Cannabis produces a variety compounds known as cannabinoids, many of which have not been detected in any other plant. How many, exactly? It's hard to say. A cannabinoid is one of a class of diverse chemical .. the essential oil of cannabis and other medicinal. THC and CBD (along with all the other cannabinoids) work in tandem in what's known as the “entourage effect” to both enhance and calm each.
and Other Cannabinoids THC
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.
Open in a separate window. Chemical structures of deltatetrahydrocannabinol and cannabidiol. Cannabinoid receptor system Another cornerstone in cannabinoid research was the identification of the specific binding sites of dTHC in the brain [ Devane et al. Cannabinoid 1 and 2 receptors CB1Rs are mainly in the brain, particularly in the substantia nigra, the basal ganglia, limbic system, hippocampus and cerebellum, but are also expressed in the peripheral nervous system, liver, thyroid, uterus, bones and testicular tissue [ Russo and Guy, ; Pagotto et al.
Functions of the endocannabinoid receptor system 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.
Cannabis plant The cannabis plant has two main subspecies, Cannabis indica and Cannabis sativa , and they can be differentiated by their different physical characteristics. Deltatetrahydrocannabinol and cannabidiol 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.
Intersubject variation in response to the psychotogenic effects of cannabis About Proposed factors determining sensitivity to psychosis in cannabis users. Sensitivity to psychosis as determined by: Possible sensitivity factors Study group Predisposition to psychosis Family history of psychotic illness McGuire et al. Conclusion 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.
J Psychoactive Drugs Biochem Biophys Res Commun J Clin Pharmacol AKT1 and DAT1 genotype modulates the effects of deltatetrahydrocannabinol on midbrain and striatal function. Mol Psychiatry 31 January epub ahead of print.
Curr Pharm Des Arch Gen Psychiatry J Biol Chem Br J Pharmacol Curr Drug Abuse Rev 5: Eur J Pharmacol Am J Addict Br J Psychiatry Handb Exp Pharmacol Eur Arch Psychiatry Clin Neurosci The State of the Drug Problems in Europe. J Affect Disord J Am Chem Soc Methods Mol Med Drug Alcohol Rev Curr Opin Psychiatry Classification of cannabinoid receptors.
J Pharmacol Exp Ther Neurochem Int 9 December epub ahead of print. Am J Obstet Gynecol A combined neurochemical and behavioral analysis. Chems Phys Lipids The structure of cannabidiol. J Clin Psychopharmacol J Clin Psychiatry Int J Obes Lond Curr Med Chem Cannabinoid receptors and their ligands: Thus, in the Netherlands, the THC content has remained stable during the last 10 years.
This study emphasized the fact that global increases in THC levels and decreases in CBD levels are largely linked to the spread of indoor cultivation practices. On average, cultivars from the Netherlands are twice as potent as imported products.
The high THC concentrations obtained from the various cannabis varieties result from technical advances in production, such as genetic manipulations, cross-breeding, and improvements in indoor hydroponic cultivation. As advanced techniques and more potent seeds have become more widely available, this has contributed to the steadily increasing THC concentrations in cannabis.
These changes may have significant real-world clinical consequences because the chances of detrimental psychological effects seem to increase when cannabis with high concentrations of THC is consumed. THC ratio also appears to be an important factor.
Some data also suggest that the CBD: THC ratio may play a role in the risk of addiction. Synthetic cannabinoids SCs emerged in the s when researchers were first exploring the endocannabinoid system and attempting to develop new treatments for cancer pain. Around the year , SC appeared on the illicit drug market, where their prevalence had long been underestimated. Since then, their place in the market has steadily increased.
More than synthetic psychoactive substances have been identified on the illicit market. There has been a steep rise over the last 5 years with the appearance of new synthetic drugs. Since , more than SCs have been identified in various products, 24 of which appeared in Today, intra-European production is closely monitored. Indeed, each SC is replaced by newer analogs within a year or two. SC use varies a great deal between different countries and populations. Compared with other new drugs on the market, the increase in consumption of SCs was particularly remarkable.
They may also be sold as tablets, capsules, or powders. SCs have different pharmacological properties than cannabis. They also do not contain any CBD whatsoever, contrary to cannabis, where it is present in varying concentrations.
Products of the same brand and sold under the same name have highly variable product compositions and concentrations. Similarly, the pharmacokinetics depends on the administration route. In some cases, the onset of psychoactive effects and physical symptoms begins a few minutes after smoking. Some users have described feeling limited in their movements, whereas no motor deficits are objectively observed.
On average, the effects last for about 6 hours, steadily decreasing until the next day. Almost 30 years ago, Andreasson et al showed an association between cannabis use and the later emergence of schizophrenia. Despite confounding factors, sufficient proof currently exists showing that cannabis use increases the risk of psychotic disorders. Over the last 5 decades, increasing THC concentrations have been observed in products available in many countries. Some studies have indicated that CBD may have antipsychotic properties.
One study has suggested an association between dose and response, showing that daily users of high-dose cannabis begin their first psychotic episode an average of 6 months earlier than those who had never used cannabis. Psychotic patients who continue to use cannabis had a significantly greater number of relapses than patients who had stopped using cannabis or had never used.
Based on studies examining the evolution of THC levels in cannabis over the last few decades, one hypothesis is that previous studies may have underestimated the impact of cannabis on existing psychosis. In fact, ecological proof seems to argue in favor of greater psychosis risk among youths who have recently been exposed to high-dose cannabis than in former generations exposed to lower THC doses.
Such an analysis, however, has yet to be performed. It is too soon to confirm this hypothesis. Current clinical data are insufficient to justify prevention measures concerning cannabis use or restriction of highly concentrated varieties.
Numerous complications have been observed in SC users. Anxious symptoms, such as ruminations, anxiety, and panic attacks, are often seen following SC use.
Sleep disorders, hyperactivity, agitation, and irritability have also been reported. Acute intoxication may be associated with cognitive disorders such as short-term memory loss. There have also been cases of paranoia, flashbacks, and suicidal ideation. Although SCs have a similar mechanism of action to THC, the different pharmacological properties, such as higher affinity for CB1 and CB2 receptors, higher efficacy, as well as the absence of CBD, result in different physiological and toxicological effects, especially concerning its pro-psychotic effects.
The psychotogenic effects of SC are increasingly alarming, with numerous reports of individuals who become psychotic after SC use. Delirious symptoms, acoustico-verbal hallucinations, and dissociative elements have all been described in individuals without a history of psychosis. SCs are potentially addictogenic because these substances can increase dopamine secretion within the nucleus accumbens and the ventral tegmental area.
Intense and severe cravings have also been reported. An increasing number of nonfatal intoxications, as well as deaths, after presentation to the emergency room or in consultation have been reported, especially in young people. THC is the psychoactive principle of cannabis, inducing the cannabis inebriation sought by many users. Its addictive potential and negative consequences are now well known. CBD seems not to induce euphoria and seems to have antipsychotic, anxiolytic, antiepileptic, and anti-inflammatory properties.
According to an evaluation in by the Institute of Medicine in the United States on cannabis as a medication, the future of medical cannabis resides in isolating its cannabinoid components and their synthetic derivatives.
Various forms of cannabis have been studied to ascertain the therapeutic properties of cannabis. It has been approved in several countries Canada, Europe , but not in the United States, as an adjunctive therapy in the treatment of spastic pain in patients with neurological disorders.
A meta-analysis reviewed randomized clinical trials worldwide of medical cannabis and cannabinoids from through The most frequently studied cannabinoid forms were medications produced by pharmaceutical companies: This study included only two trials using plant-based cannabis smoked and vaped. The same level of proof was shown for nabiximols or smoked THC in the treatment of chronic cancer pain and neuropathic pain. This meta-analysis showed that CBD was not significantly more efficient in treating psychosis than a usual antipsychotic, such as amisulpiride, or depression compared with nabiximols.
Finally, one very small crossover trial with six patients was not able to detect an effect of cannabinoids on intraocular pressure. A systematic review by the American Academy of Neurology examined publications from through November concerning the use of cannabinoids in the treatment of multiple sclerosis, movement disorders, and epilepsy. The other formulations seemed to be effective in these indications, but with lower levels of proof.
Proof was insufficient to conclude as to the efficacy of smoked cannabis. In other neurological indications, such as Huntington disease and Tourette syndrome, proofs were judged insufficient. Cannabinoids would seem to have some therapeutic interest in the following indications: However, there are currently insufficient levels of proof. Indeed, a Cochrane review from , for example, concluded that there were insufficient levels of proof for cannabinoids in the treatment of epilepsy.
They remain the subject of preclinical and human research. In animal studies, CBD has shown significant antiepileptic activity, reducing seizure severity. Recent studies in young patients suffering from severe, treatment-resistant epilepsy have shown that CBD may have a specific indication in these forms. Due to its implications in the reward system, endocannabinoid signaling represents a potential therapeutic target in treating addictions. The results from randomized, controlled trials suggest that CB1 receptor agonists such as dronabinol and nabiximols may be effective in treating cannabis withdrawal.
Dronabinol may also decrease opioid withdrawal symptoms. Rimonabant, an inverse agonist of CB1 receptors, has shown promising effects in tobacco cessation; it also causes adverse psychiatric effects.
Few clinical trials have examined the effect of cannabinoids in treating alcohol-use disorder; those examining rimonabant have shown negative results.
Fourteen studies were found, nine in animals and five in humans. Some preclinical studies suggest that CBD may have some therapeutic properties in treating opioid-, cocaine-, and psychostimulant-use disorders.
Some preliminary data suggest that it could be advantageous in treating cannabis and tobacco-use disorder in humans. One randomized, double -blind clinical trial compared the use of CBD versus amisulpride for 4 weeks in, respectively, 20 and 19 patients with psychosis. A potential advantage for CBD is its milder side effects: The understanding of the relationship between sleep and cannabinoids has been obscured by significant methodological differences resulting in mitigated results.
The results from the literature seem to favor a beneficial effect of acute cannabis intoxication on sleep. On the other hand, regular cannabis use seems to have a negative impact on sleep quality. Different cannabinoids seem to have a differential impact on sleep. One study has suggested a therapeutic potential for dronabinol and nabilone on sleep disorders and nightmares. Thus, there is preclinical evidence and some clinical evidence for therapeutic properties regarding a number of diseases.
However, larger controlled clinical trials are needed to show efficacy and safety for each disorder. Cannabis use and its negative consequences have increased over the last several years in parallel with increasing cannabis potencies. SCs seem to be particularly popular among cannabis users.
This emerging market represents a specific public health problem in light of the severe complications in relation to their use. What the risks are of developing a psychotic disorder after SC administration remains a fundamental question. This is an emerging area of research in which more robust epidemiological studies must be developed.
These must provide detailed information concerning not only the quantity and the frequency of cannabis use, but also, and more importantly, the type of cannabis used. The use of SCs must also be more largely examined in light of the severe consequences associated with their use.
The legislative policies that have been established to reduce the risks in relation to cannabis have long represented an obstacle to research concerning medical cannabis use. Improved knowledge of the endocannabinoid system and of exocannabinoids has proven that cannabis may have significant therapeutic effects. Despite sparse research, certain countries, such as the United States, have authorized the use of plant-based medical cannabis.
National Center for Biotechnology Information , U. Journal List Dialogues Clin Neurosci v.
Cannabis, a complex plant: different compounds and different effects on individuals
When a deficiency or other defect occurs, it can often lead to disease. When cannabis is ingested, cannabinoids immediately bind to the endocannabinoid. SCs have different pharmacological properties than cannabis. These molecules are particularly lipophilic and are full agonists of CBD receptor 1 (CB1) and CBD . In this article we first provide an overview of the biochemical basis of cannabis research by examining the different effects of the two main compounds of the.