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Official websites use. Share sensitive information only on official, secure websites. Corresponding author. E-mail address: Marta. Di Forti. This is an open access article distributed under the Creative Commons Attribution License 4. The spread of laws legalising cannabis for medicinal or recreational use has been accompanied by more relaxed attitudes towards cannabis. Data from the United States show that in states that have legalised cannabis, prevalence of daily, weekly, and monthly cannabis use was CBD does not induce euphoria but may exert anxiolytic, antiepileptic, anti-inflammatory, and analgesic properties Figure 1. This diagram graphically illustrated first, the differential and in fact opposite psychiatric and cognitive effects of THC and of CBD, and second, how both compounds derive from the same precursor. Therefore if, for instance, a Cannabis sativa plant is genetically driven to the production of high quantity of THC, it will only be capable to synthesise small quantities of CBD. Nevertheless, discontinuation of long-term frequent cannabis use can induce anger, decreased appetite, irritability, nervousness, restlessness, and sleep difficulties, 13 , 79 suggesting that the alleviation of abstinence symptoms contributes to the maintenance of daily cannabis use. Cross-sectional and prospective studies demonstrate a causal link between cannabis use and psychotic disorder, with greater risk for cannabis users, compared to nonusers. A meta-analysis by Large et al. Another study showed that if subjects had used high-potency cannabis daily, their illness onset was, on average, 6 years earlier 31 compared to never users. Boydell et al. The first, clear evidence of the impact of cannabis use on rates of psychotic disorder comes from the EUGEI study. Further independent evidence comes from Portugal that has registered a steady increase in the rate of hospital admissions for psychotic disorders with comorbid CUD. The self-medication hypothesis suggests that patients with psychotic disorders use cannabis to seek relief from their symptoms. More recently, Mendelian randomization investigated the relationship between cannabis use and randomly assorted genetic variants that are associated with psychosis, which were used as proxy for psychosis itself. Mendelian randomization studies have suggested that cannabis use initiation is partly explained by common genetic variants associated with risk of schizophrenia, thus proposing a direction of causality from schizophrenia genes to cannabis use ie, reverse causality rather than from cannabis use to schizophrenia and other psychosis. On the contrary, heavy cannabis use increased the risk for psychotic disorders independent of the individual's schizophrenia PRS. A meta-analysis indicates that patients with a psychotic disorder who continue to use cannabis after their illness onset experience a worse clinical and functional outcome than those who stop. Some evidence begin to suggest that individuals at ultra-high risk for psychosis have higher rates of CUDs 14 and, conversely, patients with CUDs are more likely to transition to psychosis. This is often considered a limitation. Nevertheless, although biological measures can provide valid and reliable measures of current use, they cannot provide data on use over time. Indeed, studies that analysed both self-reported information and laboratory data indicated that cannabis users are reliable in reporting how frequently they use and the type they used. Administration of cannabis and THC has shown to precipitate, with a dose—response relationship, the onset of transient positive psychotic symptoms eg, ideas of reference, paranoid delusions, hallucinations, depersonalization, or derealization and, to a less extent, negative symptoms eg, blunted affect in healthy volunteers and to temporary exacerbated psychotic symptoms in schizophrenia patients. The Dunedin study was the first to indicate adolescents as a group particularly vulnerable to the psychotogenic effect of cannabis use. Subjects with a family history of psychotic disorders have a greater sensitivity to the psychotogenic effect of cannabis 66 and if they develop a cannabis-induced psychotic disorder, they are more likely to transition to schizophrenia. Another potentially vulnerable population might be represented by individuals exposed to childhood adversity, which may enhance the psychotogenic effect of cannabis, through sensitization. Several studies observed that the joined effect of early trauma and cannabis use on psychosis was greater than their independent effect, 54 , 62 , 63 , 70 but the findings were not fully consistent. Two meta-analyses 47 , described a modest residual cannabis-related impairment in measures of both overall and specific cognitive functions after 12 hours to 25 days of abstinence, with no residual cognitive impairment after 25 days of abstinence. In young adults, chronic cannabis use most commonly affects immediate recall and verbal reasoning 12 , 38 , but not spatial working memory; however, the latter is affected in adolescents, 55 suggestive of a differential effect on the developing brain. Both in adolescents and adult users, attention is impaired during cannabis intoxication and persists for several weeks. Regular cannabis use is associated with lack of motivation for naturally rewarding activities, which is a core feature of depressive disorders. Evidence for a weaker association between cannabis use and anxiety disorders comes from a meta-analysis, estimating ORs from 1. All prescribed and recreational drugs have adverse effects, even those coming from plants, fruits, and flowers as we have learnt from the use of tobacco, alcohol, and opium. Cannabis is not an exception Tables 1 and 2. Therefore, at a time of changes in the laws concerning cannabis use, it is of clinical and public health importance to provide evidence-based and clear information on what we know concerning 1 the acute and persistent adverse effects and 2 how to screen for those individuals more susceptible to experience them when cannabis is used recreationally or medicinally. This table illustrates the findings from meta-analyses that report an association between several mental health outcomes, cognition, and cannabis use. Summary of the mental health and cognitive acute and persistent adverse effects associated with cannabis use. Di Forti reports personal fees from Janssen, outside the submitted work. The remaining authors have no conflict of interest to declare. Sponsorships or competing interests that may be relevant to content are disclosed at the end of this article. As a library, NLM provides access to scientific literature. Find articles by Lucia Sideli. Find articles by Giulia Trotta. Find articles by Edoardo Spinazzola. Find articles by Caterina La Cascia. Find articles by Marta Di Forti. Published by Wolters Kluwer Health, Inc. Open in a new tab. Summary of meta-analyses reporting adverse effects associated with cannabis use. Family history of psychosis 2. High polygenic risk score for schizophrenia 3. Dose—response relationship with THC content high-potency cannabis and daily use 2. Similar articles. Add to Collections. Create a new collection. Add to an existing collection. Choose a collection Unable to load your collection due to an error Please try again. Add Cancel. Marconi et al. High levels of cannabis use increase the risk of psychotic outcomes with a dose—response relationship. Large et al. Relationship between cannabis use and earlier onset of psychotic illness. Schoeler et al. Continued cannabis use after onset of psychosis predicts adverse outcome than for nonusers. Gibbs et al. Association between cannabis use and both the exacerbation of manic symptoms in those with previously diagnosed bipolar disorder and new-onset manic symptoms. Gobbi et al. Cannabis consumption in adolescence is associated with increased risk of developing depression in young adulthood. Lev-Ran et al. Heavy cannabis use may be associated with an increased risk for developing depressive disorders. Twomey et al. Cannabis use is no more than a minor risk factor for the development of elevated anxiety symptoms in the general population. Grant et al. There might be decrements in the ability to learn and remember new information in chronic users, whereas other cognitive abilities are unaffected. Schreiner et al. A small negative residual effect of cannabis use on overall cognitive performance, no evidence of lasting residual effect.

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Based on current literature and trends of increasing cannabis potency, we postulate that most medical cannabis products with THC and CBD have ratios capable of producing significant acute intoxication and are similar to recreational products. We will test this by organizing products into clinically distinct categories according to TCH:CBD ratios, evaluating the data in terms of therapeutic potential, and comparing the data obtained from medical and recreational programs and from states with differing market policies. Methods: We utilized data encompassing online herbal dispensary product offerings from nine U. Results: A significant number of products These results were consistent, regardless of differing market policies in place. Conclusions: Despite the distinct goals of medical and recreational cannabis users, medical and recreational program product offerings are nearly identical. Patients seeking therapeutic benefits from herbal cannabis products are therefore at a substantial risk of unwanted side effects, regardless of whether they obtain products from medical or recreational programs. Efforts are needed to better inform patients of the risks associated with high potency cannabis and the interaction between THC and CBD, and to help shape policies that promote more therapeutic options. The pharmacologic effects they each exude are quite distinct. For instance, CBD does not produce acute intoxication, has been proven to treat refractory epileptic syndromes in children, and may have anti-inflammatory, anxiolytic, and antipsychotic indications Zuardi et al. Yet, there is currently no substantial evidence that CBD alone has analgesic efficacy in humans—the primary indication for which patients seek out cannabis in the United States U. Boehnke et al. On the other hand, THC produces the acute intoxication associated with cannabis and has been linked to multiple undesirable effects, such as paranoia, memory impairment, increased risk for psychotic illness, and cannabis dependency and the development of cannabis use disorder CUD Di Forti et al. Notably though, THC has shown promising analgesic efficacy Abrams et al. Furthermore, adverse event potential and subsequent treatment discontinuation seems to increase at higher THC concentrations utilized in these studies. This parallel between THC concentration and intoxication and adverse event potential is increasingly becoming an issue as the potency of cannabis available rises ElSohly et al. As a result, a difficult balancing act between analgesia and acute intoxication ensues. This discrepancy between the goals of medical and recreational products presumably should be reflected in the potency of the products each type of market offers. However, our previous findings demonstrated that average THC concentrations advertised online in medical programs are similar to those in recreational programs Cash et al. Moreover, frequent medical cannabis users prefer inhaled cannabis with high levels of THC Boehnke et al. The accessibility of high potency products could create a misconception about the safety of cannabis and downplay the risks and side effects associated with products containing high THC concentrations. It also leaves patients looking to use cannabis for medical purposes with mostly products outside the realm of what is considered potentially suitable for therapeutic purposes Romero-Sandoval et al. This sentiment is strongly supported by the International Association for the Study of Pain IASP , which recently released a report which concluded that much more research is needed to determine the benefits and risks of cannabis for the treatment of pain before there is a chance cannabis can be endorsed for such usage IASP Presidential Task Force on Cannabis and Cannabinoid Analgesia, While these previous findings are certainly alarming, they only show a partial picture of the cannabis products offered in legal U. It is therefore important to determine whether the products available in dispensaries are pharmacologically safe for patients medicinal or the general public adult use or recreational , not only by means of THC concentrations, but also CBD concentrations and the ratio of THC:CBD. Our previous findings clearly show that when analyzing the types of products offered in legal cannabis markets based solely on THC, the majority of products contain levels not recommended i. We identified some products that are more pharmacologically amenable to medical purposes, based on their THC levels i. In other words, it is clinically relevant to garner whether or not the existing products contain these two cannabinoids at concentrations and ratios that are suitable for patients. This study subsequently will test this hypothesis following these aims: 1 identify and categorize the THC:CBD ratios associated with different clinically meaningful pharmacologic effects when administered in conjunction via inhalation, 2 characterize the cannabis products available online within the determined ratio categories, 3 evaluate whether the probable pharmacologic effects of products labeled as recreational differ from the probable effects of products labeled as medical, and 4 determine if varying types of market structures e. We utilized the publicly available data set from our previously published study Cash et al. The data sampling included online dispensary product offerings from nine U. At the time of sampling, all of the Northeastern states as well as NM had legalized only the medical use of cannabis, and CA, CO, and WA had legalized cannabis for both medical and recreational use. Additionally, medical and recreational products were offered in separate facilities in WA, while both medical and recreational products were allowed to be offered in the same building in CO, and products were not differentiated medical or recreational in CA. Inhaled cannabis has a more favorable pharmacokinetic profile than other routes of administration and has shown analgesic efficacy for various chronic pain conditions, the most common reason cited for seeking out medical marijuana in the U. Wilsey et al. Herbal products flowers and pre-rolls were therefore the focus of the sampling. While further investigation into concomitant administration of THC and CBD, their pharmacological interaction, and the resulting effects is certainly needed, this theme remained consistent throughout a thorough review of the literature Pennypacker and Romero-Sandoval, Mean and standard deviation analysis was performed for each state and for distinct medical and recreational program comparisons. We found that most of these products, Of the 3, products with CBD content information Proportion of products by CBD content information provided per state. Total products sampled per state listed below each graph. We noticed that not all evaluated states offered products belonging to all four THC:CBD categories we consider clinically meaningful. Total products per state listed below each graph. They reveal current product offerings do not reflect scientific evidence regarding what concentrations of THC and CBD could be potentially therapeutic. It is notable that products with lower THC, considered suitable for medical purposes, might in fact not have significant analgesic value Dalton et al. This leaves patients with mostly highly intoxicating options. Moreover, these findings are consistent across both medicinal and recreational programs, and in markets that offer both medical and recreational products e. These findings also remain true regardless of whether they coexist in the same building e. This could potentially lead to unwanted side effects as patients do not have all the information on the drug they are taking. This theme can be helpful to note, especially for the significant number of products that do not offer information on CBD content. There are a few product exceptions in Washington medical and Colorado medical programs where there is more variation in CBD content, even in the high potency products. While there are certainly not enough of these outlying products to change the overall market makeup, this variation seems to indicate that medical programs recognize a demand for products different than those in the recreational market. Still, based on the literature, these products with high potency THC and high CBD concentrations likely produce significant unwanted psychotropic effects and can be harmful to patients seeking chronic pain relief Wilsey et al. Beyond recent research demonstrating the effects of cannabis constituents, the momentum of current policy trends elicits a pressing need to understand the clinical therapeutic value of the cannabis available in the emerging market. As of February , 37 states have legalized the medical usage of cannabis, and 18 states and Washington, D. Meanwhile, the rise of the opioid epidemic in U. Cannabis is advantageously place to be, and is often cited as an one of these alternatives Caldera, In fact, presence of medical cannabis programs may be associated with a reduced opioid usage Lucas, In the midst of the U. We understand that our data show advertised products rather than consumer acquired products. However, our data matches the natural supply and demand dynamic of any commodity, for which cannabis is not an exception. Thus, the frequency of products identified in our study in terms of THC and CBD concentrations encompasses the frequency of product sales describe by others Smart et al. Furthermore, our data frequency of potent herbal products align with data on cannabis exposure from the National Poison Data System which shows that exposures more often involves plant material than other processed forms of cannabis products e. Similarly, it is important to note that the data used in this study was collected in Cash et al. This is a limitation of the study as some of the data may have changed. However, the trends on market behavior this paper highlights are still relevant. If there are any pertinent changes, they are likely detrimental as the potency of cannabis has continually been increasing over the past several decades ElSohly et al. These themes are not limited to just the herbal market, but have been reflected in the edible cannabis market as well Steigerwald et al. It is also relevant to highlight the expansion of the CBD product market. We therefore believe that this data is still highly relevant and reflective of the current market overall. In addition to the decreasing ratio recently noted, clinically meaningful options—those that can likely prove beneficial to patients—are offered in all states; they are just in the minority and need to be teased out. The hurdles ahead to salvage the medical cannabis market seem to be in two categories. This will result in a more informed patient population. It can also help sway the demand away from high potency products and reduce incentives for the cannabis market to continually increase the potency of their offerings. Secondly, adequate policies regarding medical cannabis should also reflect the pharmacology and clinical correlates. This can be achieved through several means. By enforcing that products advertised for medical purposes actually have efficacy based on scientific literature, new policies can help expose the medically relevant products and segregate them from the recreational products. This could prove extremely meaningful, as it has been shown that patients regard the information provided by dispensaries as safe and reliable Capler et al. Policies can also highlight the various clinically relevant ratios, fleshing out and offering substantial options in the therapeutically relevant categories. Lastly, policies can recommend dispensing medical products in a stepwise fashion, with the more potent products offered on a more stringent basis, such as after lower potency options proved ineffective for a patient. This can ensure an overall safer market for patients looking to achieve therapeutic benefits from cannabis without the risk of amplifying THC acute effects. Therefore, many of the products marketed for medical purposes are counter indicated pharmacologically and potentially harmful Romero-Sandoval et al. On the other hand, options that are likely the most suitable for therapeutic use are limited, even in medical programs. Ultimately, these results can be used to better inform patient populations and relevant policies and help steer the herbal medical cannabis market to be more reflective of clinical evidence. Publicly available datasets were analyzed in this study. Funding acquisition: ER-S. Methodology: ER-S. Project administration: ER-S. Resources: ER-S. Supervision: ER-S. The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher. Abrams, D. Neurology 68 7 , — Andreae, M. Pain 16 12 , — Arkell, T. Bergamaschi, M. Neuropsychopharmacology 36 6 , — Drug Saf. Boehnke, K. Intern Med. Health Aff. Millwood 38 2 , — Pain 21 , — Caldera, F. Case Rep. Capler, R. Are Dispensaries Indispensable? Drug Policy 47, 1—8. Cash, M. PLoS One 15 3 , e Chandra, S. Psychiatry Clin. Dalton, W. Influence of Cannabidiol on DeltaTetrahydrocannabinol Effects. Davenport, S. Drug Policy 91, Devinsky, O. Di Forti, M. High-potency Cannabis and the Risk of Psychosis. Psychiatry 6 , — Dilley, J. JAMA Netw. Open 4 5 , e Ellis, R. Neuropsychopharmacology 34 3 , — Elsohly, M. Synthetic Cannabinoids: Analysis and Metabolites. Life Sci. ElSohly, M. Psychiatry 79 7 , — Psychiatry Cognitive Neurosci. Neuroimaging 6 6 , — Englund, A. Freeman, T. Addiction 10 , — Grotenhermen, F. Cannabinoids for Therapeutic Use. Drug Deliv. Hall, W. Yale J. PubMed Abstract Google Scholar. Iseger, T. Izzo, A. Trends Pharmacol. Joy, J. Marijuana and Medicine: Assessing the Science Base. Leweke, F. Psychiatry 2, e Lucas, P. Harm Reduct. Pennypacker, S. Pharmacotherapy 40 11 , — Romero-Sandoval, E. Cannabis for Chronic Pain: Challenges and Considerations. Pharmacotherapy 38 6 , — Smart, R. Addiction 12 , — Solowij, N. Steigerwald, S. Pain 4 , — Wallace, M. Pain 16 7 , — Ware, M. Wilsey, B. Pain 14 2 , — Pain 17 9 , — Zuardi, A. Keywords: cannabidiol, tetrahydrocannabinol, marijuana, medical marijuana, herbal cannabis, cannabis market, potency, intoxication. Cannabis Markets Overshoot. The use, distribution or reproduction in other forums is permitted, provided the original author s and the copyright owner s are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. Alfonso Romero-Sandoval, earomero. Disclaimer: All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher. Top bar navigation. About us About us. Sections Sections. About journal About journal. Article types Author guidelines Editor guidelines Publishing fees Submission checklist Contact editorial office. Sarah D. Materials and Methods Data Collection We utilized the publicly available data set from our previously published study Cash et al. Statistical Analysis Mean and standard deviation analysis was performed for each state and for distinct medical and recreational program comparisons.

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