Cannabis has been used all over the world for hundreds of years, both for recreational and medicinal purposes. The plates obtained by sieving the dried leaves of the cannabis plant and the powders on the flowers formed on the top of the plant and pressing under heat are generally wrapped with tobacco and smoked like a cigarette. According to the World Health Organization (WHO), even just 2-3 milligrams of cannabis when smoked is enough to produce the desired effect in most people. The main active ingredient responsible for the pharmacological effects of cannabis is 9-THC / 9-tetrahydrocannabinol (THC). THC is a fat-soluble substance that quickly passes to the brain and other organs. This substance plays a leading role in cannabis treating psychiatric illnesses.
It is thought that cannabis and its active ingredient THC, which is known to have been used since ancient times and which is widely used today, has a potential therapeutic value in psychiatric diseases as well as in other medical fields. However, there is a need for scientific studies that will enlighten the mechanisms of action of cannabis and demonstrate its potential therapeutic value and side effects on an evidence-based basis in order to re-enter the field of cannabis and its derivatives into drug codices. For these studies, first of all, legal and bureaucratic obstacles to scientific research should be removed. While conducting these studies, on the other hand, the public should be educated about the addictive potential of cannabis and other important drawbacks and misunderstandings regarding the fact that cannabis is a “harmless herbal medicine” should be prevented.
THC, the main component of marijuana, is a fat-soluble substance and quickly passes to the brain and other organs. THC alters the activity of CB1 and CB2 cannabinoid receptors on nerve cells, on which endogenous cannabinoid substances (endocannabinoids) in the body also affect. The endogenous cannabinoid system is thought to play a role mainly in brain neuromodulation. After the endocannabinoid precursors are synthesized from the membranes of postsynaptic neurons, the glutamate, dopamine, and Gamma-aminobutyric acid (GABA) it is on become active due to the activation of the cell.
Potential Medical Effects of Cannabis
The euphoric (pleasure) effect of cannabis has been known for thousands of years. In the writings of the Chinese Emperor Shen Nung dated 2737 BC, cannabis tea was suggested as a medicine for rheumatism, gout, malaria, and memory disorders; It has been noted that too much consumption causes impotence, blindness, and “seeing demons”. In the medical field, cannabis was used in the 19th and 20th centuries for its pain-relieving and sleep-inducing effects. Various sources mention that cannabis was recommended as a drug in the years of the First World War for complaints such as headache, stagnation, loss of appetite, and some bleeding and epilepsy. Cannabis has been proposed for painless birth in the last century.
French doctor Louis Aubert-Roche observed in medical observations in North Africa that Egyptians using marijuana were less susceptible to diseases such as plague and typhoid affecting Europe, and in his book published in 1840, he recommended cannabis to treat the symptoms of plague and typhoid. In 1890, Queen Victoria’s physician, Sir John Russell Reynolds, reported that cannabis was “the most useful drug in the treatment of painful diseases such as dysmenorrhea, migraine, neuralgia, as well as convulsions and insomnia.” Sir William Osler, known as the father of modern medicine, used the phrase “The best cure for migraine” for cannabis in his medical textbook written in 1915.
Cannabis use in pain management is a frequently used “self-medication” option among patients who have to live with chronic pain. Although the exact mechanism of the pain-relieving action of cannabinoids is not known, there is preliminary evidence that these substances are safe and effective for the treatment of neuropathic pain (especially fibromyalgia and rheumatoid arthritis). It is thought that THC produces mild and moderate analgesic effects by changing the release of neurotransmitters in the dorsal root ganglia and periaqueductal gray areas of the spinal cord. In the systematic analysis of randomized controlled trials using blood-cannabinoids in the treatment of non-cancer chronic pain, cannabinoids have been reported to exert a significant analgesic effect compared to placebo, and even improve sleep disorders.
Cannabinoids are also used by cancer patients for their anti-nausea due to chemotherapy, as well as their pain-inhibiting and appetite-enhancing effects. Similarly, publications have been made that it can be used as an anti-nausea and appetite enhancer in diseases with no definitive treatment such as AIDS. Current treatments for multiple sclerosis (MS), the demyelinating disease of the central nervous system, are ineffective in some patients or lead to serious side effects. It has been suggested that cannabis may be useful in the treatment of conditions such as spasticity, pain, tremors, and bladder dysfunction in MS. In the USA, two synthetic drugs, the main active ingredient of cannabis Δ9-THC derivative, are in medical use: Dronabi-nol (Merinol®) and nabilone (Cesamet®).
These drugs may be prescribed to treat nausea and vomiting caused by chemotherapy in patients who do not respond adequately to conventional antiemetic treatments. In a randomized, double-blind, placebo-controlled clinical study conducted in individuals with Acquired Immune Deficiency Syndrome (AIDS), the appetite-stimulating effect of dronabinol measured with a visual analog scale at doses varying between 2.5-20 mg/day was found to be statistically significant. In the same study, decreased nausea and improvement in body weight and affect were reported. The issue that cannabis can medically be a safe and effective treatment for cancer and AIDS, as well as multiple sclerosis, pain, glaucoma, epilepsy, and some other diseases, has aroused the interest of both scientists and patients.
Psychiatric Disorders and Cannabis
An important issue that should not be forgotten when discussing the medical use of cannabis is the high prevalence of psychiatric disorders among people using cannabis. According to a national survey (NDSHS) conducted in Australia in 2004, psychiatric disorders were observed in 11% and 14% of cannabis-free men and women, while 21% and 29% of men and women with active cannabis use had a mental health disorder. In DSM-IV-TR, 8 psychopathological conditions caused by cannabis as the main responsible substance were reported. The cases of cannabis poisoning (toxication) and withdrawal associated with cannabis use are generally regarded as undisputed.
The issue of marijuana addiction is still controversial. Besides these direct causes of cannabis, it is thought that it may worsen pre-existing psychiatric disorders (panic, depression, psychosis) or cause the emergence of a disease that has not yet emerged. Johns et al. Reported a longer duration of cannabis poisoning in people diagnosed with schizophrenia or personality disorder. Although it has been reported that cannabis is used for “self-treatment” in anxiety disorders, there are no studies showing that cannabis can be used as an anxiolytic.
All of these studies point out that cannabis, even if it does not directly lead to a psychiatric disorder, may cause more disorders in some susceptible individuals with a family history of psychiatric history. In addition to these warnings, the THC content in the genetically modified cannabis plant has significantly increased from 1-5% to 10-15% since the late 1960s. This increase may cause cannabis to have more effect, to have more pronounced psychiatric effects, and to increase cannabis addiction.
Use of Cannabis in Psychiatric Diseases
Whether cannabis is an effective treatment for psychiatric diseases such as depression, bipolar disorders, anxiety, and similar mood disorders as well as its use in biological diseases is a matter of debate. Some depressed patients claim that thanks to cannabis use, their mood improves, they become connected to life, they start walking and cycling, they have regular meals and sleep, and are able to do things they had never thought of doing in a depressed state. In the Medical Cannabis Handbook, the first edition of which was published in 1997, it was mentioned that cannabis has the feature of “fighting against depression”.
In a study published by Denson in 2006, among 4400 adults who answered questions on the internet, those who regularly used cannabis reported less depressive mood and more positive affect than non-users. In a study conducted among AIDS patients, more than half of the patients using cannabis reported that cannabis has positive effects on anxiety, depression, pain, and appetite, improving their health status and general well-being. Some women have also been reported using cannabis to improve their symptoms in premenstrual syndrome (PMS).
Many anecdotal reports similar to these and the experiences of doctors from their patients indicate that cannabis (and its active ingredient THC) may also be potential uses in psychiatric diseases. In some publications, it has been reported that cannabis may be beneficial in improving symptoms or reducing the side effects of drugs in some patients who do not benefit from conventional treatment. Besides these, another important point that has been advocated is that it may be possible to reduce or eliminate the use of opiates, stimulants (Ritalin), tranquilizers, sleeping pills, antidepressants, and other psychiatric drugs with the use of medical marijuana. However, sufficient and controlled studies have not been conducted on any of these issues yet.
Psychiatric Disorders That Cannabis Can Treat
- Mood Disorders
It is also argued that cannabis use may have a mood-improving effect. The first publication referred to in this regard is the report of the Cannabis Committee, formed in 1944 by the Mayor of New York, LaGuardia, from doctors who were members of the AMA. According to this report, cannabis can be used in two main therapeutic applications. The first of these is the treatment of various types of depression, the second is the appetite enhancing effect, which is quite different and interesting.
Considering that the main effects of antidepressant drugs currently used in the treatment of depression are to increase serotonin neurotransmission, increase the tonic activity of hippocampal 5-HT1A receptors, stimulate neurogenesis, and modulate (decrease or increase) the firing activity of noradrenergic neurons, it is interesting that cannabinoid agonists. Similarly, endocannabinoid enhancers have been shown to increase serotonin release and noradrenergic neuron activity in the hippocampus, and also support neurogenesis.
On the other hand, when CB1 cannabinoid receptors, which are commonly found in brain regions associated with emotional regulation and stress response, were genetically eliminated in mice, they resulted in increased anxiety behavior, while the use of selective CB1 endocannabinoid receptor antagonist rimonabant in humans led to increased anxiety and suicide. Although a “state of well-being and recovery” has been reported after cannabis use in depressed people, the general loss of motivation and decrease in productivity suggests that this “well-being” state may be an illusion. Although there are not yet well designed, controlled clinical studies in the medical literature, these observations suggest that cannabis or CB1 endocannabinoid receptor agonists may provide some benefit in the treatment of depression.
Cannabis use is quite common in bipolar disorder (BD), another mood disorder. Dr. Grins-poon, Professor of Psychiatry at Harvard Medical School, stated in his book (Marijuana: Forbidden Drug) published in 1997 that 30-40% of patients with bipolar disorder do not benefit from traditional treatment; He wrote that cannabis may be useful in improving symptoms or reducing lithium side effects in these patients. Although some patients with a diagnosis of bipolar disorder insist that some BD symptoms improve with cannabis use, the literature reports that cannabis use causes manic symptoms in BD and may trigger the formation of BD in sensitive individuals. A relationship has been observed between cannabis use and the duration of the manic state. While using cannabis at an early age increases the risk of bipolar disorder, lifetime use of cannabis increases the risk of getting bipolar disorder five-fold.
- Anxiety Disorders
Anxiety and panic attacks are the most common acute symptoms associated with cannabis use. However, contrary to expectations, increased use of cannabis is frequently observed in patients with anxiety disorders. It has been suggested that long-term cannabis use increases the risk of developing anxiety disorders as well as other psychiatric disorders. Cannabinoid-induced anxiety responses are thought to produce different anxiety responses according to the sensitivity of cannabinoid receptors in GABAergic and glutamate neurons. Cannabis use is also common in Post Traumatic Stress Disorder (PTSD) patients, and some patients argue that cannabis has effects on reducing PTSD symptoms.
Female patients diagnosed with PTSD due to sexual trauma reported that cannabis use shortened the time to fall asleep, increased sleep hours, and most importantly, the frequency of trauma-related blackouts decreased significantly. Recently, a group of researchers applied to examine the safety and efficacy of 5 different doses of cannabis in patients with PTSD resistant to drug therapy or psychotherapy. However, the FDA halted the clinical study due to various problems with the protocol design. Although it has been reported that cannabis is used for “self-treatment” in anxiety disorders, there are still no reliable clinical studies showing that cannabis can be used as an anxiolytic or anxiogenic.
The activity of cannabinoid receptors on nerve cells can also be altered by the inhibition of fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL) enzymes that terminate the action of endogenous cannabinoids. Endocannabinoid catabolic enzyme inhibition has been reported to exert anxiolytic-like effects in rats by increasing brain levels of endogenous cannabinoids. Interestingly, catabolic enzyme inhibition did not cause changes in locomotor behavior compared to rats receiving THC directly, which is evidence that this enzyme inhibition did not sedate while treating anxiety. Thus, catabolic enzyme inhibition could be a potential target in the treatment of anxiety disorders.
- Sleeping disorders
Frequently encountered sleep disorders in the clinic are observed as highly comorbid with psychiatric disorders. Daily cannabis users argue that cannabis is also effective in sleep disorders and has far fewer side effects than other drugs. In a study conducted in Canada, in a group of fibromyalgia patients with a sleep disorder, synthetic THC nabilone (0.5-1.0 mg) was tried alternately with amitriptyline (10-20 mg), and although sleep improved in both groups, nabilone was more effective and has been reported to cause fewer side effects.
The authors suggest that low-dose nabilone may be considered as an alternative to amitriptyline in sleep disorders due to painful illnesses. On the other hand, it was found that the rate of sleep disorders after quitting cannabis was high (32%) in cannabis addicts. The most common sleep problems are reduced sleep time, delayed falling asleep, and slow-wave sleep. However, it should be kept in mind that the use of cannabis as a drug for sleep disorders may increase the risk of cannabis addiction in patients as both positive and negative reinforcers.
- Psychotic Disorders
Cannabis psychosis, a known feature of cannabis for a long time, has recently come to the fore with the claim that this psychosis can turn into schizophrenia. Some researchers, who reported that schizophrenia symptoms started at an earlier age in schizophrenia patients using cannabis, argued that schizophrenia started to be seen more with the increase of cannabis use in young people. However, it was found in the screenings that the overall incidence of schizophrenia did not increase or even decreased in the last 30 years.
Another theory that points out that psychosis may turn into schizophrenia states that cannabis use may reveal schizophrenia symptoms at an earlier age and therefore cannabis may cause schizophrenia with a worse prognosis. Since cannabis increases dopamine release, the relapse rate may increase even more in schizophrenics using cannabis. Similarly, although long-term cannabis use has been reported to increase the risk of depression and suicide, many authorities consider cannabis use and genetic and environmental-flooding factors to be common, rather than direct cause-and-effect relationships.
Recent studies have clearly demonstrated that cannabinoids can produce transient symptoms similar to schizophrenia in healthy individuals and may increase symptoms in schizophrenia patients. In a study conducted by Yale University researchers, 0 mg, 2.5 mg, and 5 mg of THC was administered intravenously to normal subjects and 13 stable schizophrenia patients receiving antipsychotic therapy, and both groups were clinically affected in the positive and negative symptoms scale (PANSS) in addition to the increase in cognitive impairment, significant increases were detected. These results show that cannabis increases the symptoms of the disease in individuals with a known psychotic disorder and has negative effects on the course of the disease.
- Attention Deficit and Hyperactivity Disorder
There are some clinical observations that marijuana use reduces the symptoms of attention deficit and hyperactivity disorder (ADHD) in some children and adults. Lester Grinspoon, a retired Harvard Medical School professor of psychiatry and cannabis activist, author of the book “Marijuana: The Forbidden Drug”, claims that cannabis is more effective than traditional treatments for some children.
In California, some children as well as adults with ADHD have been reported to be treated with cannabis. Accordingly, cannabis slows down fast thoughts in ADHD that make it difficult to focus. Another important point claimed is that the potential dangers of cannabis are less than stimulant drugs such as methylphenidate and amphetamine used in ADHD treatment. However, there are no credible studies in the medical literature showing how cannabis affects ADHD symptoms.
In recent years, there has been a decrease in the age of first use of cannabis, and with it an increase in prevalence with continued use of cannabis among young people. Animal and human studies show that the effects of cannabis use on cognitive development depend on the age at which cannabis use begins. Chronic cannabis use hinders further personal and professional education. Biologically speaking, cannabis use in the maturing brain during critical developmental periods can cause permanent changes in brain structure and brain function. Therefore, the effects of frequent cannabis use during adolescence may be more severe than for adult users.
- Substance Abuse
Cannabis was featured as a treatment for standard delirium tremens in some medical texts published in the USA in the 19th century. However, cannabis use in alcohol withdrawal has not become widespread due to its limited impact and negative evaluations. Some researchers have suggested that blood-cannabinoids act as neuronal damage protectors in different models, and thus have argued that cannabis may have benefits in excitotoxicity after alcohol withdrawal. In an in vitro study examining this neuronal damage protective effect of cannabis, HU-210, a blood-cannabinoid agonist, has been shown to reduce N-methyl-D-aspartate (NMDA) mediated neuronal deaths due to ethanol deprivation.
This protective effect is thought to be due to the reduction of NMDA-mediated excess calcium influx into the cell by cannabis agonist administration. In the same study, it was shown that inhibition of the cannabinoid system with the CB1 receptor antagonist rimonabant increased NMDA-mediated toxicity in alcohol-deficient neurons. These results show that endocannabinoid system stimulation is protective against hyperexcitability developing during alcohol withdrawal.
Structural brain abnormalities were frequently observed in adolescents with alcohol use disorder, but in a brain imaging study conducted in 2009, more intense neuropathology was observed in heavy alcohol drinkers compared to control, and brain structures very close to control roles were observed in alcohol and heavy marijuana users. It has been claimed that this unexpected situation observed in those who use alcohol and cannabis together occurs because cannabis has a neuronal damage protective effect by preventing alcohol-induced oxidative stress or excitotoxic cell death.
The effects of cannabis on reducing opioid withdrawal symptoms are also known. Ramesh et al. Demonstrated that naloxone-induced opioid withdrawal symptoms in morphine-dependent mice were reduced by increasing (by catabolic enzyme blockade) levels of endogenous cannabinoids AEA or 2-AG. These results show that endocannabinoid catabolic enzymes may be a promising method in opioid addiction treatment.
Medical Cannabis Research
Medical marijuana is defined as the use of synthetic forms of cannabis and cannabinoids in certain diseases as a form of treatment recommended by a doctor. Although unbiased scientific studies that demonstrate the potential therapeutic value and side effects of cannabis on an evidence-based basis are not yet available, many scientific and medical institutions support scientific studies on medical cannabis. The American Medical Association (AMA) states in the medical marijuana report published in 1996 that alternative treatment methods in the effective patient care should be freely discussed between the patient and the doctor and that these treatments should not have criminal sanctions for both parties.
Similarly, another medical association, the American College of Physicians, wanted to investigate the medical use of cannabis by reviewing all evidence-based potential benefits of cannabis, first removing cannabis from the Schedule 1 group, followed by efficacy and optimal for the proposed medical conditions. They want to dose studies to begin. However, many legal regulations are needed in order to conduct clinical studies with a substance whose possession and use is a crime.
Many groups working for the legalization of cannabis advocate the idea that “each person can decide on his own health” rather than the medical effects of cannabis, and try to decriminalize cannabis use as much as possible. According to them, the implementation of very strict drug policies for minor crimes resulted in the imprisonment of thousands of people and the loss of control of these substances. With this in mind, the Dutch government has allowed the sale of cannabis – regardless of the need for medical use – in controlled settings called “coffee shops”. In the United States, however, there is an interesting situation: According to the Food and Drug Administration (FDA), cannabis has no recognized medical use and thus possession of cannabis is still a federal crime.
Nevertheless, some states may allow limited use of cannabis for medical purposes with their special laws. For example, according to the Medical Marijuana Act of the State of Rhode Island in 2006, patients/persons who received a form from their physician saying “The potential benefits of marijuana use outweigh the risks”, a special ID card and with this card the right to keep 2.5 ounces (70 grams) cannabis and to grow 12 cannabis plants is granted. Those who do not want to cultivate cannabis themselves can buy cannabis by showing their cards from Compassionate Care Centers, which are also created through the state. In the law, certain medical diseases (cancer, glaucoma, AIDS, Hepatitis C, epilepsy) and other chronic diseases are is also indicated as a debilitating illness or medical condition (extreme nausea, cachexia, chronic pain, muscle spasms, and Alzheimer’s agitation).
Although psychiatric disorders are not included in this list yet, it has been reported that “some other conditions” can be accepted with the approval of the state Ministry of Health with an article added to the law. Colorado, which is among the states that legally allow marijuana possession for medical use, legalized cannabis in 2000. According to the law, the groups of patients who can use medical marijuana are defined as cancer, glaucoma, HIV / AIDS, and multiple sclerosis. In addition, people were allowed to possess and use cannabis on the recommendation of any physician for “severe nausea”, “severe pain” and “debilitating medical conditions”. Colorado has adopted the “caregiver model” for the proper use of medicinal cannabis. Accordingly, each patient can grow 6 plants for their use, as well as provide cannabis for 5 additional patients. The aim is to prevent people who grow cannabis from moving away from the “medical” purpose and making profits.
From 2000 to 2007, approximately 2,000 patients were enrolled in the program. However, in 2007, a state court ruled that the per capita limit of “5 patients” was unconstitutional. In the following two years, more than 100,000 Colorado people applied for medical marijuana patient cards to the program that opened it this way, and more than 1,000 dispensaries were opened in the state to meet this intense demand. However, while only 3% of patients enrolled in the Colorado Department of Health for medical cannabis use cannabis for cancer and HIV / AIDS, 94% received a permit for cannabis use with an uncertain diagnosis of “severe pain”. Across the state, three out of four people who use medical marijuana are under the age of 40, according to information that exacerbates this fearful picture. Considering that dispensaries’ bedside earnings are around $ 5,000 a year and a good dispensary has several hundred regular customers, it is obvious that cannabis has turned into a large-money trade under the name of “medical use”.
According to an article published in Time magazine, cannabis is the most money-making agricultural product in the United States. Considering that an ounce (~ 28 grams) of cannabis, which is 22 million pounds of cannabis distributed nationwide, is $ 100, the annual gain is estimated at $ 35.8 billion. Although the vast majority of Americans are against drugs, they have supported the proposal for medical cannabis, which is presented in surveys as an “alternative pain reliever for patients”, and politicians have invested in these “easy to earn” issues.
Authorities dealing with substance abuse claim that the practice of medical marijuana is a delusion of this big money-laden industry. According to them, the drug dealers in the streets were replaced by “caregivers”. Cannabis, which is a drug substance, is defined as “medicine”, and addicts using drugs are defined as “patients” and using drugs is defined as a kind of “receiving treatment”. With these distortions of meaning, cannabis is tried to be presented to the public as a “harmless herbal medicine”.
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