaxation, cannabis (marijuana) commonly-used substances worldwide for decades.

Transitory use of the drug debilitates reasoning and planning. In prolonged studies, teens who smoke marijuana have lower IQs afterwards. When puff on, marijuana releases cannabinoids, which produce neurotransmitters in brain. These cannabinoids give medicinal value to Marizona.The cannabinoids acknowledge dissimilar domains of the brain exert influence on memory, pleasure and muscle movement. Marijuana has delta-9-tetrahydrocannabinol (THC) which binds to CB1 brain cannabis receptor.

THC acts by preventing the delivery of L-glutamate, GABA, noradrenaline, dopamine, 5-HT and acetylcholine.

INTRODUCTION: Toxicity of marijuana shows similar symptoms to that of serotonin (1). The number of cases of drug abuse are increasing in emergency departments (ED) in the USA, because of legalization of Cannabis sativa (2) Psychotic states, cardiac toxicity, and neurotoxicity have been reported as clinical sequelae of THC-induced toxicity (3).

Serotonin disorder shows dilated pupils, tremor, deep tendon hyper-reflexia, and flushed skin with diaphoresis (4) High cannabis customers have as much dopamine in comparison to non-users (5) Long-term use of Cannabis, revamp the balance of brain dopamine (6) Drug abuse increase phasic dopamine events, which theoretically promote drug seeking (7,8). Disrupting endocannabinoid signaling, prove to be good achievement in addiction treatment (9,10). Two CB-specific receptors have been identified and there is evidence of at least one additional subtype (11).

The CB1 receptor subtype is primarily located in CNS, whereas the CB2 receptor subtype is found mainly in the periphery (12) The complexities have negative values comparing the effects of various cannabis products on THC bioavailability, pharmacokinetics and pharmacological effects (13).

nausea or pain, and Irritable Bowel Syndrome.

After smoking, marijuana discharge cannabinoids, in turn act as neurotransmitters in our brain. The Cerebellum controls in coordination.

Neurotransmission Signals pass from one neuron to another neuron inside the brain. These signals are translated into thoughts memories, emotions and reactions to the high society. Electric charge passed through neurons. When the signals move into the electric charge, neurotransmitter chemicals are released.

These neurotransmitters, at the synapse fire and sends message to the next neuron or stay at reposing or sleeping. A change in neurotransmitters can influence thoughts, moods, sensations and access to memory. G proteins intracellular signaling inhibition of adenylyl cyclase decrease in cyclic adenosine monophosphate.

Stimulation of potassium channels Blockage of N-type calcium channels Inhibits the release of a variety of neurotransmitters- GABA, nor-epinephrine, and acetylcholine Boost the release of brain endorphin neurotransmitters Raise dopamine release in the nucleus accumbency . Biosynthesis of Cannabinoid There are several compounds that are achieved by non-enzymatic modification reactions:

Cannabis principally influence on brain development, (14, 15).

Chronological record of significant events Cannabis Sativa is known for many decades first in 1964: structure of d-9tetrahydrocannabinol (THC) was determined and in 1990: Rimonabant (Acomplia), a CB1 receptor blocker is developed RimonabantSR141716, the first cb1 antagonist reported. Chinese Emperor Shen Nung- recommended its use for a variety of ailments 2400 BC.1899- Cannabinol isolated from cannabis resin.

It has also been prescribed for: glaucoma, anxiety, depression, anorexia, frequent

There are only three enzymes with the biosynthesis of cannabinoids 16, 17, 18) Cannabinoid receptor and advanced research There are two cannabinoid receptors: CB1 and CB2 receptors. These receptors have a well define expression profiles: the CB1 is localized in neuronal tissue and the CB2 is found on cells of immune origin.

CB1 and CB2 are both class A (rhodopsin-like) GPCRs. CB1 receptors, situated in the CNS targets: appetite, immune cells, motor activity, pain perception, short term memory, and process of thought, mainly. The CB2 receptors targets adipose tissue, bone, CVS, CNS, eyes, guts, immune system, kidneys, liver, pancreas, reproductive system, respiratory system, skeletal muscle, skin, tumors (19,20,21).

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E-ISSN No : 2454-9916 | Volume : 7 | Issue : 6 | Jun 2021 Experts say that the vote will have no immediate impact on loosening international controls because governments will still have jurisdiction over how to classify cannabis (22).

Recent advances in diagnostic technology Research Drug testing provides objective information regarding an individual's recent use or exposure to illicit drugs.

Neurotransmission: Signals pass from one neuron to another neuron inside the brain. These signals are translated into

Pro Increasing use of marijuana both medicinally and recreationally (23,24) may lead to increased health risks resulting from exposure to both cannabinoids and the toxic chemicals found in marijuana smoke (25,26) Traditionally, cannabinoids,and two major metabolites of THC, 11-nor-9-carboxy-THC (COOH-THC) are measured in the urine of people to assess their exposure to marijuana products and smoke. (27,28).

Organ

CB1 receptor

CB2 receptor

Brain

- Nociception - Drug addiction - Neuroprotection - Neurotransmission - Appetite and food intake - Control of motor functions - Mood, cognition and perception

- Nociception - Neurogenesis - Neuroprotection - Neuroimmune modulation

Despite the mass loss during sample preparation, the detection sensitivity achieved in this method for urine samples were 10-100 times the values (0.2-5.0 ng/mL) reported in the literature (29,30). Progress in drug testing prompted the Substance Abuse and Mental Health Services Administration (SAMHSA) in the United (31).

Cardiovascular - Heart rate system - Hypotension - Cardiac dysfunction - Decrease in myocardial contractility

- Cardioac protection

Contrast to urine, sweat, or hair, a positive result from an oral fluid test can be interpreted with greater confidence as being attributable to very recent drug use, that is, generally within 24 h, and not the consequence of drug use that occurred days to weeks earlier (32).

Liver

- Antisteatosis - Antifibrogenesis

- Steatosis - Fibrogenesis - Insulin resistance

Spleen and - Immunomodulation immune system

For marijuana, the primary route of drug entry into oral fluid appears to be direct deposition during use. (33, 34, 35).

- Immunomodulation Auto radiographic studies of radiolabeled THC in the monkey (Hapalejacchusspecies) indicated accumulation in the parotid (37).

Skeletal muscle - Energy expenditure - Oxygen consumption - Insulin resistance Bones

THC was identified by TLC, in oral fluid 30 min after injection. (38) Regulation of bone strength and mineral density

Gastrointestinal - GIT motility - Energy balance Others

- Cancer - Nausea, Messi, and diarrhea

- Cancer

Drug Interactions and Research i. A total of 380 drugs are known to interact with cannabis. ii. 26 major drug interactions iii. 354 moderate drug interactions MOST FREQUENTLY CHECKED INTERACTIONS WITH CANNABIS ARE: i. amphetamine / dextroamphetamine ii.

Alcohol beverages iii. lorazepam iv.

Diphenhydramine v. duloxetine vi.

Omega-3 polyunsaturated fatty acids vii.

Cyclobenzaprine viii.

Clonazepam ix.

Lamotrigine x.

Escitalopram xi.

Pregabalin xii.

Quetiapine xiii.

Acetaminophen xiv.

Vitamin B12 (cyanocobalamin) xv.

Vitamin C (ascorbic acid) xvi.

Vitamin D3 (cholecalciferol) xvii.

Alprazolam xviii. Ondansetron xix.

Sertraline xx.

Cetirizine Medical cannabis around the world Over the recent years there has been an unstrung debate about the regulation of cannabis and jurisdiction to amend the country's legislation to allow for medical or therapeutic use of cannabis.

A United Nations commission voted on December 2020 to remove cannabis for medicinal purposes from a category of the world's most dangerous drugs.

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A preliminary study of the disposition of radiolabeled THC administered by the intravenous route to humans revealed no evidence of THC excretion in saliva (36)

Oral fluid testing for cannabinoids offers some advantages over urine testing.

(39) Basically, there are fundamental dispositional and kinetic differences between oral fluid and urine that account for the differences observed in their time course of detection. Foremost in consideration are the different mechanisms involved in the disposition of THC and THCCOOH in oral fluid and urine, respectively. The time course of THCCOOH's appearance in urine (as free and conjugated metabolite) is determined by a host of pharmacologic and physiologic factors including marijuana strength (THC content), amount consumed (dose), time of sampling relative to use, and metabolic and renal characteristics of the individual undergoing testing. With smoked marijuana, THC appears immediately in blood after the first puff of marijuana smoke and reaches peak concentrations rapidly.

Huestisetal.(40) reported finding means of 7.0 and 18.1 ng/mL of THC in plasma specimens from six subjects after their first puff from low- (1.75% THC) and high-dose (3.55% THC) marijuana cigarettes, respectively.

Average peak THC plasma concentrations were reached in 8 rain after the beginning of marijuana administration and prior to the end of smoking protocol. Upon entry into the bloodstream, THC undergoes broad distribution to body tissues.

Hepatic uptake is rapid,and subsequent biotransformation occurs with the formation of many cannabinoid metabolites (41). THCCOOH (free and conjugated) appears in blood slowly relative to THC. Time to peak concentrations of THCCOOH after smoked marijuana ranged from 1.4 to 2.4 h.

The detection times by various immunoassays for THCCOOH in urine following smoking of a single marijuana cigarette for an occasional user is generally 1-3 days, but considerable inter subject variability is often encountered (42).

The urinary detection time for chronic marijuana users during cessation of use may be extremely long, that is, weeks to months (43). THC appears in oral fluid as direct contact of cannabis with the oral mucosa during marijuana use.

The passive diffusion of THC from blood back to oral fluid remains a possible contributory (44). Need for better understanding Smoking Smoking marijuana defacement the human respiratory apparatus. Smoking marijuana has been linked to the considerable size of air bubbles in the lungs amidst young to middleaged adults, almost entirely heavy smokers of marijuana.

Research shows that smoking marijuana causes chronic bronchitis and mutitate the cell border of the airways, accompany the manifestations including chronic cough, phlegm formation, and wheeze.. More research is needed into the effects of marijuana on health, principally lung health. It is used very commonly by the young, sometimes only a few times; there is no evidence that occasional use is

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E-ISSN No : 2454-9916 | Volume : 7 | Issue : 6 | Jun 2021

harmful. At first the user feels 'high' and then drifts into a peaceful, drowsy state heightened by unusual mental image.

Skin flushing, rapid pulse and dilated pupils may convey that a person has taken Cannabis, usually by smoking a 'joint'. many addicts use more than one drug.

That physical dependence can occur is doubted, but marked psychological dependence is common. Traumatic Brain Injury (TBI) Pre-exposure to THC before TBI Studies have shown an inconclusive decreased mortality (45) or no effect on mortality (46) on the influence of preinjury use of marijuana, which is just evidence for the need of more research to make a valid conclusion on this matter. Studies so far have great variation in pre-exposure THC is defined, therefore it is difficult to make a definite conclusion at the present time.

Post-exposure to THC after TBI Studies have demonstrated some improvements in outcomes on THC+ patients who sustain a traumatic brain injury. CBD has been proposed as a pharmacological tool post TBI, although the exact mechanism requires further research. (47). Studies in mice suggest CBD prevents hippocampal loss, protects white matter, and increased neurogenesis These studies had also seen benefits of CBD administration post injury but not preinjury.

(48) Studying shed to new light Neurodegenerative disorders Alzheimer's Disease (AD) Cannabinoids in a preclinical setting have shown to ameliorate behavioral and cognitive dysfunctions seen in Alzheimer's disease.

They also target pain pathways, Aß and tau processing, inflammation, among others all playing a crucial role in the management of patients with AD. (49) Another review of studies done in transgenic mice as well as neuronal cultures implied that the CBD might be useful to treat and prevent AD because CBD components could suppress the main causal factors of AD. This same review suggested that using CBD/THC in combination was more useful than using CBD or THC alone. (50) Advance research is essential in clinical settings to make definite conclusions.

ment for Seizure disorder, Lennox-Gastaut Syndrome, and Dravet syndrome.

(64). In Europe it varies from country to country some allowing dronabinol (THC) 30% of countries, others allowing Nabilone (synthetic THC) 30% of EU, and others allowing Nabiximols (THC/CBD mix) 77% of european countries.

(65) Common medicinal marijuana compounds (66) Cannabis based Main Compound medicine

Mode of Medical (m) use administration or potential (p) use

Herbal Cannabis/ Cannabis sativa THC preparations

Smoked Oral Oils Dried flowers Topical ointment Vaporized

No marketing authorization Neuropathic pain (m)

Nabiximol/ Sativex™

CBD/THC mix and other cannabinoids CBD≅THC

Buccal spray

Neuropathic pain (m), Spasms (m) in: a-Multiple Sclerosis, bParkinson's and cTourette's

Oral THC

Δ-9Oral Tetrahydrocannabino l

Compassionate grounds appetite stimulant, weak evidence (p)

Dronabinol

Synthetic THC

Oral capsules Oral solution

Compassionate grounds appetite stimulant in HIV cachexia (p) Antihemetic in chemotherapy (p)

Nabilone

Synthetic THC analogue

Oral capsules

Compassionate grounds appetite stimulant in HIV cachexia (p) Antihemetic in chemotherapy (p)

Epidiolex

Purified CBD

Oral solution

(m) Seizures of Lennox-Gastaut Syndrome, and Dravet syndrome FDA approved (p) Seizures resistant to other medications

Cannabidivarin (CBDV)

CBDV

Marijuana in Multiple Sclerosis.

Studies in animal models have demonstrated the therapeutic potential of cannabinoids forcuring diseases like MS. It is now known that CBD derivatives have neuroprotective effects, decreasing inflammation in demyelinating animal models. A clinical setting Meta analysis of cannabinoids of 2018 concluded a limited and mild reduction of symptoms like: subjective spasticity, pain in patients with MS. The meta analysis considered them overall safe drugs in patients with MS. (51) Marijuana in Pain High thoughts Acute pain There are inconsistent results and limited samples in the current literature, there needs to be more and larger studies to make any judgement on the efficacy of cannabinoids in treating acute pain.

Some small studies reported mild improvement and others did no better than placebo (52).

Chronic neuropathic pain Multiple studies have unanimously shown neuropathic pain reduction, and it has been concluded they are an effective adjuvant therapy in chronic neuropathic pain (53), most studies have recommended cannabinoids as a third and fourth line treatment for patients with neuropathic pain (54). It has been shown that THC may act on chronic pain by reducing the limbic system connectivity of the amygdala with the primary somatosensory cortex.

(55) Cancer pain A 2020 meta analysis on cancer related pain of adults concluded there was no added pain decrease benefit to adding cannabinoids to patients treated with opiates, this study also discouraged the use of cannabinoids as part of a cancer pain regimen due to increased adverse effects (56). Use of cannabidiols is especially discouraged in advanced stages of cancer (57). Non Neuropathic Cancer abdominal pain. No benefit has been shown from adminestingcannabidiols (58). Non-neuropathic Noncancer rheumatic pain.

THC/CBC reduced pain significantly at movement and pain at rest.

Marijuana in Suicidal tendencies Due to its known ability to induce euphoria and relaxation, cannabis (marijuana) has been commonly-used substances worldwide for decades. (59) It is known that monthly cannabis use is consistently associated with suicidal ideation and major depressive episodes (60).

The study concluded cannabinoids at the time are not justified as a treatment of any of these conditions (61,62).CBD formulations have demonstrated potential in animal models by reducing anxiety, depresion, and stress related behavior, and improvement in psychotic disorders. These findings prompt the need for human studies of CBD in these disorders. (63) Break through Treatments: The variability of strains and derivatives from marijuana, different doses and modes of administration, makes it hard to rely on studies and make recommendations to patients.As of this day the FDA as published on their official FDA.gov webpage has only approved the drug Epidiolex (purified CBD extract) as a treat-

International Education & Research Journal [IERJ]

Cannabidiolic CBDA Acid (CBDA) THCA-A Tetrahydrocannab inolic acid A (THCA-A)

(p) Epilepsy None

Cannabyciclol Inactive metabolites None (CBL) Cannabinol (CBN) Cannabigerol (CBG) Cannabichromine (CBC)

(p) Immunomodulator in animal models

Currently no known medical use

Despite an increased interest in cannabinoids in recent years, their pharmacokinetics, pharmacodynamics, side effects, long term benefits and or complications.

Ares of future research: Several studies are scrutinize the probable pain-relieving properties and systems of action of materials in cannabis. including minor cannabinoids and terpenes .

The objective of these studies is to buid up the evidence regarding cannabis components and whether they have probable aspects in pain administration.Hence good scope is there for further research on hemp(Cannabis).Current research disputes with the federal government's attitude that cannabis is a threatening substance worthy of absolute criminalization.

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Shortened version of large work: Eventually we can summarise cannabis sativa is a double edge sword which has narrow therapeutic index and should be used cautiously and research activities must be under strict jurisdictional vigilance. Cannabinol has a potential to generate wonderful prognosis when used in combination therapy for the neurodegenerative disorders like multiple sclerosis, Alzheimer's etc. The use cannabinol in medicine can't be overwhelmed by misusing to have euphoric effect by smoking, consumption of marijuana is very dangerous even the threshold potential of the drugs acting at the receptor site of neurotransmitters like acetylcholine, GABA and dopamine are having higher probabilities to get altered and lead to serious medical emergencies. Cannabis has to be investigated further to have a better potential and safe dosage administration with decreased addiction and produce a good prognosis as it is having very narrow therapeutic index.

Bottom line: Cannabis acts on Cannabinoid receptors CB1 and CB2. Cannabis can cause psychological dependence but no physiological dependence like alcohol and other substances. Cannabis induced psychosis causes hallucinations and is also responsible in causing Schizophrenia in people with susceptible genes. Cannabis also is used medically for acute pain, cancer pain and also chronic neuropathic pain. THC toxicity can cause neurotoxicity and cardiac toxicity. Epidiolex is a drug which is approved by FDA for treatment of epilepsy.

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Research Paper

E-ISSN No : 2454-9916 | Volume : 7 | Issue : 6 | Jun 2021

2019;22(4):225-230.

LII.

Halladay JE, Munn C, Boyle M, Jack SM, Georgiades K. Temporal Changes in the Cross-Sectional Associations between Cannabis Use, Suicidal Ideation, and Depression in a Nationally Representative Sample of Canadian Adults in 2012 Compared to 2002. Can J Psychiatry. 2020;65(2):115-123.

LIII.

Haleem R, Wright R. A Scoping Review on Clinical Trials of Pain Reduction With Cannabis Administration in Adults. J Clin Med Res. 2020;12(6):344-351

LIV.

De Vries M, van Rijckevorsel DCM, Vissers KCP, Wilder-Smith OHG, van Goor H; Pain and Nociception Neuroscience Research Group.

Tetrahydrocannabinol Does Not Reduce Pain in Patients With Chronic Abdominal Pain in a Phase 2 Placebo-controlled Study. ClinGastroenterolHepatol.

2017 Jul;15(7):1079-1086.e4. doi: 10.1016/j.cgh.2016.09.147. Epub 2016 Oct 5

LV.

Amaniti A, Sardeli C, Fyntanidou V, Papakonstantinou P, Dalakakis I, Mylonas A, Sapalidis K, Kosmidis C, Katsaounis A, Giannakidis D, Koulouris C, Aidoni Z, Michalopoulos N, Zarogoulidis P, Kesisoglou I, Ioannidis A, Vagionas A, Romanidis K, Oikonomou P, Grosomanidis V. Pharmacologic and NonPharmacologic Interventions for HIV-Neuropathy Pain. A Systematic Review and a Meta-Analysis. Medicina (Kaunas). 2019 Nov 28;55(12):762. doi: 10.3390/medicina55120762.

LVI.

Mücke M, Phillips T, Radbruch L, Petzke F, Häuser W. Cannabis-based medicines for chronic neuropathic pain in adults. Cochrane Database Syst Rev. 2018;3(3):CD012182. Published 2018 Mar 7

LVII.

Boland EG, Bennett MI, Allgar V, et alCannabinoids for adult cancer-related pain: systematic review and meta-analysisBMJ Supportive & Palliative Care 2020;10:14-24.

LVIII.

Black N, Stockings E, Campbell G, et al. Cannabinoids for the treatment of mental disorders and symptoms of mental disorders: a systematic review and metaanalysis [published correction appears in Lancet Psychiatry. 2020 Jan;7(1):e3].

Lancet Psychiatry. 2019;6(12):995-1010.

LIX.

FDA regulation of Cannabis and Cannabis derived products. FDA.org website: Updated 1/22/21. Accessed 4/26/21

LX.

Orsolini L, Chiappini S, Volpe U, et al. Use of Medicinal Cannabis and Synthetic Cannabinoids in Post-Traumatic Stress Disorder (PTSD): A Systematic Review. Medicina (Kaunas). 2019;55(9):525. Published 2019 Aug 23

LXI.

Botsford SL, Yang S, George TP. Cannabis and Cannabinoids in Mood and Anxiety Disorders: Impact on Illness Onset and Course, and Assessment of Therapeutic Potential. Am J Addict. 2020;29(1):9-26.

LXII.

García-Gutiérrez MS, Navarrete F, Gasparyan A, Austrich-Olivares A, Sala F, Manzanares J. Cannabidiol: A Potential New Alternative for the Treatment of Anxiety, Depression, and Psychotic Disorders. Biomolecules.

2020;10(11):1575. Published 2020 Nov 19.

LXIII.

FDA regulation of Cannabis and Cannabis derived products. FDA.org website: Updated 1/22/21. Accessed 4/26/21.

LXIV.

European Monitoring Centre for Drugs and Drug Addiction publication on Medical Use of cannabis and cannabinoids of 2018 (EMCDDA website) Accessed 4/26/21.

LXV.

Poyatos L, Pérez-Acevedo AP, Papaseit E, et al. Oral Administration of Cannabis and Δ-9-tetrahydrocannabinol (THC) Preparations: A Systematic Review.

Medicina (Kaunas). 2020;56(6):309.

LXVI.

Levinsohn EA, Hill KP. Clinical uses of cannabis and cannabinoids in the U n i t e d S t a t e s . J N e u r o l S c i . 2 0 2 0 A p r 1 5 ; 4 11 : 11 6 7 1 7 . d o i : 10.1016/j.jns.2020.116717. Epub 2020 Jan 30.

International Education & Research Journal [IERJ]

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