High potency cannabis creates memory problems related to free recall, source memory and false memories

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Even before the pandemic made Zoom ubiquitous, Washington State University researchers were using the video conferencing app to research a type of cannabis that is understudied: the kind people actually use.

For the study, published in Scientific Reports, researchers observed cannabis users over Zoom as they smoked high-potency cannabis flower or vaped concentrates they purchased themselves from cannabis dispensaries in Washington state, where recreational cannabis use is legal. They then gave the subjects a series of cognitive tests.

The researchers found no impact on the users’ performance on decision-making tests in comparison to a sober control group but did find some memory impairments related to free recall, source memory and false memories.

While the findings are in line with previous research on low-potency cannabis, this study is one of the few to investigate cannabis that contains much more than 10% tetrahydrocannabinol (THC), the plant’s main psychoactive ingredient. This is only the second known study to examine the effect of cannabis concentrates.

“Because of federal restrictions to researchers, it was just not possible to study the acute effects of these high-potency products,” said Carrie Cuttler, WSU psychologist and lead researcher on the study.

“The general population in states where cannabis is legal has very easy access to a wide array of high- potency cannabis products, including extremely high-potency cannabis concentrates which can exceed 90% THC, and we’ve been limited to studying the whole plant with under 10% THC.”

While 19 states and Washington D.C. have legalized cannabis for recreational use, the U.S. federal government still classifies it as a Schedule 1 drug, implying it has a high potential for abuse and no medicinal benefits. Until recently, researchers interested in studying cannabis were limited to using low-potency plants of around 6% THC supplied by the National Institute of Drug Abuse. In June, the U.S. Drug Enforcement Administration indicated it may allow some companies to start growing cannabis for research purposes.

For this study, which began in 2018, Cuttler and her colleagues found a way to study the effects of high-potency cannabis while still complying with federal guidelines. The study participants bought their own products and used them in their own homes.

They were never in a laboratory on federal property, and the researchers never handled the cannabis themselves. Participants were not reimbursed for their purchase. Instead they were compensated for their time with Amazon gift cards.

All participants were over 21 and experienced cannabis users who reported no past negative reactions to cannabis like panic attacks. The study’s method was cleared by WSU Division of the Office of the Attorney General and the university’s research ethics board.

The 80 participants were divided into four groups: two groups used cannabis flower with more than 20% THC but one containing cannabidiol (CBD), a non-psychoactive component of cannabis, and the other without CBD. Another group vaped cannabis concentrates with more than 60% THC that included CBD. A fourth group remained sober.

For all cannabis using groups, the researchers found no effect on a range of decision-making tests including risk perception and confidence in knowledge. On a few memory tests there were also no significant differences between the cannabis-using and sober groups, including prospective memory, the ability to remember to do things at a later time, such as attend an appointment.

The cannabis-using participants also did well on temporal order memory, the ability to remember the sequence of previous events.

However, the groups that smoked cannabis flower with CBD did worse on verbal free recall trials- they were unable to recall as many words or pictures that were shown to them compared to the sober group. This finding was contrary to a small number of previous studies indicating CBD might have a protective effect on memory. The groups that used cannabis without CBD and the group that used concentrates, performed worse on a measure of source memory which means being able to distinguish the way previously learned information was presented.

Finally, all three cannabis-using groups did poorly on a false memory test—when given a new word and asked if it had been presented before, they were more likely to say it had when it had not.

There was also an unexpected finding: people who vaped the high-potency concentrates with more than 60% THC performed comparably to those who smoked cannabis flower. This may have been because they tended to self-titrate – using less of the drug to achieve a similar level of intoxication and impairment as the people who smoked the less-potent cannabis flower.

Cuttler said this was cause for cautious optimism on the little-studied but widely available concentrates.

“There’s been a lot of speculation that these really high-potency cannabis concentrates might magnify detrimental consequences, but there’s been almost zero research on cannabis concentrates which are freely available for people to use,” said Cuttler. “I want to see way more research before we come to any general conclusion, but it is encouraging to see that the concentrates didn’t increase harms.”


Following nicotine and alcohol, cannabis is the most commonly used psychoactive substance in the world, with a global prevalence of 5.1% in 2016 (1, 2). Cannabis is an illegal substance in most countries but is increasingly becoming a legal drug in various states in the USA, in Portugal and Uruguay, and, as of 2018, nationwide in Canada (3). The trend toward legalization of recreational cannabis use corresponds with heightened acceptance, reduced perception of risk, and an increase in cannabis use among adolescents and adults (4–6).

Cannabis contains over 100 distinct cannabinoids, several of which have demonstrated psychoactive properties (7). Two of the most widely researched cannabinoids are delta-9-tetrahydrocannabinol (THC), and cannabidiol (CBD), which directly modulate the endocannabinoid system in humans. The endocannabinoid system is comprised of at least two cannabinoid receptor types, CB1 and CB2, which are involved in various brain functions, including pain, motivation, memory, mood, and reward processing (8, 9).

THC is the principal psychoactive constituent of the cannabis plant and produces a wide range of transient and dose-dependent effects by acting as an agonist at CB1 receptors (10). In animal models, THC administration reduces anxiety at low doses but increases anxiety at higher doses (11). It also produces transient psychotomimetic effects, including perceptual distortions, paranoia, and euphoria (12). There is evidence that acute administration of THC interferes with numerous behavioral and cognitive processes, including emotional processing, episodic memory, attention, working memory, and reward processing [e.g., (13–15)].

In contrast to THC, CBD has a low affinity for CB1 and CB2 receptors, and its molecular mechanism of action remains poorly understood (7). CBD is thought to inhibit the hydrolysis and reuptake of endocannabinoids and modulate cannabinoid receptors (16, 17) CBD produces markedly different psychological effects in comparison to THC and does not adversely impact cognitive or motor performance during intoxication (18, 19). CBD is devoid of any psychomimetic effects, and both human and animal evidence suggests that CBD has anxiolytic properties (20, 21). Co-administration of CBD and THC may alter the pharmacological effect of THC, such that CBD enhances some of THC’s desirable effects while attenuating some of its adverse effects (20, 22–24). For example, a recent systematic review investigating CBD’s psychoactive properties, suggested that CBD may offset the psychosis-like effects of THC (25).

Recently, there have been concerns surrounding the increased levels of THC found in present day cannabis, combined with reduced levels of CBD (26). This high-potency cannabis is gaining popularity with recreational users despite a growing body of literature indicating that potent cannabis preparations are associated with adverse health outcomes, including increased risk of psychosis, hypomania, impulsivity, and cannabis use disorder (27–29). Furthermore, with substantial legalization, decreased perceptions of risk associated with cannabis may arise, which may further increase current cannabis use prevalence. For example, nationally representative data from adults across the United States indicated that the perceived risk of recreational cannabis use decreased from 51.3% in 2002 to 40.3% in 2012 (30), even though the THC potency of cannabis has increased from 8.9% in 2008 to 17.1% in 2017 (31). These changes in perception of risk emphasize the need for continued research on the behavioral effects of cannabis use, since there is significant variance concerning the potential harms and benefits of cannabis use.

This systematic review examines experimental, cohort, and cross-sectional studies to determine the effects of cannabis use on behavioral, cognitive, mental health and psychosocial adverse outcomes in non-clinical populations. We sought to address the following aims: (1) to determine the effects of cannabis use on the prevalence and severity of adverse outcomes in people without medical or psychiatric disorders and (2) to determine risk factors associated with the development of adverse outcomes in cannabis users.

Discussion
Cognition

Concerning cognitive impairments, there is moderate evidence that chronic cannabis use and acute THC intoxication may negatively impact verbal, working, and episodic memory, executive functioning, and divided and sustained attention in users. However, cannabis does not appear to affect all cognitive domains, as impairments in visuospatial memory, processing speed, inhibitory control, and IQ were less consistent with mixed results.

Our review suggests a dose-dependent relationship between chronic cannabis use and verbal, episodic, and working memory impairments, but primarily among individuals who began use in adolescence. These findings coincide with preclinical animal models which have found that repeated exposure to THC during adolescence, but not adulthood, negatively impacts multiple cognitive domains, including memory, throughout the lifespan (156, 157).

We also found modest evidence for improvements in cognition with cannabis abstinence, as some studies comparing non-users and past users demonstrated similar levels of performance among laboratory assessments (36, 65, 66). Given the brain’s plasticity, restoration of neurocognitive abilities may be expected.

A recent meta-analysis investigating residual cognitive impairments in cannabis users found no significant deficits among individuals who had abstained for at least 25 days (158). However, additional well-controlled prospective designs monitoring cognition from current use through cessation of use and over extended periods of abstinence are needed.

Among studies investigating the effects of acute THC administration, the evidence implicates greater impairment in cognition among recreational cannabis users and non-users in comparison to chronic cannabis users [e.g., (48, 61, 70, 79)]. In fact, a recent review evaluating the development of tolerance among cannabis users obtained comparable findings suggesting that cognition was most impaired upon acute THC intoxication (159), suggesting minimal tolerance.

Despite these findings, mixed evidence for numerous cognitive domains in this review arose, which may be due to variability in the control variables employed, cognitive tests utilized, operationalization of cognitive domains, participants’ cannabis use histories, and cannabis exposure heterogeneity. Irrespective of these limitations, the effects obtained in this systematic review suggest that impairment of numerous cognitive domains can persist well-beyond the period of acute intoxication and consequently adversely impact everyday functioning in cannabis users.

Motivation

Although the research concerning the effects of cannabis on motivation among non-clinical populations is limited, the evidence suggests a moderate negative relationship between cannabis use and motivation. These findings align with the “amotivational syndrome,” a term first coined by Smith [(160), p. 43] which purports that individuals who use cannabis are characterized by “a loss of desire to work or compete”, in addition to reduced emotional reactivity and interest in attaining goals (161).

While cannabis use may adversely impact motivation, the results need to be interpreted with caution due to certain methodological limitations. All of the included studies were cross-sectional, which significantly limits our understanding concerning the directionality between these two variables.

Moreover, the conception and operationalization of motivation greatly differed across studies. While some of the included studies employed self-report measures such as the Apathy Evaluation Scale (AES) to measure apathy, other studies utilized performance-based tasks and operationalized motivation as perseverance in working for a monetary reward.

Despite these methodological limitations, the evidence concerning cannabis use and reduced motivation aligns with studies suggesting that chronic cannabis users demonstrate reduced occupational and educational attainment compared to non-users [e.g., (107, 111, 112)]. Nevertheless, the field can significantly benefit from controlled, large-scale prospective designs evaluating motivation throughout the life trajectory while considering the impacts of the frequency of cannabis use, age of onset for use, and the influence of other substance use on motivational outcomes.

Psychosocial Functioning

With a global trend toward legalization and decriminalization of cannabis for medical and/or recreational uses, the potential psychosocial harms accompanying cannabis use remain a major public health concern. Use of cannabis by adolescents is widespread and our findings suggest that chronic cannabis use throughout this developmental period is strongly associated with reduced educational and occupational attainment among this population.

Nevertheless, the mechanisms linking cannabis and educational and economic risks are unclear. However, early age of onset, frequent or heavy use, and predictors of early use (e.g., childhood conduct or depressive symptoms), may undermine educational and occupational attainment. Consequently, delaying use onset and reducing the frequency of cannabis use patterns among adolescents may be beneficial in minimizing disruptions to educational goals and economic success.

While much of the evidence focuses on post-secondary or high school educational attainment, only one study included in the review followed a birth cohort until middle adulthood (107). The authors found that persistent cannabis use throughout adulthood corresponded with adverse mental health, substance use, and psychosocial outcomes, even after controlling for relevant confounding factors.

Moreover, the authors denoted individual and childhood factors predicting persistent cannabis use in adulthood, including novelty-seeking, parental substance use, deviant peer affiliation, and conduct disorder diagnosis in adolescence. While additional, well-controlled studies are required to substantiate these findings, regardless of causality, our review indicates that individuals who utilize heavy amounts of cannabis for an extended period may experience adverse consequences to their social and economic well-being throughout the lifespan.

Psychiatric Outcomes
Depression and Anxiety

The review obtained mixed evidence concerning the relationship between cannabis use and depressive symptomology. Numerous studies implicated a dose-dependent relationship between cannabis use beginning in adolescence and increases in depressive symptomology. However, this effect was inconsistent across studies, which may be attributed to methodological differences within the literature.

For example, differences surrounding the follow-up period and assessments of cannabis use frequency and levels may have precluded other authors from distinguishing a relationship between cannabis use and depressive symptomology. Moreover, the reported association between cannabis use and depression may have been influenced by variation among the controlled variables across the studies reviewed.

A modest proportion of the cohort studies obtaining a significant relationship between adolescent cannabis use and increased depressive symptomology in adulthood did not account for additional substance use, such as nicotine and alcohol [e.g., (117, 118)]. This is of significance because alcohol and tobacco use are prevalent among cannabis users, and these substances may independently elevate individual susceptibility to depression if used throughout adolescence (162–164).

Concerning the effects of cannabis use on anxious symptomology, while individuals frequently report cannabis as an effective agent to relieve anxiety, [e.g., (165)] the evidence suggests a moderate dose-dependent relationship between cannabis use and heightened anxious symptomology.

One potential exception surrounding these findings is in the case of cannabidiol (CBD). Among two randomized, double-blind, placebo-controlled, experimental designs, relative to placebo, CBD reduced anxiety on a social stress test among a sample of non-clinical participants (134, 136). While these findings implicate an anxiolytic effect of CBD, future research is necessary to evaluate whether these effects persist long-term.

Despite these findings within the anxiety literature, there are some noteworthy methodological considerations. Similar to the findings surrounding cannabis and depression, controlled factors varied across studies. Several cohort designs did not obtain significant relationships between cannabis use and anxiety disorders after controlling for other substance use and childhood psychosocial variables [e.g., (117, 127, 135)], while studies that did not control for one or more of these variables did obtain significant findings [e.g., ((63, 129)].

Secondly, follow-up times of cohort designs significantly varied, ranging from 1 to 35 years, with attention directed toward adolescents and young adults. Consequently, the effects of cannabis use on anxious symptomology during middle and late adulthood are poorly understood.

Although the review suggests cannabis as heightening anxious symptomology and possibly depressive symptomology, the mechanism underlying this relationship has not been clearly established. A neurobiological explanation has been put forward suggesting that THC may perturb endocannabinoid system CB1 receptor signaling, which has been linked to psychopathology and dysregulation of emotional experiences (166).

Animal models have also demonstrated that administering THC during adolescence elevates symptoms reflecting anhedonia and anxiety in adulthood and is paralleled by neurotransmitter changes, including a diminution in serotonin, which is a neurotransmitter linked to depression, and increases in norepinephrine, which is a neurotransmitter linked with anxiety (167, 168). Interestingly, a recent preliminary study of 28 days of cannabis abstinence in people with major depression and cannabis use disorder suggests clinically relevant improvements in depression, anxiety and motivation (169).

A second explanation for the relationship between cannabis and elevated anxious and depressive symptomology utilizes a psychosocial lens (170). Cannabis use is associated with numerous adverse psychosocial outcomes, including unemployment, increased affiliation with deviant peers, and poorer educational outcomes (106, 112), which are all factors that may increase risk of developing an anxious or depressive disorder.

Psychosis

We found a strong relationship between chronic cannabis use and an increased risk for psychosis. T

his relationship persisted independent of alcohol [e.g., (143, 153)] and tobacco [e.g., (124, 138, 152)] use. In comparison to non-users, cannabis users have an earlier age of onset of psychotic disorders (143, 147, 151). Moreover, the association between cannabis use and psychotic symptomology is elevated with heavier, more frequent, and earlier use (27, 132, 138, 143). These findings coincide with a large meta-analysis which analyzed over 20,000 subjects, and found that the onset of psychosis is 2.7 years earlier in cannabis users than in non-users (171).

Although the evidence supports a relationship between cannabis use and psychotic symptoms, these findings may be confounded by tobacco use, as a significant proportion of cannabis users also smoke cigarettes. Moreover, many longitudinal studies observing a relationship between cannabis use and increased psychotic symptomology or a diagnosis of a psychotic disorder, had not recorded tobacco use [e.g., (138, 144, 148)].

A recent meta-analysis found that daily tobacco use correlates with an increased risk of psychosis, in addition to an earlier onset of a psychotic disorder (172). However, other evidence suggests that acute nicotine or tobacco use does not exacerbate the positive and negative symptoms of psychosis in schizophrenia [e.g., (173, 174)], and that abstinence does not alter schizophrenia psychosis (175).

Despite the potential confounding role of tobacco use in longitudinal designs, direct evidence obtained within experimental studies demonstrate a clear temporal association between THC-intoxication and increased psychotic symptomology, including positive, negative, and cognitive symptoms [e.g., (24, 53, 146)].

Further, reports of psychosis within randomized, placebo-controlled, experimental studies of THC administration are commonly made, and among some individuals, psychosis persists beyond the acute intoxication phase (15, 176, 177). Therefore, the primary symptom clusters present in schizophrenia are also frequently present in varying degrees during THC-intoxication.

Overall Strengths and Limitations

One of the major strengths of this review includes its behavioral focus: we addressed important questions concerning the clinical, cognitive, and psychosocial outcomes associated with cannabis use. Our findings provide evidence that there are numerous risks associated with cannabis use, which is likely of significant interest to public health officials, educators, policymakers, researchers, healthcare practitioners, and the general public.

Additionally, extending our review to a broad array of outcomes allowed us to detect major gaps in the current literature. A final strength of this review is that we employed a methodologically rigorous and comprehensive approach in collecting our evidence by following PRISMA guidelines (32).

Although we performed a comprehensive, systematic review, there are important limitations to note. As previously discussed, many of the studies across the investigated domains did not control for important confounding factors such as alcohol, tobacco and other substance use, or familial and other psychosocial variables [e.g., (58, 63, 74, 129)].

Accordingly, the possibility that the negative impacts of cannabis use upon the outcomes explored are attributed to confounding factors cannot be dismissed. An additional limitation of the present systematic review is the heterogeneity of the included studies insofar as study methodology, outcome measures assessed, and duration of follow-up.

Participants differed on various socio-demographic characteristics and cannabis use parameters, including age of onset, lifetime use, abstinence periods for former users, and frequency of use. Moreover, the potency of cannabis used, and relative concentrations of THC and CBD are also important to consider and were infrequently discussed in the included studies. These methodological differences have likely contributed to the mixed findings, and should be addressed in future research.

Despite these limitations, we did identify a trend where frequent or heavy cannabis use in adolescence was typically a significant risk factor for numerous adverse outcomes in adulthood, including worsened educational attainment, reduced IQ, and the development of an anxiety disorder, major depressive disorder and psychosis (See Table 2 for a summary of the quality of the evidence).

Our findings suggest that the adolescent brain is especially vulnerable to the effects of cannabinoids (especially THC) in comparison to the adult brain. Prior research has demonstrated that exposure to endogenous cannabinoids modifies the endocannabinoid system, which is a major player in shaping neurodevelopmental processes, including modulating neuroplasticity and regulating synaptic connections (178–180).

It is possible that cannabis use during adolescence disrupts these neurodevelopmental processes. Consequently, this may produce enduring changes in brain structure and function that underlie many of the adverse cognitive and clinical outcomes associated with adolescent cannabis use.

reference link : https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7920961/


More information: Carrie Cuttler et al, Acute effects of high-potency cannabis flower and cannabis concentrates on everyday life memory and decision making, Scientific Reports (2021). DOI: 10.1038/s41598-021-93198-5

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