08/27/24

To Reschedule or “Deschedule” Marijuana?

Photo by Aphiwat chuangchoem: pexels.com

The DOJ and DEA published proposed rules in the U.S. Federal Register to reschedule marijuana from Schedule I to Schedule III. The DOJ was also soliciting comments on the proposal on or before July 22, 2024. Forbes said the proposal initiates a 62-day public comment period, a necessary step in the federal rulemaking process. This action was taken after the Department of Health and Human Services (HHS) recommended the reclassification, stating that marijuana had a currently accepted medical use. But the action won’t legalize marijuana for adult use, which would require it to be completely “descheduled” by the Controlled Substances Act (CSA).

The DEA’s notice indicated that if marijuana is reclassified to Schedule III, the regulatory controls for Schedule III substances, when appropriate, would apply. These controls would include existing marijuana-specific requirements and any additional ones necessary to meet U.S. treaty obligations. The major change for the cannabis industry with the reclassification of marijuana to Schedule III, would allow marijuana businesses to take certain deductions on their federal tax returns.

The manufacture, distribution, dispensing, and possession of marijuana would still be subject to the criminal prohibitions of the CSA. Drugs containing substances defined as “marijuana” under the CSA would also remain subject to the prohibitions in the Federal Food, Drug, and Cosmetic Act.

Writing for Harvard Law, Victoria Litman pointed out that once comments are received, the DEA will review all evidence and generally respond to the comments when publishing the final rule. After publication, the DEA’s final rule will not go into effect for 30 days, during which time parties who submitted comments, and can demonstrate they have a standing, could challenge the final rule in court. SAM, Smart Approaches to Marijuana, is already soliciting funds for their “Rescheduling Legal Defense Fund.”

Litman thought there are two primary issues that will be challenged. First is the impact of rescheduling on U.S. adherence to United Nations treaty obligations. Second, was the way HHS determined that marijuana has a currently accepted medical use (CAMU). She pointed out how rescheduling would not resolve all the challenges faced by legal state marijuana businesses and wouldn’t necessarily make research easier.

Additionally, U.S. Senators Elizabeth Warren and John Fetterman have sent a letter to the DOJ and DEA urging that marijuana be descheduled altogether from the CSA. In their letter they said the case for removing marijuana from Schedule I was overwhelming. However, they thought the DEA should remove cannabis from the CSA altogether:

Although HHS recommended rescheduling, its analysis could support a decision to deschedule— particularly its emphasis on the fact that marijuana has less adverse outcomes (including less potential of an overdose) and less potential of abuse than substances that are descheduled (alcohol) or scheduled below Schedule III (such as benzodiazepines).

While there would be important policy benefits including the first federal acknowledgement of marijuana’s medical uses, “it would not automatically permit marijuana to be used as a medicine.” Marijuana as an approved medicine would still need to have FDA drug approval, DEA registration for manufacturers, “and compliance with prescription regulations in order to be legally prescribed under federal law.” Furthermore, the criminal penalties for marijuana would continue as long as marijuana remained in the CSA. They concluded the DEA had never kept a drug in Schedule I after HHS recommended removing it.

A History of the FDA and Drug Regulation in the U.S. said the original Food and Drug Act was passed in 1906. The Federal Food, Drug and Cometic Act of 1938 required new drugs demonstrate their safety before selling them. The Controlled Substances Act was part of the Comprehensive Drug Abuse Prevention Act of 1970. It combined existing federal drug laws and expanded their scope, including federal law enforcement pertaining to controlled substances. It is the primary legislation for drug control in the U.S., and has been amended several times. Warren and Fetterman said:

It is imperative that the DEA remove marijuana from Schedule I as several members of Congress and state attorneys general have urged. The DEA should do so promptly; its past record of taking years to resolve rescheduling petitions should not be repeated here. Furthermore, the DEA and HHS should be fully transparent about the evidence relied upon in the course of their review processes. The Biden Administration has a window of opportunity to deschedule marijuana that has not existed in decades and should reach the right conclusion— consistent with the clear scientific and public health rationale for removing marijuana from Schedule I, and with the imperative to relieve the burden of current federal marijuana policy on ordinary people and small businesses.

Senators Warren and Fetterman don’t seem to think the HHS recommendation to reclassify marijuana from Schedule I to Schedule III goes far enough. They want to see marijuana removed entirely from the CSA. They also think the DEA should make its decision quickly, and not take time to resolve problems raised by the rescheduling petitions, as it has in the past. This raises the question, what’s the rush?

John Fetterman has made the legalization of recreational marijuana part of his political platform from the time he was the Lieutenant Governor of Pennsylvania. He did a Statewide Cannabis Listening Tour in 2019. He also called for PA to go “full Colorado,” meaning approve recreational marijuana. See these articles and others on Fetterman’s endorsement of legalizing recreational marijuana: “From the Frying Pan Into the Fire with Recreational Marijuana In PA” and “Should Pennsylvania Go ‘Full Colorado’ with Marijuana?” Part 1 and Part 2.

Marijuana Moment observed that the director of the Office of National Drug Control Policy (ONDCP) said rescheduling was “going to be really important to remove barriers to critical research and perhaps drug development, and it could also lead to more research into the benefits of medical marijuana.” The historic nature of the proposed actions “Cannot be minimized,” he said. Yet Marijuana Moment thought he overstated what this reform would accomplish. The FDA hasn’t typically approved botanical substances like marijuana as prescription drugs. According to the Congressional Research Service, (CRS) further action from the FDA is needed before marijuana products can become available by prescription.

Without a doubt this is a political issue in a contentious presidential election year, but it’s also a business concern. Flowhub said the cannabis industry was expected to reach $40 billion in 2024, adding $115.2 billion to the economy. There are currently 440,445 full-time equivalent positions supported by legal cannabis. The anticipated financial windfall to the cannabis industry may lead them to minimize or ignore some of the potential repercussions of either rescheduling or descheduling marijuana. Given the “historic nature” with either decision, shouldn’t the DEA carefully consider the impact of the proposed actions?

STAT News said the public health use of marijuana has surpassed what we know about the cannabis plant from research. “We’re really at this point trying to play catch-up.” The complexity of the cannabis plant compared to other medications creates problems for the FDA when deciding how to regulate it.

Cannabis contains over 500 distinct compounds and over 100 different cannabinoids. THC, delta-9-tetrahydrocannabinol, is the main psychoactive cannabinoid. CBD, cannabidiol, is a non-psychoactive cannabinoid with demonstrated medically useful properties. Selective breeding of cannabis over the past two decades has increased THC levels, while reducing the CBD levels. “There are concerns that the significantly elevated THC content of modern cannabis may be exacerbating the potential health detriments, particularly in relation to cognitive and psychiatric disorders.”

STAT raised several concerns that should be considered by medical research into—and our understanding of—cannabis. First, will reclassification have much of an impact on clinical trials into marijuana’s potential as a medicine? Many top cannabis researchers are skeptical.

The FDA requires research extensive tests for a new drug in humans to submit an extensive amount of data outlining the drug’s absorption and metabolism rates and toxicology studies on lab animals. Cannabis is no different. This is to help protect participants in clinical trials from adverse effects from potentially dangerous drugs. Researchers have complained the FDA’s review of INDs (investigational new drugs) has been too strict and slow, creating a backlog of studies waiting to begin. More than 150 research applications for studies into cannabis were pending before the FDA as of March 2024, according to a recent to the head of the Drug Enforcement Administration.

Second, there are many unanswered questions about cannabis from a basic scientific perspective. For example, how do the dozens of cannabinoids influence the brain; what changes when people consume cannabis in different forms; and what does this mean for the potential for misuse? There have been multiple reports that high-potency cannabis increases the risk of psychosis, including this recent longitudinal study by Hines, Heron and Zammit. Also see (“Gambling with Cannabis and Psychosis” and “PREPARING to Legalize Cannabis”).

Third, politics could also get in the way, but it’s unlikely that rescheduling will take place before the November 2024 election. The formal regulatory process takes time, particularly when there is one with one such “historic” implications. STAT said there were over 7,000 comments on the proposed rescheduling by May 30, 2024. There are some Republican lawmakers opposed to the rescheduling, but it remains to be seen if they would sink the proposal in its entirety.

On the other hand, a coalition of Republican and Democratic senators came together on a bill in 2020 meant to lower research barriers and press federal agencies for these answers. It was signed into law in December 2022. Both pro-marijuana and anti-marijuana people have thought further medical research would prove their point. Why don’t we simply wait and find out what the research says?

01/30/24

Continue to Keep Marijuana Medical in PA

Photo by Alesia Kozik: https://www.pexels.com/

Medical marijuana has been available in Pennsylvania since February of 2018. Fortunately, progress to the legalization of recreational marijuana has not occurred yet. I’ve been urging for almost six years that we wait for the research into the risks and benefits of marijuana use can be reliably researched. Here are three recently published research articles to reflect on that suggest going ‘full Colorado’ in Pennsylvania may not be a good idea.

In August of 2023, The British Medical Journal (BMJ) published “Balancing risks and benefits of cannabis use” by Solmi et al. Their research was an umbrella review of 101 meta-analyses that have reported on the safety of cannabis, cannabinoids or cannabis-based medicines. According to the 2019 Global Burden of Disease Study, Solmi et al said more than 23.8 million people have cannabis use disorder (CUD). In the U.S., the prevalence of CUD was estimated at around 6.3% in a lifetime. In Europe, around 15% of people aged 15 to 35 reported using cannabis in the past year.

In Europe, over the past decade, self-reported use of cannabis within the past month has increased by almost 25% in people aged 15-34 years, and more than 80% in people who are 55-64 years. Cannabis or products containing tetrahydrocannabinol (cannabinoids) are widely available and have increasingly high tetrahydrocannabinol content. For instance, in Europe, tetrahydrocannabinol content increased from 6.9% to 10.6% from 2010 to 2019. Evidence has suggested that cannabis may be harmful, for mental and physical health, as well as driving safety, across observational studies but also in experimental settings. Conversely, more than a decade ago, cannabidiol was proposed as a candidate drug for the treatment of neurological disorders such as treatment-resistant childhood epilepsy. Furthermore, it has been proposed that this substance might be useful for anxiety and sleep disorders, and even as an adjuvant treatment for psychosis. Moreover, cannabis-based medications (ie, medications that contain cannabis components) have been investigated as putative treatments for several different conditions and symptoms.

There was converging evidence of an increased risk of psychosis in adolescents and adults, and with psychosis relapse in people with a psychotic disorder. There was an association between cannabis and general psychiatric symptoms such as depression and mania; and detrimental effects on memory, verbal delayed recall, verbal learning and visual immediate recall. “Across different clinical and non-clinical populations, observational evidence suggests an association between cannabis use and motor vehicle accidents.” There was also evidence of an association with somnolence (drowsiness) with cannabinoids and cannabidiol. Cannabis-based medicines were associated with visual impairment, disorientation, dizziness, sedation and vertigo.

In addition to the association of cannabis and psychosis, cannabis use is associated with a worse outcome after onset, including poorer cognition, lower adherence to antipsychotics and a higher risk of relapse. “In other words, use of cannabis when no psychotic disorder has already occurred increases the risk of its onset, and using cannabis after its onset, worsens clinical outcomes.” Mood disorders have their peak of onset close to that for cannabis use, raising concern because of the associations noted in this study between cannabis and depression, mania and suicide attempt. High THC content cannabis is thought to serve at a gateway to other substances, especially in younger people.

With regard to the therapeutic potential of cannabis-based medicines, cannabidiol was beneficial in reducing seizures in certain forms of epilepsy. They were also beneficial for pain and spasticity in multiple sclerosis, as well as for chronic pain in various conditions. In patients with chronic pain, the effects of prolonged use of cannabinoids needs to be tested “because current findings only come from short term randomized controlled trials.” Active comparisons between cannabidiol and available options for epilepsy, cannabis-based medicines and other pain medications, other treatments for muscle spasticity in multiple sclerosis are needed with a focus on efficacy and safety to inform future guidelines.

In conclusion, Solmi et al said converging and convincing evidence supported the association of marijuana use with poor mental health and cognition and the increased risk of car crashes. Cannabis use should be avoided in adolescents and young adults when neurodevelopment is still occurring, when mental health disorders begin and cognition is important for optimizing academic performance and learning. Cannabidiol could be considered as a potential treatment option in epilepsy. Cannabis-based medicines could be considered for chronic pain across different conditions, and for nausea and vomiting and for sleep in cancer.

Law and public health policy makers and researchers should consider this evidence synthesis when making policy decisions on cannabinoids use regulation, and when planning a future epidemiological or experimental research agenda, with particular attention to the tetrahydrocannabinol content of cannabinoids. Future guidelines are needed to translate current findings into clinical practice.

The 2022 National Survey on Drug Use and Health (NSDUH) released in November of 2023, 22% of people 12 or older reported using marijuana in various ways (smoking, vaping, dabbing, eating or drinking, lotion or cream, taking pills or some other way). The percentage was highest among young adults, 18 to 25 (38.2% or 13.3 million people), followed by adults over 26 (20.6%, 45.7 million people), then adolescents 12 to 17 (11.5%, 2.9 million people). Among people 12 or older in 2022, 6.7% or 19 million people, has a CUD (cannabis use disorder) in the past year. The percentage of young adults 18 to 25 with CUD was 16.5% or 5.7 million people. Adolescents aged 12 to 17 with CUD was 5.1%, or 1.3 million people. These figures were higher than the data reported in the following article, “Cannabis-Related Disorders and toxic Effects,” perhaps reflecting more recent data.

In December on 2023, The New England Journal of Medicine published “Cannabis-Related Disorders and Toxic Effects” by Daniel Gorelick. The article reviewed the seven cannabis-related disorders defined in the DSM-5-TR. The author said worldwide, an estimated 209 million persons between 15 and 64 used cannabis in 2020. In the U.S., an estimated 52.4 million people 12 and older used cannabis in 2021, representing 18.7% of that age group. And 16.2 million persons met the diagnostic criteria for CUD.

Cannabis use disorder occurs in all age groups but is primarily a disease of young adults. The median age at onset is 22 years (interquartile range, 19 to 29). In the United States, the percentage of 18-to-25-year-old persons with current (past-year) cannabis use disorder in 2021 was 14.4%. Younger age at initiation of cannabis use is associated with faster development of cannabis use disorder and more severe cannabis use disorder.

The major risk factors for developing CUD are the frequency and duration of cannabis use. And the core feature is loss of control, reflected in persistent use despite adverse consequences. The potency and amount of cannabis are also risk factors, but they have not been well studied because of the difficulty in quantifying the amount and potency of the THC content of products. “The potency of cannabis has doubled over the past 2 decades, according to analyses of samples seized by U.S. law enforcement, which may contribute to the increased risk of cannabis use disorder and cannabis-induced psychosis.” The risk of CUD increases with the frequency of use: 3.5% prevalence of CUD with yearly use (less than 12 days per year); 8.0% with monthly use (up to 4 days per month); 16.8% with weekly use (up to 5 days per week); and 36% with daily or near daily use.

Several clinical and sociodemographic factors are associated with an increased risk of cannabis use disorder, including the use of other psychoactive substances such as alcohol and tobacco; having had adverse childhood experiences (such as physical, emotional, or sexual abuse); having a history of a psychiatric disorder or conduct problems as a child or adolescent; depressed mood, anxiety, or abnormal regulation of negative mood; stressful life events (such as job loss, financial difficulties, and divorce); and parental cannabis use. These significant associations do not necessarily indicate a direct causal influence on cannabis use disorder, because many of these factors are also highly associated with both cannabis use and frequent cannabis use.

Gorelick told Medical Xpress almost 50% of people with CUD have another diagnosable psychiatric disorder such as major depression, PTSD or generalized anxiety disorder. He said: “There is a lot of misinformation in the public sphere about cannabis and its effects on psychological health with many assuming that this drug is safe to use with no side effects.” About 1 in 10 people who use cannabis will become addicted and if you start using before the age of 18 the risk rises to one in six. Cannabis use accounts for 10% of all drug-related emergency room visits and is associated with a 30 to 40 percent increased risk of car accidents.

He concluded that CUD and heavy or long-term cannabis use have clear adverse effects on physical and psychological health. He thought research on the endocannabinoid system is needed to better explain the pathophysiology of these effects and to develop treatments. In other words, continue to keep marijuana medical in PA until we have reliable research to determine whether or not recreational marijuana should be legalized. So far, it’s not looking to be a wise move.

For more information on marijuana and the concerns with legalization, search for “marijuana” or “cannabis” on this website or see, PREPARING to Legalize Cannabis.” For more information on marijuana legalization in Pennsylvania, see “Keep Marijuana Medical in PA,” “Waiting Before Pennsylvania Goes ‘Full Colorado’” and others.

07/4/23

PREPARING to Legalize Cannabis

Marijuana legalization in the US has been steadily moving forward in a piecemeal, state-by-state way for several years now. According to the National Conference of State Legislators, as of April 24, 2023 38 states and the District of Columbia have legalized cannabis products for medical use, and 22 states and the District of Columbia have legalized the recreational use of marijuana. Apparently anticipating the inevitability of legalization on a national level, Congressman Dave Joyce introduced H.R. 2598, the PREPARE (Post-Prohibition Adult Use Regulated Environment) Act on April 13, 2023, “To establish a Commission on the Federal Regulation of Cannabis to study a prompt and plausible pathway to the Federal regulation of cannabis.” Hakeem Jefferies, the Minority Leader of the House of Representatives, told Forbes: “The PREPARE Act will give lawmakers a bipartisan platform to legislate not only a fair and responsible end to prohibition but also a safer future for our communities.” However, two studies published in May of 2023 suggest that ending the so-called “prohibition” of marijuana may not be a responsible or safe action for some members of our communities.

The movement towards recreational marijuana legalization is promoted by a widespread sense that casual cannabis use is benign. However, a Columbia University study by Sultan et al, “Nondisordered Cannabis Use Among Adolescents,” found that teens who used marijuana recreationally were 2 to 4 times more likely to develop depression and suicidality than teens who didn’t use it at all. The lead study author, Ryan Sultan, said in a Columbia University press release, “We were surprised to see that cannabis use had such strong associations to adverse mental health and life outcomes for teens who did not meet the criteria for having a substance use condition.”

Their study found that adolescents with nondisordered cannabis use (NDCU) and cannabis use disorder (CUD) had increased odds of adverse psychosocial events. Both were significantly associated with adverse psychosocial events in a stepwise gradient manner. Sultan said their study was the first to identify that subclinical, nondisordered cannabis use has “clear adverse and impairing associations for adolescents.”

In line with past studies, cannabis use among adolescents was associated with greater odds of depression and suicidal ideation. These in turn were associated with long-term adverse educational and occupational attainment outcomes “and increased risk of harmful substance use in adulthood.” There was also evidence of worse executive control, decreased attention and deficits in episodic memory. Compared to nonusers, adolescents in NDCU and CUD groups were around 2-3 times more likely to experience cognitive deficits.

We observed a stepwise severity gradient for the odds of psychosocial associations among nonuse, NDCU, and CUD. This severity gradient was also observed in prevalence values for adverse psychosocial events across all degrees of cannabis use. Furthermore, this observation was corroborated by a stepwise cannabis use frequency trend between NDCU and CUD.

The researchers thought their findings were particularly concerning given the increasing popularity of marijuana as states continue to move toward making the drug legal. They concluded that with the growing acceptance of both medicinal and recreational cannabis use in the US, “clinicians should be vigilant to screen, evaluate, and treat cannabis use in adolescents.”

The second study was a huge Danish study of over 6 million people that discovered a strong association between cannabis use disorder and schizophrenia. The research team included Nora Volkow, the Director of the National Institute on Drug Abuse (NIDA). The study, “Association between cannabis use disorder and schizophrenia stronger in young males than in females,” analyzed health records spanning over 5 decades in order to estimate the fraction of schizophrenia cases that could be attributed to cannabis use disorder. A Scientific American review of the study said it found up to 30% of the schizophrenia diagnoses—around 3,000 in total—could have been prevented if men between the ages of 21 and 30 had not developed cannabis use disorder. The Scientific American review said:

The Danish epidemiology study does not offer hard-and-fast proof of the cannabis-schizophrenia connection, which could be accomplished only through randomized controlled trials. But this link is supported by the fact that marijuana use and potency have risen markedly—from 13 percent THC content in Denmark in 2006 to 30 percent in 2016—alongside a rising rate in schizophrenia diagnoses. “While this isn’t proving causality, it’s showing that the numbers behave exactly the way they should, under the assumption of causality,” says Carsten Hjorthøj, the study’s lead author and an associate professor at the Mental Health Services in the Capital Region of Denmark and the University of Copenhagen.

This study won’t resolve the long-running debate over the statistical cause-and-effect relationship between cannabis and schizophrenia. For example, David Nutt thought the research was intriguing, but it also raised more questions. He asked whether some of the cases may have been misdiagnosed with schizophrenia rather than an alternative diagnosis—like cannabis-induced psychosis. Along with the researchers, he pointed to the lack of data on the participants’ frequency of cannabis use or age of first use or the amount of THC in the products they used.

However, Robin Murray, a professor of psychiatric research at the Institute of Psychiatry at King’s College London and co-editor in chief of the medical journal Psychological Medicine said the Danish study examined specific factors more closely—gender and age—than previous investigations of the possible link between cannabis and schizophrenia. He thought it added to the growing body of research that has gradually discounted other factors to cannabis as a trigger for schizophrenia, making the connection more plausible, “So causal effect is almost certain.” For more on cannabis and schizophrenia, and Robin Murray’s own research into marijuana, see “Gambling with Cannabis and Psychosis” and “Cannabis and Psychosis: More Reality Than Satire.”

Psychiatric Times periodically published articles to educate its readers on cannabis and its association with schizophrenia. In “Cannabis Confusion” John Miller noted that he’s read numerous articles in the psychiatric literature that made conflicting conclusions about the effects of cannabis on cognition, its risk of psychosis, addictive potential, and its effects on suicidality, depression, anxiety, and pain relief. He thought there was only one consistent finding: Heavy cannabis use during brain development increases the risk of psychosis and cognitive impairment.

A likely explanation for the wide-ranging discrepancies is that cannabis is the product of a plant that is not a single molecule or pure substance. Many articles with the word cannabis in the title can be discarded as meaningless unless the authors took the additional step of testing all of the cannabis used by their study subjects for the quantitative and qualitative molecules present.

He noted that as more states legalize cannabis for medical or recreational use, it is likely that federal laws will eventually make cannabis use legal on a national level. “That will create an opportunity to require a comprehensive analysis and disclosure of all the components of the numerous strains of cannabis currently being sold in state dispensaries or on the streets.”

Fuller Torrey, a research psychiatrist specializing in schizophrenia, commented in “Is Cannabis Use Increasing Schizophrenia?” on an earlier Danish study that claimed the use of cannabis was a likely cause of the increasing incidence of schizophrenia over the past two decades. He noted that an increasing incidence of schizophrenia, or psychosis in general has also been reported in England, Switzerland and Canada. Torrey also gave citations and links to the various studies that supported his statement. He also thought the move towards legalizing recreational use in the US meant that “a possible relationship between cannabis use and increasing schizophrenia is potentially very important and needs to be confirmed.” He said:

It is an embarrassment to American medicine that NIMH has so little to contribute on such an important question. At a minimum, NIMH should issue a request for proposals to try and confirm the Danish study in another country which has appropriate data so that we will have a definitive answer to this question.

In “Does Cannabis Cause Psychosis?” Brian Miller reviewed several research studies of the relationship between cannabis and psychosis and concluded there was a robust association between cannabis use and the risk of psychosis, with evidence of a dose-response relationship, “which supports the plausibility of a causal association.”

Comorbid cannabis use is highly prevalent in psychosis (especially FEP [first episode of psychosis], with declining use over time), with strong evidence for an earlier age of onset of illness, as well as effects of psychopathology and cognition. In patients with psychosis, continued cannabis use is associated with antipsychotic nonadherence, illness relapse, and longer hospitalizations. These findings raise the possibility of a dose-response relationship between current cannabis use and transition to psychosis. Findings suggest that targeting cannabis use during the UHR [ultra-high risk] period may confer significant benefits on long-term outcomes. Continued cannabis use is also a potential target for intervention to improve antipsychotic adherence and other outcomes in patients with psychosis. Future research in this area is clearly warranted to elucidate mechanisms and novel treatment strategies for relevant populations.

Further research is needed to clarify the potential harms and adverse effects from using cannabis and marijuana products. While not yet proved conclusively, it does seem that there is a causative connection between schizophrenia and using marijuana for some people, but not for all people. Although this is more evident with heavy users (those who could be classified as having a cannabis use disorder), the Sultan et al study found there were even adverse mental health and life outcomes for teens that used marijuana, but did not meet the criteria for a substance use condition.

Cannabis use among adolescents increased the odds of depression and suicidal ideation among adolescents. Consistent with past research, there was also evidence of worse executive control, decreased attention and problems with episodic memory. When compared to nonusers, adolescents who used marijuana were 2 to 3 times more likely to experience cognitive deficits.

Heather Baccus spoke to America Reports on Fox News of how she believes her son’s marijuana use led to his psychotic break a few months before he committed suicide in July of 2021. Randy began using marijuana when he was 15 and had a cannabis user disorder within a year. By the time he was 21, he was experiencing delusions and paranoia. Heather said he thought it was helping him with his anxiety and depression, which she said he did not have until after he began using marijuana.

He knew that he would manage and function fairly well in life, but he was paranoid. He thought his roommates were out to get him. He thought that people at work were out to get him. He would quit a job quickly. He accused one of his employers of being in the mob. When he had a full-blown attack in March of 2021, he called us and said the mob was coming after him, that they were coming after us, and he just was out of sorts.

There is a video clip of a short interview with Nora Volkow, the director of NIDA and a coauthor of the above cited Danish study in the Fox News article. She said marijuana is not as benign as we would like it to be and is associated with psychosis. “High doses, regular use can be harmful.” She said there were likely three possibilities. Marijuana use triggers an episode in some individuals that have a latent risk for psychosis. In others, it may just accelerate the timing of the psychosis. Finally, it may also trigger a psychotic event that would not otherwise happen.

The PREPARE Act sounds like a responsible, proactive step to take before we move towards national legalization of marijuana. But I don’t believe we are thinking about the concurrent increase with adverse mental health concerns like depression, suicidal ideation and psychosis. What do we need to do to PREPARE for that?

05/23/23

The Loophole with Delta-8

You may have seen storefront signs saying something like, “Delta-8 Sold Here”, and wondered what they could be selling. In states where recreational marijuana is not legal you would most likely think it certainly couldn’t be referring to that, and you would be right. It is technically not THC or delta-9-tetrahydrocannabinal, the main psychoactive ingredient in cannabis sativa. But according to the Agriculture Improvement Act of 2018, any part of the cannabis plant containing .3% or less of THC by dry weight is now defined as hemp. And there’s the loophole that has been exploited to permit delta-8 THC to be legally sold in markets that so far have restricted the legalization of marijuana.

In December of 2018, the Senate easily passed the Agriculture Improvement Act of 2018, 87 to 13. In, “How Delta-8 THC Works, and Why Experts Are Worried About It,” The New York Times reported that at the insistence of Mitch McConnell, the bill legalized industrial hemp as a crop. The hope was that hemp could be used for construction products and plastic composites and help vendors of CBD, a non-psychoactive compound found in cannabis sativa or “hemp.” But what happened was the 2018 Farm Bill allowed hemp to be used as a precursor for synthesizing delta-8-THC, which has a nearly identical chemical structure to delta-9-THC. And delta-8 is psychoactive, producing a “high” similar to delta-9. See the graphic below from “Marijuana Variant of Concern.”

Here is why designating hemp as cannabis sativa containing less than .3% in the 2018 Farm Bill was so significant. According to the pro-marijuana website Weedmaps, most cannabis plants contain negligible amounts of CBD, less than 1%. However, hemp plants average between 12% and 18% CBD. The Center for Disease Control and Prevention (CDC) noted that CBD does not produce a high as THC does. At this point in time, there is only one FDA approved medicine containing purified CBD from hemp, Epidiolex, which is approved to treat seizure disorders.

But the 2018 Farm Bill removed “hemp from the federal Controlled Substances Act, effectively legalizing CBD if it comes from hemp.” CBD is now marketed in many consumer products: foods, oils, lotions, capsules, and cosmetics. Science is still learning about CBD and the CDC said CBD products are not risk free. They can lead to liver damage, drowsiness or sleepiness, diarrhea or changes in appetite, and mood changes like irritability. They may also lead to serious side effects when used in combination with other medicines or drugs.

There is a lot we do not know about CBD. Currently, we do not know how CBD use affects a person over time. We also do not know how different modes of CBD use (smoking, vaping, eating, applying to skin, etc.) affect a person.

CDC released a Health Alert Network (HAN) Health Advisory in 2021 to inform consumers that CBD can be synthetically converted into Delta-8 THC, which is psychoactive and not well understood. This alert warns consumers about the potential for adverse events due to insufficient labeling of products containing THC and CBD.

THC most often refers to delta-9 THC, the most common THC isomer in cannabis. But there are several other isomers that occur naturally in cannabis, including delta-8 THC, which is estimated to be approximately 50-75% as psychoactive as delta-9 THC. The CBD-to delta-8 THC conversion process uses a solvent, acid, and heat to produce concentrations of delta-8 THC higher than those found naturally in the cannabis plant. “This conversion process, used to produce some marketed products, may create harmful by-products that presently are not well-characterized.”

The 2018 Farm Bill led to an expanding and unregulated market for delta-8-THC, according to Leas et al, which sought to measure public interest in delta-8. The researchers looked at the global rate of recommended searches that mentioned delta-8-THC from January 2011 through August 2021. The search trends were stable from 2011 through 2019. But they increased by 257% from 2019 to 2020 and 705% from 2020 to August 2021. The global trend of delta-8-THC searches was driven primarily by increases in the U.S., where the rate increased by 466% from 2019 to 2020 and by 850% from 2020 to August 2021. “By 2021, the rate of searches for delta-8THC in the US was at least 10 times higher than [the] rate of delta-8-THC searches in any other country or territory.”

The growth in searches following legalization of hemp in the US as well as the greater interest in US States with more restrictive delta-9-THC policies suggests that delta-8-THC may be meeting a demand for legal use of THC in markets that do not permit use of delta-9-THC. The one-year lag following the legalization of hemp could potentially be explained by a need for developing an infrastructure to produce and ship delta-8-THC products. For example, one manufacturer claims to have created “USA’s first federally legal THC-dominant product since cannabis prohibition started,” after it developed a method of synthesizing delta-8-THC in September of 2019. By 2021, hundreds of Delta-8-THC manufacturers existed throughout the US, and many offered to ship products to consumers and wholesale to retailers in states that did not permit use of delta-9-THC.

While public interest in delta-8-THC seemed to be concentrated in the US, some manufacturers have opened offices in Europe. One manufacturer, Just Delta, has offices in the UK. Leas et al said global and US jurisdictions should clarify whether methods of converting cannabinoids to THC compounds are legal under existing hemp and cannabis laws. They recommended a public-health-focused approach that clarifies definitions of THC compounds to include delta-8-THC and other THC isomers; and disallows the use of methods that convert CBD to THC, “at least until these can be determined to be safe.”

The NYT article, “How Delta-8 THC Works,” reported that a survey of delta-8 users said they were less anxious, less paranoid, and had a nicer high than with delta-9 THC. “The most common experiences when using delta-8 were relaxation, euphoria and pain relief.” There were reports of some difficulty concentrating, problems with short-term memory and an altered sense of time, but not to the same extent as with regular marijuana. The explanation for the differences between delta-8 THC and delta-9 THC is probably that there’s less delta-8 THC in the CB1 receptors, “so people are less likely to experience the more distressing symptoms” when they get too high.

Manufacturers of delta-8 products argue that delta-8 may chemically be THC, but legally it now is hemp. “Since you can extract CBD from hemp, and CBD is not THC, [then] it’s still considered hemp.” The lack of regulation around delta-8 in the US is the biggest concern of many public health experts. In a paper published in December of 2022, none of the delta-8 products tested contained the amount of delta-8 they claimed. All 27 had potentially harmful byproducts, presumably from the manufacturing process, including lead and mercury.

Between January 2021 and February 2022 national poison control centers handled over 2,000 calls about delta-8. Forty-one percent involved children accidentally ingesting products with delta-8. “One of those cases resulted in death.” Without federal regulation, 14 states have banned delta-8, or all unregulated forms of THC, including delta-10. Ironically, this includes several states where recreational marijuana is legal, including Colorado and New York. Delta-10 is illegal in Colorado and New York as well.

Eric Leas, the lead researcher in the above study that assessed public interest in delta-8-THC, said in “The Hemp Loophole,” that “the loopholes that allow THC compounds to be sold as hemp ought to be closed.” He said the regulatory system for recreational marijuana makes it a safer product than delta-8. The manufacturing quality checks and other regulatory requirements such as labeling rules about potency and licensing distributers act as important public health standards. None of these protections currently exist for delta-8. All the experts interviewed for “How Delta-8 THC Works,” including those supportive of legalizing marijuana, recommended against using delta-8. “There is no way to ensure its safety.”

08/2/22

The Future of Marijuana Legalization in Pennsylvania

The World Drug Report for 2021 reported that roughly 200 million people used cannabis in 2019, roughly 4% of the global population. North America has the highest number of cannabis users, with an estimated 14.5% of its population use in 2019. The percentage of THC (∆9-THC), the main psychoactive ingredient in cannabis, rose from around 4% in 1995 to 16% in 2019. Although THC is responsible for the development of mental health disorders in long-term, heavy cannabis users, the percentage of adolescents who view regular cannabis use as harmful has decreased by as much as 40% during the same time period. While the potency of cannabis has increased four-fold since 1995, fewer young people see it as harmful.

Such a mismatch between the perception and the reality of the risk posed by more potent cannabis could increase the negative impact of the drug on young generations. Scientific evidence has demonstrated the harm to health caused by regular use of cannabis, particularly in young people. Evidence from surveys suggests a link between a low perception of risk and higher rates of usage. This is the case not only in Europe and the United States, but also in other parts of the world.Aggressive marketing of cannabis products with a high Δ9-THC content by private firms and promotion through social-media channels can make the problem worse. Products now on sale include cannabis flower, pre-rolled joints, vaporizers, concentrates and edibles. The potency of those products varies and can be unpredictable – some jurisdictions where cannabis use is legalized set no limit on THC content – and may be a public health concern.

(See the following charts from the World Drug Report for 2021)

In 2020, 14.6% of high-school students reported past-month use of cannabis. There was a significant increase in the daily or near-daily use of cannabis in the past two years (20919 and 2020). The daily or near-daily use of marijuana was estimated at 4.1% among high-school students in 2020, compared with almost 1% in 1991. In the past few years, the debate about medical marijuana and measures allowing for the non-medical use of cannabis in the United States have led adolescents to perceive cannabis as less harmful than was true in the past.

In the United States, the decreasing perception of risk from occasional or regular use of cannabis is considered to be a spillover effect as debates over measures allowing the medical and non-medical use of cannabis in the states considering those measures extend to other states, and the result of an increase in regular cannabis use, which comes to be perceived as less risky among users, as well as media coverage of the medical use of various cannabis products in many states containing claims of the medical benefits of cannabis products, including those of CBD.

Not only are there concerns for increases in mental health disorders among youth, there are other concerns with how cannabis effects young adults. Cannabis use among adolescents was found to be related to impaired cognition; showing delayed effects on self-control, working memory and concurrent effects on delayed memory recall and perceptual reasoning (ability to think and reason using pictures or visual information). So, exactly what are the risks when individuals, particularly adolescents and young adults, use marijuana? A meta-analysis published in The Lancet Psychiatry suggested the equivalent of one joint can induce psychotic and other psychiatric symptoms in healthy adults with no history of a major mental illness.

In “Psychiatric symptoms caused by cannabis constituents: a systematic review and meta-analysis,” the researchers their findings highlighted the acute risks of cannabis use, as “medical, societal, and political interest in cannabinoids continues to grow.” Significantly, they concluded that CBD (the second most common cannabinoid in cannabis) did not induce psychiatric symptoms; and the evidence that it moderated the induction of psychiatric symptoms was inconclusive. These effects were larger with intravenous administration than with inhaled.

Commenting on the results for Medscape, senior investigator Oliver Howes said “As clinicians, we need to be aware that the medical use of marijuana comes with a risk of inducing psychiatric symptoms, even in people with no vulnerability, and this needs to be factored into decisions to prescribe and to monitor.” Even if the symptoms are short-lived, people need to be aware of them because not only van they be distressing, but they can also affect decision-making and behavior. With regard to the failure of the researchers to find evidence that CBD moderates the psychotic effects of THC, Howes said, “I think it’s fair to conclude there’s a lack of consistent evidence that CBD is protecting against THC’s effect.” The mean age of the subjects ranged from early to late 20s.

An editorial of the study by Carsten Hjorthøj and Christine Merrild Posselt said the finding that low doses of THC can induce psychotic symptoms was “extremely worrying,” because they were similar to those found in medical marijuana. They also said there was no clear evidence that concurrent administration of CBD reduces symptoms induced by THC. “The authors failed to find any clear evidence that concurrent administration of cannabidiol (CBD) reduced these symptoms. Indeed, such an ameliorating effect was observed in only one of four included studies.”

This growing scientific consensus is not reflected in the mainstream public discourses, which have a major effect on the political agenda to decriminalise or legalise cannabis. It also appears that, in many places (eg, several US states), the first thing to be legalised is medicinal cannabis followed by increasing decriminalisation and sometimes complete legalisation of cannabis. It is thus of utmost importance that the public and politicians are informed of the most up-to-date evidence on cannabis. Adding to the state of this evidence is the systematic review and meta-analysis by Guy Hindley and colleagues in The Lancet Psychiatry. The authors demonstrate that Δ⁹-tetrahydrocannabinol (THC) leads to an increase in total symptoms, which was assessed in nine studies, with ten independent samples, involving 196 participants: standardised mean change in scores (assessed with the Brief Psychiatric Rating Scale and the Positive or Negative Syndrome Scale) 1·10 (95% CI 0·92–1·28, p<0·0001). The effect sizes were also large for other symptoms (including general psychiatric symptoms), and were induced even with low doses of THC, somewhat similar to the doses often seen in medicinal cannabis, which we find extremely important and worrying.

The significance of the above research findings should not be lost on Pennsylvania citizens and politicians. As the availability of cannabis increases in the state, as the potency of THC in that marijuana increases, we will see a corresponding increase of psychosis and other mental health-related problems among regular users. This is the future of marijuana legalization in Pennsylvania.

Medical marijuana has been legal in Pennsylvania since April 6, 2016. The first dispensary opened in the Pittsburgh area in Butler PA, on February 1, 2018. But medical marijuana dispensaries continue to spring up like “weeds.” The Weedmaps website indicated there were 39 dispensaries in the Pittsburgh area. Nineteen advertised they provided Curbside pickup.

John Fetterman, the current lieutenant governor of Pennsylvania, is running for the office of U.S. Senator and wants to see Pennsylvania “go full Colorado.” Its governor, Tom Wolf, has publicly supported the legalization of recreational marijuana. There has been legislation proposed by two state senators, the Adult-Use Cannabis Act, to legalize recreational marijuana in the state. See “Should Pennsylvania Go ‘Full Colorado’ With Marijuana?” Part 1 and Part 2.

06/21/22

Gambling with Cannabis and Psychosis

Biological evidence supports a causal link between marijuana and psychosis. Additionally, this seems to be dose-dependent—with higher potency marijuana, there is an increased likelihood of a psychotic disorder. What is not clear, however, is whether at a population level patterns of cannabis use influence the levels of psychotic disorder. A new study published in The Lancet Psychiatry reported there is a strong link between high-potency marijuana and psychosis. “The odds of psychotic disorder among daily cannabis users were 3·2 times higher than for never users, whereas the odds among users of high potency cannabis were 1·6 times higher than for never users.”

If an individual began using marijuana before the age of fifteen, the odds were slightly increased, but not independent of the frequency of use or the potency of cannabis used. Compared with individuals who never used marijuana, those who used high-potency marijuana daily had four-times higher odds of psychosis. People who were using high-potency marijuana doubled their risk of psychotic disorder. “Our results show that in areas where daily use and use of high potency cannabis are more prevalent in the general population, there is an excess of cases of psychotic disorder.” The researchers estimated that 20% of the new cases of psychotic disorder could have been prevented if the daily use of cannabis had been arrested.

The study drew its data on first-episode psychosis cases from 17 areas in England, France, the Netherlands, Italy, Spain and Brazil. The novelty of this study was its multicenter structure and the availability of incidence rates for all the sites. The use of high-potency cannabis was a strong predictor of psychotic disorder in Amsterdam, London, and Paris where it was widely available. In the Netherlands the THC content can reach as high as 67%. See the chart below.

In conclusion, our findings confirm previous evidence of the harmful effect on mental health of daily use of cannabis, especially of highpotency types. Importantly, they indicate for the first time how cannabis use affects the incidence of psychotic disorder. Therefore, it is of public health importance to acknowledge alongside the potential medicinal properties of some cannabis constituents the potential adverse effects that are associated with daily cannabis use, especially of highpotency varieties.

Susan Gage, a psychologist and epidemiologist at the University of Liverpool, wrote a commentary on the study. Commenting for NPR, she said: “What this paper has done that’s really nice is they look at rates of psychosis and cannabis use in lots of different places where underlying rates of psychosis are different.” With regard to the finding that cities with more easily available high-THC marijuana have a higher rate of new diagnoses of psychosis, she said: “That’s a really interesting finding, and that’s not something anyone has done before.”

However, there are some who seek to minimize the findings. In “Psychosis is the last marijuana side effect you should be worried about,” on the Popular Science website, Kat Eschner not-so-subtly dismissed the findings as “an ableist morality fable,” comparing it to the film, Reefer Madness. For more on the film Reefer Madness, see “Remembering Reefer Madness.” She acknowledged that for a specific population of marijuana users, there was a link, but “overemphasizing the connection poses its own problems.” She quoted a University of York mental health and addiction researcher, Ian Hamilton, who pointed out the connection between cannabis and psychosis has been known for a long time and said: “I think we have to be careful we don’t exaggerate the risk.” But that was not all Hamilton had to say on the matter.

Hamilton published his own research into the association of cannabis and psychosis, in the journal Addiction. The University of York press release on his study indicated that while the population level risk of developing psychosis was low, and those vulnerable to developing serious mental health problems is relatively rare. But for individuals who already have schizophrenia, marijuana can make their symptoms worse. He said: “The research was clear that the more high potency cannabis used, the higher the risk of developing mental health problems, even if they are relatively low in number. For those who already had schizophrenia cannabis exacerbated the symptoms.”

Professor Robin Murray, a Scottish psychiatrist and Professor of Psychiatric Research at King’s College, London, “cautioned that cannabis is not as safe as was once thought.” In an editorial for the British Journal of Psychiatry, he said 10 of 13 longitudinal studies showed cannabis users are “at significant increased risk of subsequently developing psychotic symptoms or schizophrenia-like psychotic illness.” The remaining three studies showed a trend in the same direction. “A recent meta-analysis reported that the odds ratio for developing psychotic symptoms or a psychotic disorder in individuals who had used cannabis over non-users reached 3.9 (95% CI 2.84–5.34) among the heaviest users.”

He noted where most forms of cannabis in the 1960s and 1970s contained less than 4% of THC and an equal proportion of CBD (which ameliorates the psychoactive properties of THC). But these have been displaced by stronger varieties, which range in THC potency from 16% up to 90% as wax “dabs.” Then there is the rise of synthetic cannabinoids. “In contrast to THC which is a partial agonist at the cannabinoid CB1 receptor, most synthetic cannabinoids are full agonists and consequently more powerful.” He noted how “the USA and Canada have embarked on a major pharmaceutical experiment with the brains of their youth.” He suggested that the UK “wait and see the outcome of the experiment.”

Researchers at Radbound University published the results of a large-scale genetic study in Nature Neuroscience. “The researchers found that people with schizophrenia are also more likely to use cannabis.” There were 35 different genes associated with cannabis use, particularly with the gene CADM2. This gene was already associated with risky behavior, personality and alcohol use. They found a genetic overlap between cannabis and the risk of schizophrenia, which was no big surprise as other studies have shown the association of cannabis use and schizophrenia. However, they also showed a causal connection.

The researchers used an analysis technique called “Mendelian randomisation” to show a causal relationship between schizophrenia and an increased risk of cannabis use. This may indicate that people with schizophrenia use cannabis as a form of self-medication. However, the researchers cannot exclude a reverse cause-and-effect relationship, meaning that cannabis use could contribute to the risk of schizophrenia.

It seems that adolescents are at a greater risk of experiencing symptoms like hallucinations, paranoia and anxiety with marijuana use. Levy and Weitzman published a research letter in JAMA Pediatrics. They found that of 146 teen marijuana users, 40 (27%) reported hallucinations and 49 (34%) said they experience paranoia or anxiety. “Compared to youth who said they had only tried marijuana once or twice, adolescents who used it every month were more than three times more likely to experience hallucinations, paranoia or anxiety.” One in four reported symptoms of depression.

Adolescents with symptoms of depression were more than three times more likely to experience paranoia and anxiety. And they were 51% more likely to report hallucinations than teens without depression. Sharon Levy, one of the researchers said:

We don’t know if the greater exposure to marijuana over time made the brain more susceptible to psychotic symptoms, whether kids who experienced psychotic symptoms became more likely to continue to use marijuana or if some third factor, such as depression, made kids both more likely to use marijuana heavily and also more susceptible to psychotic symptoms triggered by marijuana. . . . Regardless of which of these explanations is most accurate, there is clearly an interaction between marijuana use and brain function.

A study published in The Journal of Child Psychology and Psychiatry found that increased use of cannabis between 13 and 16 was associated with a higher likelihood of having psychotic-like experiences (PLEs). The lead author of the study said: “Our findings confirm that becoming a more regular marijuana user during adolescence is, indeed, associated with a risk of psychotic symptoms.” Going from occasional use to weekly or daily use increased an adolescent’s risk of PLEs by 159%. Also see: “Psychosis and Adolescent Marijuana Use.”

It seems clear that as a society we are moving towards increased use and availability of marijuana. And where recreational marijuana has been legalized, there appears to be more potent forms of marijuana and an increasing incidence of psychosis. While a 1:20,000 risk of developing symptoms of psychosis is negligible, it won’t remain that rare as people play the odds with marijuana and psychosis.

This article was originally posted on 5/21/2019.

12/28/21

Don’t Use Marijuana If You’re Pregnant

Should you use marijuana if you are pregnant? As a growing number of states legalize the medical and recreational use of marijuana, it’s reasonable to assume there will be an increase of women using marijuana while they’re pregnant. The American College of Obstetricians and Gynecologists (ACOG) estimates between 2 and 5 percent of women use marijuana while they are pregnant. Several studies found that increases to 15-28% among young, urban, socioeconomically disadvantaged women. So, what are the potential consequences to prenatal exposure to marijuana?

A Healthline article, “Cannabis Use During Pregnancy,” said research has linked neurodevelopmental issues such as ADHD and higher levels of stress and anxiety in children whose mothers used marijuana while pregnant. A study published in the Proceedings of the National Academy of Science (PNAS) found a relationship between maternal cannabis use and a higher potential risk for anxiety, aggression and hyperactivity in early childhood. This corresponded with pervasive reductions in immune-related gene expression in the placenta, which has been associated with anxiety and hyperactivity. “Future studies are needed to examine the effects of cannabis on immune function during pregnancy as a potential regulatory mechanism shaping neurobehavioral development.”

Commenting on the study to Healthline, Dr. Jordan Tishler, president of the Association of Cannabinoid Specialists, said: “It surely contributes to our growing knowledge of the risks associated with cannabis use during pregnancy, and further supports the take-home message to women that, at present, our understanding leads us to recommend not using cannabis during pregnancy and breastfeeding.” Dr. Scott Krakower, a child and adolescent psychiatrist, agreed there is a strong correlation between anxiety and marijuana use. However, he said it’s unclear why marijuana users have more anxiety.

That is either because, A, you’re more anxious and you’re more likely to use marijuana, or B, using marijuana is possibly worsening the anxiety over the long run.

A 2011 study, “Lasting impacts of prenatal cannabis exposure,” examined human longitudinal studies that showed the long-term influence of prenatal exposure to marijuana. The researchers concluded that prenatally cannabis-exposed children had cognitive deficits, suggesting that maternal use had interfered with the proper maturation of the brain.

Cannabis consumption during pregnancy has profound but variable effects on offspring in several areas of cognitive development. Most of the information on the long-term consequences of prenatal exposure to cannabis comes from longitudinal studies of the OPPS [Ottawa Prenatal Prospective Study] and MHPCD [Maternal Health Practices and Child Development Study] cohorts. By comparing data from the cohorts, a pattern emerges where maternal cannabis use is associated with impaired high-order cognitive function in the offspring, including attention deficits and impaired visuoperceptual integration.

In Marijuana Use During Pregnancy and Lactation,” the Committee on Obstetric Practice of the ACOG said because of concerns about impaired neurodevelopment, as well as maternal and fetal exposure to the adverse effects of smoking, “women who are pregnant or contemplating pregnancy should be encouraged to discontinue marijuana use.”

Obstetrician–gynecologists should be discouraged from prescribing or suggesting the use of marijuana for medicinal purposes during preconception, pregnancy, and lactation. Pregnant women or women contemplating pregnancy should be encouraged to discontinue use of marijuana for medicinal purposes in favor of an alternative therapy for which there are better pregnancy-specific safety data. There are insufficient data to evaluate the effects of marijuana use on infants during lactation and breastfeeding, and in the absence of such data, marijuana use is discouraged.

Many women who use marijuana continue to do so when they are pregnant (34-60%). A study, “Prevalence and patterns of marijuana use among pregnant and nonpregnant women of reproductive age,” found that 18.1% of pregnant women reporting marijuana use in the past year met the criteria for a substance use disorder. Certainty about the effects of marijuana on pregnancy and the developing fetus is difficult in part because users often use other drugs and in part because of other confounding variables. Marijuana smoke contains many of the same carcinogenic toxins as tobacco smoke. Adverse socioeconomic conditions like poverty and malnutrition can result in outcomes otherwise attributable to marijuana.

Marijuana use alone was not associated with an increased risk of lower birth weight. However, women who used marijuana at least weekly during their pregnancy were at increased risk of giving birth to a newborn weighing less than 5.5 pounds. Several studies noted statistically significant smaller birth lengths and lower birth weights. “These findings were more pronounced among women who used more marijuana, particularly during the first and second trimesters.” The clinical significance of these findings is still uncertain.

Because of concerns of impaired neurodevelopment and maternal and fetal exposure to the adverse effects of smoking, women who are pregnant or considering pregnancy should be encouraged to stop using marijuana. The ACOG gave the following recommendations:

Before pregnancy and in early pregnancy, all women should be asked about their use of tobacco, alcohol, and other drugs, including marijuana and other medications used for nonmedical reasons.
Women reporting marijuana use should be counseled about concerns regarding potential adverse health consequences of continued use during pregnancy.
Women who are pregnant or contemplating pregnancy should be encouraged to discontinue marijuana use.
Pregnant women or women contemplating pregnancy should be encouraged to discontinue use of marijuana for medicinal purposes in favor of an alternative therapy for which there are better pregnancy-specific safety data.
There are insufficient data to evaluate the effects of marijuana use on infants during lactation and breastfeeding, and in the absence of such data, marijuana use is discouraged.

In “Cannabis Use in Pregnancy May Lead to a More Anxious, Aggressive Child,” The New York Times noted the findings of the PNAS study added weight to a growing body of evidence linking cannabis use during pregnancy to psychiatric problems in children. A behavioral neuroscientist at Queens College said, “We have a long way to go to educate pregnant women, policymaker and even OB-GYN doctors in this issue.”

Studies have shown that THC can pass through the mother’s bloodstream to the placenta and then to the fetus. This is the case no matter how the cannabis is consumed, whether from smoking it, eating it or being exposed to it through vapors, oils or creams. If they contain THC, “they’re all going to pass through to the baby,” Dr. El-Chaâr said.

Many questions about marijuana use during pregnancy don’t yet have clear answers. For now, Dr. El-Chaâr urged caution. “What I would tell patients is that there’s no known safe amount.”

04/13/21

Telling the Truth About Marijuana and Psychosis

In January of 2019 Alex Berenson’s book, Tell You Children: The Truth About Marijuana, Mental Illness and Violence, was published. He hoped it would at least make his readers skeptical of the pro-marijuana arguments that advocates have peddled for the last twenty-five years. He said, “I hope it will open your eyes to the mental illness and violence that marijuana causes in your community.” In his career as a reporter, he made some enemies and gave an example of when private detectives, who were hired by an angry executive, chased him down the Long Island Expressway. “Yet nothing in my career prepared me for the reaction to this book.”

The article in Wikipedia on Tell Your Children, seemed to capture the rancor Berenson stirred up. He was said to have made “harsh” claims that cannabis use causes psychosis and violence, claims that were denounced by members of the scientific and medical communities. Two scientists who wrote an opinion piece for The Guardian said his assertions were “misinformed and reckless.” A group of 75 scholars and medical professionals signed an open letter that disagreed with Berenson, accusing him of cherry-picking data, attributing cause to mere associations and selection bias. “His work is a polemic based on a deeply inaccurate misreading of science.”

In an Afterword Berenson wrote in October of 2019 for the e-book edition, he said it was crucial to understand that these critics did not claim his book presented false or incorrect data, or was in any other way was “factually inaccurate.” “They can’t, because it doesn’t and isn’t.” He added that “misinterpret” and “cherry-pick” were word critics used when they could not find actual factual errors. He found the anger against what he wrote almost bizarre. “One can be aware that cannabis can cause mental illness and still favor legalization. But the cannabis industry, academics, and journalist-advocates would rather try to shout down anyone who raises it.”

Despite the attacks, both pro- and anti-legalization forces have said the book has affected the public debate. Berenson said, “And the evidence about the serious health harms has only mounted since January [of 2019].” Let’s look at some of this new evidence about the serious health harms from marijuana. There were two studies published in JAMA Psychiatry that appeared to support Berenson’s understanding of the science. Follow the links and see if he has been misreading the science.

A study done in 2018 and published in March of 2019 in JAMA Psychiatry found that prenatal cannabis exposure may be associated with a small increase in the proneness for psychosis during middle childhood. Another study published in May of 2019 in the journal JAMA Psychiatry suggested that risks for cannabis use problems and anxiety disorders were higher among those using high-potency cannabis. There was a small increase in the likelihood of psychotic experiences, but this risk decreased with an adjustment for the frequency of cannabis use.

Dr. Marta Di Forti is one of the leading researchers in the world for cannabis and psychosis. In a previous meta-analysis Di Forti and other researchers showed there was a positive association between the extent of cannabis use and the risk of psychosis. They observed “a consistent increase in the risk of psychosis-related outcomes with higher levels of cannabis exposure” in all the studies included in the meta-analysis. “Although this meta-analysis shows a strong and consistent association between cannabis use and psychosis, a causal link cannot be unequivocally established.”

Di Forti and others also noted that epidemiological evidence demonstrates that cannabis use is associated with an increased risk of psychosis in “Traditional marijuana, high-potency cannabis and synthetic cannabinoids: Increasing risk of psychosis.” The researchers said concern that cannabis might induce psychosis is not new. In 1896 the Scottish psychiatrist T. Clouston visited the Cairo asylum and noted that 40 out of 253 people in the hospital had insanity attributed to the use of hashish. By the 1960s, this view was commonly ridiculed as ‘reefer madness.’ The implication was that those who believed marijuana could induce psychosis were mad, rather than those who consumed it. This seems to be the thrust of the approach from those scholars and medical professionals that signed the open letter disagreeing with Berenson.

However, there have been several longitudinal studies showing cannabis as a risk factor for psychosis. “Nine out of twelve found that cannabis use was associated with a significantly increased risk of psychotic symptoms or psychotic illness.” In a 2015 study for Lancet Psychiatry, Di Forti and others found that high-potency cannabis users in south London had three times the risk of having a psychotic disorder than those who never used cannabis.

The following link is to a talk Dr. Di Forti gave in December of 2019 before the American College of Pharmacology, where she presented data from her research in South London, at a clinic where she works. First, she asked, does the frequency and type of cannabis matter?

The charts below from her presentation showed that individuals who used hash did not have rates that were statistically different than the controls. However, she had already said that hash was found to have a combination of THC and CBD, where the “skunk” or high-potency cannabis had very little CBD. Notice in the first graph that the probability of an individual experiencing a psychotic disorder increased as the frequency and strength of cannabis increased to daily use of high-potency skunk. The second chart shows both the use of high-potency cannabis and daily use of high-potency cannabis increased the chance of having a first-episode psychosis by 53% and 25% respectively.

Di Forti then asked, why should potency matter? Why should the amount of THC in cannabis matter? The results of a 2016 study she contributed to, “The Effects of continuation, frequency, and type of cannabis use on relapse,” found that once someone had a psychotic episode, if they continued to use cannabis, especially high-potency skunk, they “are much more likely to have a bad clinical outcome.” There was an increased risk of relapse, there were more relapses, there were fewer months until a relapse occurred, AND more intense psychiatric care was needed after the onset of psychosis.

Adverse effects associated with continued use of cannabis after the onset of a first episode of psychosis depend on the specific patterns of use. Possible interventions could focus on persuading cannabis-using patients with psychosis to reduce use or shift to less potent forms of cannabis.

In May of 2019, Di Forti and others published this research in The Lancet. The strongest independent predictors of whether an individual would have a psychotic disorder or not were daily use of cannabis and the use of high-potency cannabis. Starting cannabis use by the age of 15 modestly increased the odds for a psychotic disorder, but not independent of the frequency of use or of the potency of the cannabis used. “The odds of psychotic disorder among daily cannabis users were 3.2 times higher than for never users, whereas the odds among users of high-potency cannabis were 1.6 times higher than for never users.” Compared with individuals who never used, individuals who used high-potency cannabis daily had four-times higher odds of psychosis. Their findings were consistent with previous evidence suggesting that using high-potency cannabis has more harmful effects on mental health than does the use of weaker forms.

Our findings confirm previous evidence of the harmful effect on mental health of daily use of cannabis, especially of high-potency types. Importantly, they indicate for the first time how cannabis use affects the incidence of psychotic disorder. Therefore, it is of public health importance to acknowledge alongside the potential medicinal properties of some cannabis constituents the potential adverse effects that are associated with daily cannabis use, especially of high-potency varieties.

Serendipitously, it seems Marta Di Forti reviewed Tell Your Children by Alex Berenson for Amazon on January 18, 2019. She titled her review “Outstanding and engaging narrative.” She said:

This book is a rare and compelling combination of journalistic rigor, elegant writing and engaging style. A unique appraisal of the sociological and scientific facts feeding the never-ending debate on the good and bad of the most popular recreational drug in the world. A “must” read for everyone that can read or listen.

In his Afterword, Berenson cited a review study of twenty-six meta-analyses and literature reviews on cannabis and psychosis, “Cannabis use and psychosis: a review of reviews” published on September 28, 2019 in the European Archives of Psychiatry and Clinical Neuroscience. He said its findings were no surprise. There was consistent support for cannabis use being a contributing cause of psychosis.

The scientific literature indicates that psychotic illness arises more frequently in cannabis users compared to non-users, cannabis use is associated with a dose-dependent risk of developing psychotic illness, and cannabis users have an earlier onset of psychotic illness compared to non-users. Cannabis use was also associated with increased relapse rates, more hospitalizations and pronounced positive symptoms in psychotic patients.

Although not research, in August of 2019 the U.S. Surgeon General published an advisory on Marijuana Use and the Developing Brain. He noted how the marijuana available today is much stronger than it was in the past. The THC concentration in marijuana plants has increased three-fold between 1995 and 2014, 4% to 12% respectively. Marijuana available in some state dispensaries has an average THC concentration between 17.7% and 23.2%. Concentrated products, known as dabs or wax, may contain between 23.2% and 75.9%.

The risks of physical dependence, addiction, and other negative consequences increase with exposure to high concentrations of THC and the younger the age of initiation. Higher doses of THC are more likely to produce anxiety, agitation, paranoia, and psychosis.

The ad hominem arguments against Alex Berenson and Tell Your Children just do not hold up. Attempting to misdirect the debate over the significance of what Berenson elegantly documents and say he should contend with the failures of marijuana prohibition, illustrates how his critics argue past him. The open letter noted above is an example of this: “Weighed against the harms of prohibition, including the criminalization of millions of people, overwhelmingly black and brown, and the devastating collateral consequences of criminal justice system involvement, legalization is the less harmful approach.” The Guardian noted that Berenson was open to that position, although he disagreed with it.

“You can believe that cannabis is a real risk for psychosis and violence and still believe it should be legal,” he said. “That’s a totally reasonable position to take. Just tell the truth.”

For more on marijuana and psychosis, see: “Cannabis and Psychosis: More Reality than Satire.”

01/10/17

Marijuana Makes You Nauseous?

Live Science reported on a study published in the August 31, 2016 issue of The Lancet that found more people are using marijuana and they are using it more often. In 2014, 13.4% of people said they had used marijuana in the previous year, an increase of 3% since 2002. The percentage of people who reported daily or near daily use rose from 1.9% to 3.5%. At the same time concerns about the risks associated with marijuana use dropped. In 2002, 50.4% of adults thought there was a great risk with marijuana use. That fell to 33.3% by 2014. But the perception of lowered risks may be premature.

The authors of the Compton et al. study thought the combination of increased marijuana use and a decreasing perception of the harm suggested there was a need for education regarding the risks of smoking marijuana. One of these health risks is for a medical condition called cannabinoid hyperemesis syndrome, or CHS. It is caused by heavy, long-term use of various forms of marijuana. Its symptoms include cyclic episodes of nausea and vomiting; some people have severe abdominal pain. A CBS Evening News report described a man who struggled with symptoms of CHS for two years before it was correctly diagnosed. Oddly, hot showers or baths seem to provide symptom relief.

CHS was first reported in 2004 by Allen et al. The ten patients were all cyclical vomiters and chronic marijuana users. Nine of the ten also had the abnormal bathing behavior of multiple hot showers or baths. The symptoms of nausea, vomiting and abdominal pain would all settle within minutes of taking a hot bath or shower. Symptoms resolved with abstaining from marijuana use in seven of the ten patients. Three of the abstaining patients resumed marijuana use and relapsed within months.

High Times described CHS as a rare form of cannabinoid toxicity that developed in chronic smokers. The author suggested with CHS, there was generally daily use in excess of three to fives times for several years. CHS is often mistaken for cyclic vomiting syndrome (CVS), because the symptoms are similar. But CVS is not caused by marijuana use. CHS is easily cured by abstaining from cannabis use.

This should not, by any means, hurt marijuana’s reputation for being the safest recreational drug around, but people need to be aware of the syndrome’s existence. If you know anyone with these symptoms tell him or her go to a doctor and stop smoking.

A 2011 review article by Galli et al., “Cannabinoid Hyperemesis Syndrome,” observed how the recognition of CHS coincided with the increased use of cannabis. Their review gave an overview of cannabinoid pharmacology that focused on the properties that seem to contributes to CHS. They also gave a clinical description of CHS and a proposed a method for clinical evaluation, which included differential diagnosis and treatment modalities.

Patients are typically young adults with a long history of cannabis use. They present with recurrent episodes of nausea, vomiting and dehydration with frequent visits to emergency departments. In almost all cases, there was a delay of several years between their chronic marijuana use and the onset of symptoms. One study reported an average duration of 16.3 years of cannabis use before the onset of symptoms. But there have been reports where the time lag was equal to or less than three years.

CHS is a recurrent disorder, with symptom-free periods. There are three phases: pre-emetic, hyperemetic, and recovery. The pre-emetic phase can last for months or years. Patients have early morning nausea, a fear of vomiting and abdominal discomfort. They maintain normal eating patterns and may even increase their marijuana use because its reported relief of nausea.

The hyperemetic phase has spasms of intense and persistent nausea and vomiting, which has been described as “overwhelming and incapacitating.” Patients vomit profusely, often without warning—up to five times per hour. There can be weight loss. Most patients have diffuse, but relatively mild abdominal pain. They are found to be dehydrated, but hemodynamically stable. The tests and work ups done at EDs are inconclusive in the majority of cases.

During this phase, patients take numerous hot showers throughout the day. As this seems to be the only measure that brings some symptom relief, it rapidly becomes a compulsive behavior. The precise mechanism for this relief is not known. It typically lasts for 24 to 48 hours, but the risk of relapse is high if the patient resumes cannabis use.

The recovery phase can last for days, weeks or months. It’s associated with relative wellness and eating patterns. “Weight is regained and bathing returns to regular frequency.”

Patients with CHS usually are misdiagnosed for a considerable length of time. One problem is that it is often confused with cyclic vomiting syndrome (CVS). “Confusion also exists in the medical literature secondary to a failure to recognize chronic marijuana use as a source of vomiting.” Although there is a close similarity of conditions, there are also significant differences.

A 2015 study by Kim et al. looked at the prevalence of patients presenting for cyclic vomiting in Colorado before and after the liberalization of medical marijuana in 2009. A secondary objective was to describe the odds of marijuana use among cyclic vomiting visits during these same time periods. The prevalence of CVS increased from 42 per 113,262 Ed visits to 87 per 125,095 ED visits after marijuana liberalization. Patients with CVS post liberalization were more likely to have documented marijuana use than patients in the pre liberalization period.

The prevalence of cyclic vomiting presentations nearly doubled after the liberalization of medical marijuana. Patients presenting with cyclic vomiting in the postliberalization period were more likely to endorse marijuana use, although it is unclear whether this was secondary to increased marijuana use, more accurate marijuana reporting, or both.

The study said it does not demonstrate causation of CHS. But it does demonstrate a preliminary association “and should serve as the foundation for future prospective studies on the association between marijuana and cyclic vomiting, the eventual establishment of formal diagnostic criteria for CHS.” Foremost among the interventions for symptomatic treatment should be counseling toward abstinence from marijuana use. The authors saw their study as a crucial first step towards establishing a formal diagnosis of cannabinoid hyperemesis syndrome.

High Times seemed to minimize the present concerns with CHS by referring to it as “a very rare syndrome” that is easily cured. CHS does not reverse marijuana’s reputation as “the safest recreational drug around” at this point. But remember that even High Times agreed the cure for CHS is to stop using cannabis. We are just entering into a time of not only increased marijuana use, but also increased daily or near daily marijuana use. As this trend grows into a population of chronic, heavy marijuana users, the safety profile for marijuana will likely change; and it seems that CHS will be part of that decreasing safety profile.

07/27/15

Clearing Away the Medical Marijuana Smoke

There have been some studies that demonstrate potential medicinal benefits of marijuana use, but they often don’t meet the clinical trial standards used by the FDA to approve medications for human consumption. With the state-by-state movement to legalize marijuana progressing, there is a need for quality scientific research into the potential medical benefits of marijuana. Although marijuana has been used recreationally and medicinally for centuries, the mechanics of how it works are not clearly understood. This is partly because there are over 400 different chemicals in cannabis. THC, the psychoactive ingredient in cannabis, was just isolated in the 1960s. What follows are reviews of some articles that look at the benefits and the concerns with medical marijuana.

Marijuana has been used as a folk medicine as far back in time as five thousand years ago. The first medical use likely occurred in Central Asia and spread from there to China and India. The Chinese emperor Shen-Nung is known to have prescribed it in 2800 BC. Between 2000 and 1400 BC it came to India, and from there to Egypt, Syria and Persia. The Greeks and Romans valued marijuana as hemp for ropes. Europeans ate its seeds and used its fibers to make paper. An urban legend falsely held that the U.S. Constitution, Declaration of Independence, and Bill of Rights were written on hemp paper. All three were actually written on parchment.

An Irish doctor, W. B. O’Shaughnessy, working in Calcutta in the 1830s, wrote a paper on the medical uses of cannabis, which were strikingly similar to those known today—vomiting, convulsions and spasticity. By 1854, the medical use of cannabis was listed in the US Dispensatory. Nineteenth-century physicians had cannabis tinctures and extracts for ailments from insomnia and headaches to anorexia and sexual dysfunction. “Cannabis-containing remedies were also used for pain, whooping cough, asthma, and insomnia and were compounded into extracts, tinctures, cigarettes, and plasters.”

The above short history on the history of medical marijuana was taken from an article by J. Michael Bostwick, “Blurred Boundaries: The Therapeutics and Politics of Medical Marijuana.” He noted how the term medical marijuana refers to botanical cannabis, which contains hundreds of compounds—including the two most often used medicinally, THC and cannabidiol (CBD). Synthetic cannabinoids are produced in a laboratory. Botanical cannabis attracts the notoriety and controversy—because it is the same substance used recreationally by “stoners” to get high.

Bostwick noted how the recreational and medical marijuana use of marijuana is not always distinct, which has medical implications for both seasoned and naïve users. For example, naïve users may decide to stop using medical marijuana because of the psychoactive effects of the THC. Although most users will experience a mild euphoria, a few experience dysphoria, anxiety and even paranoia.

As cannabis strains are bred that amplify THC content and diminish counteracting cannabidiol, highs become more intense but so do degrees of anxiety that can rise to the level of panic and psychosis, particularly in naive users and unfamiliar stressful situations.

The Bostwick article reviewed the often-blurred relationship between medical and recreational users. He discussed a Canadian study that found medical cannabis use often followed recreational use; and that most medical users continued using marijuana recreationally. Another study of 4100 Californians found that medical users preferred inhaling their medication. Smoked cannabis has a more rapid response and is easier to titrate so that users get the analgesic effects without the higher levels favored by recreational users seeking the high. Given some of the medical problems from smoking marijuana, using vaporizers or nasal sprays may be an effective alternative delivery system.

Doctor Robert DuPont, in his book The Selfish Brain: Learning from Addiction, referred to marijuana as “a crude drug, a complex chemical slush.” Marijuana and hashish contain over 420 different chemicals, falling into 18 different chemical families. THC and cannabidiol (CBD), are only two of sixty-one cannabinoids, chemicals found only in the marijuana plant. THC is highly soluble in fats, and this quickly passes the blood-brain barrier. The factor, plus the fact that it is insoluble in water, means that it is trapped in bodily organs like the brain and reproductive glands, remaining there of days or even weeks afterwards.

Grant et al. reviewed evidence on the medicinal usefulness of marijuana in “Medical Marijuana: Clearing Away the Smoke.” They noted that most of the studies on the efficacy and safety of cannabinoids for pain and spasticity have occurred since the year 2000. A series of randomized studies at the University of California Center for Medicinal Cannabis Research (CMCR) found that cannabis significantly reduced pain intensity. A significantly greater proportion of individuals reported at least 30% reduction in pain on cannabis; the threshold of decreased pain intensity generally associated with improved quality of life. Medium doses of 3.5% THC cannabis cigarettes were as effective as higher dose (7% THC).

Oral preparations of synthetic THC (dronabinol, Marinol) and a synthetic THC analogue (nabilone, Cesamet) are legally available. Studies suggest that dronabinol significantly reduces pain. The effects on spasticity are mixed: “there may be no observable change in examiner-rated muscle tone, but patients report significant relief.” There has been less research done with nabilone, but there have been reports of modest analgesia. Dronabinol and nabilone are FDA-approved for control of acute and delayed nausea and vomiting from cancer chemotherapy.

Alternative delivery systems for cannabis include vape-pens, sublingual devices, and others that use a metered spray device. The advantages to such systems seem to be the use of known cannabinoid concentrations, predetermined dosing portions, and time-out systems that may help prevent overuse.

There are side effects, which are dose-related in terms of severity. Grant et al. reported that they seem to decline over time and are of mild to moderate severity. “Reviews suggest the most frequent side effects are dizziness or lightheadedness (30%-60%), dry mouth (10%-25%), fatigue (5%-40%), muscle weakness (10%-25%), myalgia [muscle pain] (25%), and palpitations (20%).” There is little data on a timeline of adverse or therapeutic effects. There have been concerns that rapid tolerance to adverse effects may indicate a corresponding tolerance to beneficial effects. But studies of oral sprays in multiple sclerosis report that you can reduce the incidence and severity of adverse effects by downward self-titration without loss of analgesia.

There are additional adverse effects, including some psychiatric side effects, especially with cannabis having high concentration of THC. See the original article for more specifics. The longer-term health risks of medicinal cannabis are unclear; most of the current evidence is based upon non-medical use. Some medical professionals indicate that effective medicinal use of cannabis requires significantly less marijuana than is typically consumed by recreational users.

In “The Current Status of Medical Marijuana in the United States,” Doctor Gerald McKenna noted how the majority of medical marijuana users in Hawaii claim they have chronic pain. He said a main problem in getting the medical profession to support the use of medical marijuana is that it is not widely used medicinally in a non-smoking form. “Authorizing use by inhalation of a drug with an unknown number of co-drugs contained in the same raw form is not supportable.” He said that supporting the use of medical marijuana by inhalation because users prefer it is akin to supporting the inhalation of any other drug taken orally. His impression is that medical marijuana laws have been passed “to bypass the illegality of marijuana.”

He did recommend removing marijuana from Schedule I controlled substance so research could be done more easily. “Until that research is done, stating that marijuana is useful for treating chronic pain, anxiety, post-traumatic stress disorder, depression, and other health conditions remains anecdotal and conjectural.”

It has become clear that the federal government needs to modify its resistance to reclassifying marijuana’s Schedule I Controlled Substance status to allow more quality research into its use and to fund that research. Otherwise, the current circus of inconsistent regulations from state to state, and unverified claims about the medicinal benefits of marijuana will have us back in the days of patent medicines, as far as marijuana is concerned. Further reflections on medical marijuana can be found in: “Let’s not Get Ahead of Ourselves,” “Is the Cart Before the Horse?” and “Marijuana Peek-a-Boo.”

Faith Seeking Understanding

Charles Sigler, D.Phil.

Tag: cannabis