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Does our brain use up more ATP after smoking cannabis?

Does our brain use up more ATP after smoking cannabis?


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kind of an amateur here.

If the firing of the neurons' signals uses up some ATP, and smoking cannabis makes them fire off more quickly, do our brains use up more ATP to sustain that rapid firing?


Drunk and High at the Same Time: How Crossfading Affects Your Body

Marijuana isn’t a drug you secretly use at parties anymore, thanks to increasing legalization. And like marijuana, alcohol can also cause feelings of relaxation, get rid of social inhibitions and make you feel downright giddy.

While alcohol and cannabis affect the brain differently, they share a similar target called the dopamine reward system . The release of dopamine helps achieve a pleasurable drug experience and increases reinforcement behavior to do it again in the future, explains Joseph R. Volpicelli, medical director of the Volpicelli Center, an addiction treatment facility in Pennsylvania. So, it shouldn’t come as a surprise that drinking and smoking simultaneously, otherwise known as crossfading, is a common practice.

When it comes to health and safety, are you setting yourself up for double trouble or enhancing your drug experience when mixing the two? Science shows that the answer boils down to how often you crossfade and which drug you use first.


How Does Marijuana Affect Your Brain?

Even though THC is the most well-known compound of the marijuana plant (or Cannabis plant), this complex plant contains over 500 of known compounds, and probably many unknown compounds.

Now, what really sets marijuana apart from the other plants in the vegetable kingdom, is a specific type of compound only found in the marijuana plant:

Cannabinoids are compounds mainly responsible for the effects of marijuana.

Because there are other types of compounds in marijuana as well, like terpenoids and flavonoids, and research suggests that these ‘other’ compounds have a separate effect on your mind and body (different than the cannabinoids), plus influence the effects of cannabinoids as well.

But cannabinoids are the main compounds that need to be looked at, to understand marijuana's effect on the brain.

And of all these cannabinoids, THC is the one that has the most profound effect on your brain. THC is currently the only known psychoactive cannabinoid in marijuana and the cannabinoid that is responsible for your ‘high’.


Neuroimaging, Cannabis, and Brain Performance & Function

"I think pot should be legal. I don’t smoke it, but I like the smell of it." —Andy Warhol

Cannabis contains various molecules which bind to receptors in the brain, aptly called "cannabinoid receptors." Familiar ligands (which bind to those receptors) include THC (tetrahydrocannabinol) and CBD (cannabidiol), binding to receptors such as the CB1 and CB2 receptors with various downstream functions on the brain.

The primary neurotransmitter involved in innate (endogenous) cannabinoid activity is "anandamide," a unique "fatty acid neurotransmitter" whose name means "joy," "bliss," or "delight" in Sanskrit and related ancient tongues. This neurotransmitter system has only relatively recently been investigated in greater detail, and the basic biology is fairly well worked out (e.g., Kovacovic & Somanathan, 2014), improving understanding of therapeutic, recreational, and adverse effects of different cannabinoids, and paving the way for novel synthetic drug development.

The increasing interest in the therapeutic and recreational use of cannabis demands a greater understanding of the effects of cannabis on the brain and behavior. Because of the controversial and politicized nature of marijuana in societal discourse, strong beliefs about cannabis obstruct our capacity to have a reasoned conversation about the potential pros and cons of cannabis use and have impeded research initiatives. Nevertheless, many states have permitted the medical and recreational use of cannabis preparations, while the federal government is swinging back toward more restrictive policies.

The jury is out

Cannabis advocates, on the other hand, may paint too rosy a picture of the benefits of cannabis preparations, downplaying or dismissing relevant information about the hazards of cannabis in specific populations at risk for certain mental disorders, the risks of cannabis use disorders, and the negative effects of cannabis on certain cognitive processes accompanied by potentially deleterious, and even dangerous, effects on decision-making and behavior.

For instance, while cannabis preparations have been shown to be useful for pain management and functional improvement in various conditions, improving quality of life, cannabis may also cause errors in judgment and delays in information processing, which can lead not only to individual problems, but may get in the way of relationships and professional activities, even leading to possible harm to others by contributing to accidents.

Cannabis has been clearly associated with precipitating the onset of and worsening some illnesses, notably psychiatric conditions. Moreover, there is a growing interest in understanding the therapeutic and pathological potential of different compounds contained within cannabis preparations, most notably THC and CBD—although the importance of other components is increasingly recognized. For example, a recent study in the American Journal of Psychiatry strongly suggests that CBD, useful for treating intractable seizures (e.g., Rosenberg et al., 2015), may be of significant benefit as an augmenting agent for some with schizophrenia (McGuire at al., 2017).

The picture is not either-or, however. A deeper understanding of how cannabis affects different brain regions (under different conditions, e.g., acute vs. chronic use, with and without different mental illnesses and substance use disorder, with individual variations, etc.) is required to ground the debate in knowledge, and provide solid, reliable scientific findings to pave the way for future research. Foundational understanding is lacking, and while there is a growing body of research looking at various aspects of cannabis effects, as is always the case with an evolving body of research early on, the methodology has varied across many small studies, without a clear framework to encourage consistent approaches to investigation.

One question of obvious importance is: What are the effects of cannabis on key functional areas of the brain? How do functional and connectivity changes within key anatomic regions (“hubs,” in network theory) spread out to the brain networks in which they are central? How does cannabis use, to the extent we understand its effects, play on within specific tasks used to study cognition? What, in general, is the effect of cannabis on brain networks, including the default mode, executive control, and salience networks (three key networks in the densely interconnected “rich club” of brain networks)?

These and related questions are more important as we come to understand better how the mind/brain gap can be bridged by progress in mapping out the human neural connectome. The expectation is that increases or decreases in activity in different brain areas in users (compared with non-users) will correlate with broad changes across functional brain networks, which are reflected in patterns of differential performance on a large group of commonly used psychological research tools which capture different aspects of mental function and human behavior.

The current study

With this key consideration in mind, a multicenter group of researchers (Yanes et al., 2018) set out to collect and examine all the relevant neuroimaging literature looking at the effects of cannabis on the brain and on behavior and psychology.

It’s worthwhile to review the meta-analytic approach used briefly and to discuss what kinds of studies were included and excluded, in order to contextualize and interpret the quite significant findings. They looked at literature including studies using fMRI (functional magnetic resonance imaging) and PET scans (positron emission tomography), common tools to measure indicators of brain activity, and conducted two preliminary assessments to organize the data.

First, they divided the studies into ones where activity in various brain areas was either increased or decreased for users versus non-users and matched up anatomic areas with the functional brain networks of which they are parts. In the second layer of refinement, they used “functional decoding” to identify and categorize different groups of psychological functions measured across the existing literature.

For example, studies look at a large but varying set of psychological functions to see how, if at all, cannabis changes cognitive and emotional processing. Relevant functions included decision-making, error detection, conflict management, affect regulation, reward and motivational functions, impulse control, executive functions, and memory, to provide an incomplete list. Because different studies used different assessments under different conditions, developing a pooled analytic approach is necessary to conduct a comprehensive review and analysis.

Searching multiple standard databases, they selected studies with imaging comparing users with non-users, with data available in the form of standard models suitable for pooled analysis, and which included psychological tests of perception, movement, emotion, thinking, and social information processing, in various combinations. They excluded those with mental health conditions, and studies looking at the immediate effects of cannabis consumption. They analyzed this curated data.

Looking at the convergence in neuroimaging findings across studies using ALE (Activation Likelihood Estimate, which transforms the data onto the standard brain mapping model), they identified which regions were more and less active. Using MACM (Meta-Analytic Connectivity Modeling, which employs the BrainMap database to compute whole-brain activation patterns), they identified clusters of brain regions which activated together.

They completed the functional decoding phase by looking at forward and reverse inference patterns to reciprocally link brain activity with mental performance, and mental performance with brain activity, to understand how different psychological processes correlate with functions in different brain regions.

Here is a summary of the overall meta-analytic "pipeline":

Yanes, Riedel, Ray, Kirkland, Bird, Boeving, Reid, Gonazlez, Robinson, Laird, and Sutherland (2018) analyzed a total of 35 studies. All told, there were 88 task-based conditions, with 202 elements related to decreased activation among 472 cannabis users and 466 non-users, and 161 elements regarding increased activation among 482 users and 434 non-users. There were three major areas of findings:

There were several areas of consistent (“convergent”) changes noticed among users and non-users, in terms of activation and deactivation. Decreases were observed in bilateral (both sides of the brain) ACCs (anterior cingulate cortex) and the right DLPFC (dorsolateral prefrontal cortex). By contrast, there was increased activation consistently observed in the right striatum (and extending to the right insula). It's important to note that these findings were distinct from one another, and this lack of overlap means they represent uniquely different effects of cannabis on different systems.

MACM analysis showed there were three clusters of co-activated brain regions:

  • Cluster 1 — ACC included whole-brain activation patterns, including connections with the insular and caudate cortex, medial frontal cortex, precuneus, fusiform gyrus, culmen, thalamus, and cingulate cortex. The ACC is key for decision-making and processing conflict and is involved with exploring and committing to a given course of action (e.g., Kolling et al., 2016), and these related areas cover a broad range of functions related to the ACC. The insula is involved with self-perception, a notable example being a visceral experience of self-disgust.
  • Cluster 2 — DLPFC included co-activation with parietal regions, orbitofrontal cortex, occipital cortex, and fusiform gyrus. As the DLPFC is involved with important executive functions, including regulating emotions, the experience of mood, and direction of attentional resources (e.g., Mondino at al., 2015) as well as aspects of language processing, and the related areas address key functions, including social information processing, impulse control, and related.
  • Cluster 3 — Striatum included whole-brain involvement, notably the insular cortex, frontal cortex, superior parietal lobule, fusiform gyrus, and culmen. The striatum is involved with reward—the so-called “dopamine hit” referenced so often—which when properly regulated allows us to pursue optimal success, but in states of under-activity leads to inaction, and in excess contributes to addictive and compulsive behaviors. The evidence reviewed in the original paper suggests that cannabis use may prime reward circuits to predispose toward addiction, and possibly blunt motivation for ordinary activities.

While these clusters are functionally distinct in terms of how they are affected by cannabis, they overlap anatomically and spatially, highlighting the crucial importance of viewed brain activity from the connectome, networked point of view in order to grasp the translation of reductive brain findings to how the mind works, and how this plays out for people in day-to-day life.

The functional decoding of the three clusters showed patterns of how each cluster correlates with a group of psychological tests: for example, the Stroop test, go/no-go task which involves fast decisions, pain monitoring tasks, and reward-assessing tasks, to name a few. I won’t review them all, but the findings are relevant, and some of them stand out (see below).

This overview of the cluster-task relationships is useful. Especially notable is the presence of the go/no-go task condition in all three functional areas:

Further considerations

Taken together, the results of this meta-analysis are profound and achieve the goals of focusing in on and distilling findings across the relevant literature investigating the effects of cannabis use on brain activation in populations without mental illness, looking at increased and decreased activity in localized brain regions, distributed clusters of distinct relevance, and the impact on key psychological processing tasks and function.

Cannabis lowers activity in both ACC and DLPFC clusters, and for people with normal brain function, this could lead to problems in executive function and decision-making. Cannabis is likely to cause inaccuracy in error monitoring, leading to misperception and performance issues due to mistakes, and may impede function during high-conflict situations, from both errors in judgment as well as from altered decision-making and subsequent execution. Decreased DLPFC activity could lead to emotional regulatory problems, as well as decreases in memory and reduced attentional control.

For people with psychiatric and medical conditions, the same brain effects could be therapeutic, for example reducing pain burden by decreasing ACC activity, alleviating traumatic memories and suppressing post-traumatic nightmares, treating anxiety with few side effects, or reducing psychotic symptoms (McGuire, 2017) by inhibiting activity in involved brain areas.

But cannabinoids also may trigger pathology, precipitating depression or psychosis, and other conditions, in vulnerable populations. Cannabis use also causes problems for the developing brain, leading to undesirable long-term effects (e.g., Jacobus and Tappert, 2014), such as reduced neurocognitive performance and structural changes in the brain.

Cannabis was shown, in contrast, to increase activity in the striatum and related areas generally. For people with normal baseline activity, this could lead to the priming of reward circuits, and as has been observed in numerous studies, could increase the risk of addictive and compulsive behaviors, predisposing to some forms of pathology. This amplification of reward activity (combined with effects on the first two clusters) may contribute to the "high" of marijuana intoxication, enhancing enjoyment and creative activity, making everything more intense and engaging, temporarily.

The authors note that all three clusters involved the go/no-go task, a test situation requiring the inhibition or performance of a motor action. They note:

"Here, the fact that distinct region-specific disruptions were linked with the same task classification may be indicative of a cannabis-related compound effect manifest across studies. In other words, a diminished capacity to inhibit problematic behaviors may be linked to concurrent reduction of prefrontal activity (ACC and DL-PFC) and elevation of striatal activity."

For some patients, cannabis reportedly alleviates symptoms of depression, characterized by core experiences of loss of enjoyment, excessive negative emotional states, and lack of motivation, among other symptoms, but heavier users are at increased risk for worsening depression (Manrique-Garcia et al., 2012).

However, in addition to potentially priming for addiction to other chemicals and enhancing experiences for those who enjoy being intoxicated with marijuana (others find it produces dysphoria, anxiety, unpleasant confusion, or even paranoia), users may find that in the absence of cannabis use, they are less interested in regular activities when they are not high, leading to decreased enjoyment and motivation.

These effects are different depending on several cannabis use-related factors, such as the timing and chronicity of use, as well as the type of cannabis and relative chemistry, given variations among different species and strains. While this study was not able to distinguish between the effects of THC and CBD, as data were not available on concentrations or ratios of these two key components in cannabis, it is likely that they have different effects on brain function which require further investigation to sort out therapeutic potential from recreational and pathological effects.

This study is a foundational study, setting the stage for ongoing research on the effects of various cannabinoids on the brain in health and illness, and providing important data to understand the therapeutic and damaging effects of different cannabinoids. The elegant and painstaking methodology in this study shines a spotlight on how cannabis affects the brain, providing significant data about the overall effects on brain networks as well as on cognitive and emotional function.

Questions of interest include the additional mapping of brain networks and correlating these findings with existing models of the mind, looking at the effect of different types of cannabis and patterns of use, and investigating the effect of cannabinoids (naturally-occurring, endogenous, and synthetic) for therapeutic purposes in different clinical conditions, recreational use, and potentially for performance enhancement.

Finally, by providing a coherent framework for understanding the existing literature inclusive of positive and negative effects of cannabis on the brain, this paper centers cannabis research more squarely in the mainstream of scientific study, providing a neutral, de-stigmatized platform to permit the debate on cannabis to evolve in more constructive directions than it historically has.

Mondino M, Thiffault F & Fecteau S. (2016). Does non-invasive brain stimulation applied over the dorsolateral prefrontal cortex non-specifically influence mood and emotional processing in healthy individuals? Front Cell Neurosci. 2015 9: 399. Published online 2015 Oct 14.

Kolling TE, Behrens TEJ, Wittmann MK & Rushworth MFS. (2016). Multiple signals in anterior cingulate cortex. Current Opinion in Neurobiology, Volume 37, April 2016, Pages 36-43.

McGuire P, Robson P, Cubala WJ, Vasile D, Morrison PD, Barron R, Tylor A, & Wright S. (2015). Cannabidiol (CBD) as an Adjunctive Therapy in Schizophrenia: A Multicenter Randomized Controlled Trial. Neurotherapeutics. 2015 Oct 12(4): 747–768. Published online 2015 Aug 18.

Rosenberg EC, Tsien RW, Whalley BJ & Devinsky O. (2015). Cannabinoids and Epilepsy. Curr Pharm Des. 2014 20(13): 2186–2193.

Jacobus J & Tapert SF. (2017). Effects of Cannabis on the Adolescent Brain. Cannabis Cannabinoid Res. 2017 2(1): 259–264. Published online 2017 Oct 1.

Kovacic P & Somanathan R. (2014). Cannabinoids (CBD, CBDHQ and THC): Metabolism, Physiological Effects, Electron Transfer, Reactive Oxygen Species and Medical Use. The Natural Products Journal, Volume 4, Number 1, March 2014, pp. 47-53(7).

Manrique-Garcia E, Zammit S, Dalman C, Hemmingsson T & Allebeck P. (2012). Cannabis use and depression: a longitudinal study of a national cohort of Swedish conscripts. BMC Psychiatry201212:112.


RESULTS

Self-rating questionnaires show a significant difference in the frequency and amount of cannabis consumption between the groups of regular and occasional smokers. However, they do not differ in age, in the years of cannabis use and or in the age at which consumption started (Table 1). The median value of the self-reported usual amount of cannabis smoked by regular users is higher than that of occasional consumers (0.4 g vs 0.3 g). The determination of cannabinoid time profiles revealed that the THCCOOH median level was significantly higher in regular smokers compared with occasional users (21 μg/l vs 0 μg/l just before smoking the joint). An equal difference was found for the participants enrolled in the same study and selected by Fabritius et al, (2013a) for the pharmacokinetic determinations.

MRI Results

When comparing gray matter volume between groups, we find that significant clusters showing a lower gray matter volume in regular cannabis users compared with occasional ones are located bilaterally in the temporal pole and in the parahippocampal gyrus. Additional clusters cover the left insula and the left orbitofrontal cortex (Figure 1). In contrast, three cerebellar clusters show the opposite behavior, with increased gray matter volume. Coordinates of the centers of gravity of the significant clusters are reported in the Montreal Neurological Institute (MNI) space and are summarized in Tables 2 and 3.

Voxel-Based Morphometry results on gray matter. Cold color bar shows regions where gray matter volume is lower in regular smokers compared with occasional ones. Hot color bar represents the opposite contrast. Maps are thresholded at P<0.005 and k>60 and superposed on a standard brain in the MNI space. Figure shows results in planes centered at −26, 7, 14 mm and −48, 10, −19 mm. Color bars represent T score.

Voxel-by-voxel correlations over the whole brain were performed merging the two groups together. Correlation analysis highlights an inverse linear correlation between GM volume and the monthly frequency of cannabis use during the 3 months before inclusion in the study. Regions with a decreased GM volume in regular smokers (Table 2) are those that exhibit this inverse correlation (P<0.005). Figure 2 (panel a) illustrates this relation in three clusters located in the left parahippocampal gyrus (P=0.004, R=−0.42), left insula (P=0.0002, R=−0.54), and right temporal pole (P=0.002, R=−0.45). The results for the other four regions are presented in the Supplementary File S1.

(a) Correlation between the modulated gray matter intensity at the center of gravity of the significant clusters and the monthly frequency of joints smoked during 3 months before inclusion in the study. Lines represent the fitting of the distribution of the values. Pearson’s correlation coefficient and P-value are shown at the bottom of each plot. (b) Mean GM volume across the four subgroups (Occasional late, Occasional early, Regular late, Regular early). Whiskers represent 95% confidence interval, horizontal lines represent significant comparisons and stars the significance level (P<0.05).

The stratification of the two groups according to the age of first cannabis use in the same clusters shows that a decrease in gray matter volume can occur with a heavy amount of cannabis consumption, independent of the years of usage (Figure 2, panel b). The comparison between the ‘Occasional late’ subgroup and both the ‘Regular’ subgroups shows a significant difference at P<0.05 in each cluster of interest. Recreational consumption begun early in adolescence (ie, ‘Occasional early’ subgroup) significantly affects the GM volume in two regions out of three. These are located in left parahippocampal gyrus (P=0.04) and right temporal pole (P=0.04) the left insula shows only a trend at P=0.09. The effect size measured by Cohen’s d was large (d>1) in each significant comparison. The results for the other four regions are presented in the Supplementary File S1.


Marijuana and mental illness: Low dopamine levels may play a role

A new review offers further insight into how long-term marijuana use might have a negative impact on mental health, after finding “substantial evidence” that the drug alters the brain’s reward system to increase negative emotions and decrease motivation.

Share on Pinterest Researchers say long-term marijuana use lowers dopamine levels in the brain, which could explain why some users develop mental illness.

The study says there is sufficient evidence to suggest marijuana, or cannabis, reduces levels of dopamine in the brain – a neurotransmitter that plays a key role in learning, movement, motivation, emotion, and reward.

Low dopamine levels have been associated with mood changes, fatigue, depression, and lack of motivation dopamine deficiency is present in a number of neurological conditions, including Parkinson’s disease and attention deficit hyperactivity disorder (ADHD).

Study leader Prof. Oliver Howes, of the Medical Research Council (MRC) Clinical Sciences Center at Imperial College London in the United Kingdom, and team recently published their results in the journal Nature.

According to the 2014 National Survey on Drug Use and Health, there are around 22.2 million marijuana users in the United States, making it the most commonly used illicit drug in the country.

Long-term marijuana use has been linked to a number of mental health conditions, including schizophrenia, anxiety, and depression, but the mechanisms underlying this association have been unclear.

Given the increased legalization of marijuana for medicinal and recreational purposes, researchers are keen to learn more about how the drug affects the brain.

For this latest study , Prof. Howes and team conducted a review of numerous studies investigating how the primary psychoactive compound in marijuana – tetrahydrocannabinol (THC) – affects the brain.

According to the researchers, there is now “substantial evidence” in animal and human studies that long-term exposure to THC leads to a decrease in levels of dopamine.

“The available evidence indicates that THC exposure produces complex, diverse and potentially long-term effects on the dopamine system,” the authors explain. “These include increased nerve firing and dopamine release in response to acute THC, and dopaminergic blunting associated with long-term use.”

The team believes this effect may explain why people who engage in long-term marijuana use are at increased risk for mental health problems.

In animal models, current research shows that marijuana use initially raises dopamine levels, fueling a sense of reward, which the team says may offer an explanation for why some users become addicted to the drug.

However, the authors point to some limitations in this area. “Fundamentally, animal studies are too short, and don’t give cannabis repeatedly or in combination with other substances,” notes Prof. Howes.

The researchers also noticed some other gaps in research, such as studies assessing what happens to the dopamine system when marijuana use is ceased.

What is more, the team notes it is important to learn more about how marijuana use affects brain development, as some women may use the drug in early pregnancy, before realizing they are expecting.

“Given the increasing use of cannabis, particularly in young people and women who may be pregnant, animal studies are needed to understand the effects of long-term cannabis use on the developing brain in a controlled way that is not possible in human studies.” says Prof. Howes.

“These studies also need to use techniques that can be translated into human studies, and to better represent human patterns of use.”

While further investigation into the effects of marijuana is clearly warranted, the researchers believe their current study helps broaden our understanding.

“ The changing patterns of cannabis use, including ‘cannavaping’ and edible products, mean it’s vital that we understand the long-term effects of cannabis on the brain.

This new research helps to explain how some people get addicted to cannabis, by showing that one of its main components, called THC, alters a delicate balance of brain chemicals.”

Co-author Dr. Michael Bloomfield, Clinical Sciences Centre, Imperial College London


It Could Increase Your Cardiovascular Risk

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"Marijuana has been shown to cause a fast heartbeat and elevated blood pressure, which can be dangerous for people with heart disease," says Dr. Sanul Corrielus . "It may also aggravate other pre-existing heart conditions in long-term users and those who are older—placing them at greater risk of a cardiovascular event," says Dr. Norris.


Cause and Effect Conundrum

Although animal studies like these have revealed several potential mechanisms by which cannabis might do harm, it’s hard to determine what this means for human teens. Increased risk of psychiatric disorders is a major concern, with schizophrenia having attracted the most attention and controversy. In double-blind, placebo-controlled studies, intravenous doses of pure THC have induced temporary symptoms resembling some aspects of schizophrenia (11, 12). But researchers are still trying to establish whether cannabis use, especially in adolescence, could lead to full-blown schizophrenia in the long run.

In a landmark 1987 study, researchers reported a link between cannabis use and schizophrenia risk among more than 45,000 Swedish military conscripts who were examined at the time of conscription around age 19 and again 15 years later. Those who had used cannabis more than 50 times before conscription were six times more likely to be diagnosed with schizophrenia by the 15-year mark. The association was weaker, though still present, after controlling for factors such as adverse childhood conditions and diagnosis of other psychiatric disorders at the time of conscription (13).

In the decades that followed, several studies yielded similar associations. In one oft-cited 2002 study, psychiatrist Robin Murray at King’s College London and his colleagues analyzed data from roughly 760 New Zealanders who had been followed since birth in the 1970s as part of a larger project, called the Dunedin Study. They found that starting cannabis use by age 15 was associated with a fourfold elevated risk of developing schizophrenia by age 26, whereas starting closer to age 18 carried only a small, nonsignificant increase in risk (14).

Heated debates linger over how to interpret such observations. “Most people would agree there’s clearly a relationship that exists between cannabis use and schizophrenia,” says neuropharmacologist Matthew Hill of the Hotchkiss Brain Institute at the University of Calgary. “I think it’s the directionality of that relationship that’s contentious.”

Theories abound, but the available data are inconclusive, leaving researchers to argue about whether cannabis can directly cause schizophrenia (Murray believes it can, especially with heavy use), or primarily triggers or accelerates schizophrenia in a subset of people already predisposed to developing the disorder. Many researchers favor the latter theory, which, according to Hill, could help explain why rates of cannabis consumption in the Western world have increased dramatically since the 1960s but rates of schizophrenia (often cited to be around 1% or less) have not changed much over time (15, 16).

It’s also possible that other factors contribute to the observed correlations. For example, some research suggests that people already predisposed to schizophrenia are more prone to use cannabis. In a sample of more than 2,000 healthy adults, one study found that those with gene variants linked to increased schizophrenia risk were more likely to use cannabis, and to use more of it than others. “This is not to say that there is no causal relationship between use of cannabis and risk of schizophrenia,” the authors concluded. “But it does establish that at least part of the association may be due to a causal relationship in the opposite direction” (17).

Complicating matters, the neurobiological mechanisms behind schizophrenia itself are not well understood, and a number of other factors—including

“Clearly there’s something unique about the adolescent brain that makes it specifically sensitive to THC.”

—Steven Laviolette

family life, smoking and alcohol use, educational experience, and more—can influence mental health outcomes. “As long as you’re studying humans, there’s always going to be the problem of real life,” says Orr. “Each person is unique and accumulates circumstances before the study and during the study.”


Abstract

Questions surrounding the effects of chronic marijuana use on brain structure continue to increase. To date, however, findings remain inconclusive. In this comprehensive study that aimed to characterize brain alterations associated with chronic marijuana use, we measured gray matter (GM) volume via structural MRI across the whole brain by using voxel-based morphology, synchrony among abnormal GM regions during resting state via functional connectivity MRI, and white matter integrity (i.e., structural connectivity) between the abnormal GM regions via diffusion tensor imaging in 48 marijuana users and 62 age- and sex-matched nonusing controls. The results showed that compared with controls, marijuana users had significantly less bilateral orbitofrontal gyri volume, higher functional connectivity in the orbitofrontal cortex (OFC) network, and higher structural connectivity in tracts that innervate the OFC (forceps minor) as measured by fractional anisotropy (FA). Increased OFC functional connectivity in marijuana users was associated with earlier age of onset. Lastly, a quadratic trend was observed suggesting that the FA of the forceps minor tract initially increased following regular marijuana use but decreased with protracted regular use. This pattern may indicate differential effects of initial and chronic marijuana use that may reflect complex neuroadaptive processes in response to marijuana use. Despite the observed age of onset effects, longitudinal studies are needed to determine causality of these effects.

The rate of marijuana use has had a steady increase since 2007 (1). Among >400 chemical compounds, marijuana’s effects are primarily attributed to δ-9-tetrahydrocannabinol (THC), which is the main psychoactive ingredient in the cannabis plant. THC binds to cannabinoid receptors, which are ubiquitous in the brain. Consequently, exposure to THC leads to neural changes affecting diverse cognitive processes. These changes have been observed to be long-lasting, suggesting that neural changes due to marijuana use may affect neural architecture (2). However, to date, these brain changes as a result of marijuana use remains equivocal. Specifically, although functional changes have been widely reported across cognitive domains in both adult and adolescent cannabis users (3 ⇓ ⇓ –6), structural changes associated with marijuana use have not been consistent. Although some have reported decreases in regional brain volume such as in the hippocampus, orbitofrontal cortex, amygdala, and striatum (7 ⇓ ⇓ ⇓ ⇓ –12), others have reported increases in amygdala, nucleus accumbens, and cerebellar volumes in chronic marijuana users (13 ⇓ –15). However, others have reported no observable difference in global or regional gray or white matter volumes in chronic marijuana users (16, 17). These inconsistencies could be attributed to methodological differences across studies pertaining to study samples (e.g., severity of marijuana use, age, sex, comorbidity with other substance use or psychiatric disorders) and/or study design (e.g., study modality, regions of interest).

Because THC binds to cannabinoid 1 (CB1) receptors in the brain, when differences are observed, these morphological changes associated with marijuana use have been reported in CB1 receptor-enriched areas such as the orbitofrontal cortex, anterior cingulate, striatum, amygdala, insula, hippocampus, and cerebellum (2, 11, 13, 18). CB1 receptors are widely distributed in the neocortex, but more restricted in the hindbrain and the spinal cord (19). For example, in a recent study by Battistella et al. (18), they found significant brain volume reductions in the medial temporal cortex, temporal pole, parahippocampal gyrus, insula, and orbitofrontal cortex (OFC) in regular marijuana users compared with occasional users. Whether these reductions in brain volume lead to downstream changes in brain organization and function, however, is still unknown.

Nevertheless, emergent studies have demonstrated a link between brain structure and connectivity. For example, Van den Heuvel et al. and Greicius et al. demonstrated robust structural connections between white matter indexes and functional connectivity strength within the default mode network (20, 21). Similarly, others have reported correlated patterns of gray matter structure and connectivity that are in many ways reflective of the underlying intrinsic networks (22). Thus, given the literature suggesting a direct relationship between structural and functional connectivity, it is likely that connectivity changes would also be present where alterations in brain volume are observed as a result of marijuana use.

The goal of this study was to characterize alterations in brain morphometry and determine potential downstream effects in connectivity as a result of chronic marijuana use. To address the existing inconsistencies in the literature that may be in part due to methodological issues, we (i) used three different MRI techniques to investigate a large cohort of well-characterized chronic cannabis users with a wide age range (allowing for characterization without developmental or maturational biases) and compared them to age- and sex-matched nonusing controls (ii) examined observable global (rather than select) gray matter differences between marijuana users and nonusing controls and (iii) performed subsequent analyses to determine how these changes relate to functional and structural connectivity, as well as behavior. Given the existing literature on morphometric reductions associated with long-term marijuana use, we expected gray matter reductions in THC-enriched areas in chronic marijuana users that will be associated with changes in brain connectivity and marijuana-related behavior.


Marijuana May Not Lower Your IQ

Around the world, about 188 million people use marijuana every year. The drug has been legalized for recreational use in 11 U.S. states, and it may eventually become legal at the federal level. In a Gallup survey conducted last summer, 12 percent of American adults reported that they smoked marijuana, including 22 percent of 18- to 29-year-olds. Those are the stats. The consequences remain a mystery.

As access to marijuana increases&mdashand while acceptance of the drug grows and perception of its harmfulness diminishes&mdashit is important to consider the potential for long-term ill effects, especially in users who start young. One of marijuana&rsquos best-documented consequences is short-lived interference with memory. The substance makes it harder to get information into memory and, subsequently, to access it, with larger doses causing progressively more problems. Much less documented, however, is whether the drug has lasting effects on cognitive abilities. Finding the answer to that question is essential. Depending on the severity of any such effects and their persistence, marijuana use could have significant downstream impacts on education, employment, job performance and income.

There are plausible reasons why the teenage brain may be especially vulnerable to the effects of marijuana use. Natural cannabinoids play an essential role in brain cell migration and development from fetal life onward. And adolescence is a crucial age for finalizing brain sculpting and white matter proliferation. The hippocampi, paired structures in the temporal lobe that are crucial in the formation of new memories, are studded with cannabinoid receptors. THC, the main ingredient behind marijuana&rsquos &ldquohigh,&rdquo acts on the brain&rsquos cannabinoid receptors to mimic some of the effects of the body&rsquos endogenous cannabinoids, such as anandamide. The compound&rsquos effects are more persistent and nonphysiological, however. It may be throwing important natural processes out of balance.

A key report on marijuana appeared in 2012. It was issued by a research group that had tracked the development of 1,000 New Zealanders born in the city of Dunedin in the early 1970s. Having assessed measures of cognition and IQ starting at age three, the researchers recorded participants&rsquo use of the drug from their early teen years through their 30s. While those who never used marijuana showed slight IQ increases over time, users experienced steady IQ declines proportional to how long they had smoked and how much. At age 38, users who had started young reported more problems with subjective thinking, and their close friends described them as having attention and memory difficulties. Those who smoked marijuana heavily as adolescents and later quit never fully returned to the baseline. The effect involved all cognitive domains, from remembering lists of words to processing information, solving problems and paying attention. The three dozen people who had used the drug most persistently had an overall decline of around six to eight IQ points. That&rsquos a big deal. So you might think, &ldquoCase closed. Smoking dope makes you dopey.&rdquo But not so fast.

In a world run by evil scientists, determining the effects of marijuana on IQ would be simple: A randomly determined half of the population would be exposed to the drug during adolescence, and the remainder would be given a placebo. Scientists could compare subjects&rsquo cognitive scores before and after marijuana use, and, presto, you would have your answer. For such answers in the real world, however, we rely on epidemiology, a branch of science that addresses population-level questions ethically. Two important longitudinal strategies for disentangling cause versus consequences are large-scale cohort studies and twin designs. The advantage of the former strategy, as used in the Dunedin study, is that each participant acts as his or her own control. Given that every child starts with a different IQ, it is simple to measure whether Johnny&rsquos or Janie&rsquos scores rise or fall over time in relation to their marijuana use (measured by individual accounts of the quantity, frequency and duration of that use.)

The second strategy proceeds from a different logic. Because twins grow up with the same family backgrounds and are genetically very similar (nearly precisely so in identical twins), they form perfect experimental controls for each other. If Twin A smokes cannabis while Twin B doesn&rsquot, then researchers have a tightly controlled mini experiment that helps rule out confounding factors such as Dad&rsquos job or the alcoholism in Mom&rsquos family. With epidemiological twin studies, a researcher is able to look across an entire sample and summarize all the relevant effects.

Two such researchers are Nicholas Jackson of the University of Southern California and William Iacono of the University of Minnesota, who worked with their colleagues to examine data from two longitudinal studies of adolescent twins in California and Minnesota. The researchers measured the twins&rsquo intelligence between nine and 12 years of age, before any drug use, and did so again between ages 17 and 20. Exactly as in the Dunedin study, marijuana users had lower test scores and showed notable reductions in IQ over time. But in Jackson and Iacono&rsquos analysis, marijuana use and IQ were completely uncorrelated, and IQ measures fell equally in both the users and abstainers. Subsequent twin studies, including one performed with U.K. data by the Dunedin team, corroborated these findings of no relationship between marijuana use and a falling IQ.

How can we explain these discrepancies? First, young marijuana users are many times more likely to also use alcohol and other illicit drugs. And when epidemiologists factor binge drinking, nicotine and other drug use into their models, marijuana&rsquos cognitive effects evaporate. Thus, IQ decline seems more nonspecifically related to general substance use. But this observation doesn&rsquot explain why IQ also falls in nonusing twins of cannabis users. Jackson, Iacono and their colleagues noted that at baseline, prior to any substance involvement, future marijuana users in one of the two cohorts they examined already had significantly lower IQ scores. Put another way, cannabis did not drag down their IQ it was already low.

Next, investigators uncovered shared underlying vulnerability factors that explained both marijuana use and IQ decreases. For example, behavioral traits such as impulsivity and excessive risk-taking predicted both substance use and lower IQ, as did being raised in a family that did not value education. Delinquent kids received lower grades because of their tendency to skip school and use drugs. So cannabis use was not a culprit in cognitive decline. A welter of inherited and environmental factors seemed to explain both.

How can we decide among apparently convincing yet opposing sets of findings? The early-middle-aged subjects in New Zealand had used cannabis over a much longer time span than had the late-teen twins in Minnesota. Perhaps adolescent cannabis use has no detectable cognitive impact except at very high levels and/or over many years. For now, investigators are eagerly awaiting data from the recently launched Adolescent Brain and Cognitive Development (ABCD) study. ABCD is following 11,000 U.S. 10-year-olds in a national epidemiological sample with serial IQ testing and brain imaging to capture the trajectories of normal brain and IQ development prior to any substance use&mdashand to document any longitudinal consequences of such use. This research has the potential to settle the issue of the relationship of adolescent marijuana use to changes in cognition. Scientists will begin to see meaningful results in the next few years, as these subjects reach their mid-teens.

Last year former Food and Drug Administration commissioner Scott Gottlieb warned about the potential harm embedded in &ldquothe great natural experiment we&rsquore conducting in this country by making THC widely available.&rdquo His concerns return us to the core issue. Physicians and lawmakers need a more accurate sense of THC&rsquos effects on adolescent minds so that parents, teachers and social planners can respond preemptively to teenage marijuana use. If long-term cognitive effects are shown to be real, this conclusion should result in appropriate plans to restrict use through educational efforts and tough legal sanctions. On the other hand, if cognitive effects are transient or better explained by sociological phenomena, we can all take a step back and direct our efforts and resources elsewhere.

Are you a scientist who specializes in neuroscience, cognitive science, or psychology? And have you read a recent peer-reviewed paper that you would like to write about? Please send suggestions to Mind Matters editor Gareth Cook. Gareth, a Pulitzer prize-winning journalist, is the series editor of Best American Infographics and can be reached at garethideas AT gmail.com or Twitter @garethideas.

ABOUT THE AUTHOR(S)

Godfrey Pearlson is a physician-scientist, a professor of psychiatry and neuroscience at Yale University and director of the Olin Neuropsychiatry Research Center at Hartford HealthCare's Institute of Living in Hartford Conn. He is also chair of the neuroscience committee of the Research Society on Marijuana. Pearlson has received research grants to study the effects of cannabis on driving impairment in human volunteers from the National Institute on Drug Abuse and the National Highway and Traffic Safety Administration. His first book, Weed Science: Cannabis Controversies and Challenges, will be published by Elsevier in July 2020.