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Simone Grant
Professor Whittet
Advanced Writing in the Discipline
3/3/17
Abstract

The current research climate of marijuana with other medication is dismal. There are currently no

studies directly analyzing the side effects of marijuana when taken with psychiatric medications,

which are prescribed to millions of Americans who face mental illnesses. This review analyses

the research done and its limitations and gives potential solutions to solve some of the

uncertainty regarding marijuana research in the United States.

Introduction

Millions of Americans face the symptoms of mental illness each year. 18.1% of adults in the U.S.

experienced an anxiety-related condition, 6.9% of adults had a major depressive episode, and an

additional 3.7% have experienced mania or psychotic-like symptoms in schizophrenia or bipolar

disorder (Mental Health by the Numbers, NAMI). These mental illnesses are frequently treated

with medications that can help to correct the imbalances in their neurotransmitter creation and

release, with common examples including antidepressants and anti-anxiety medications,

stimulants, mood stabilizers, and antipsychotics. (Mental Health Medications, NIMH) These

medications come with their own side effects depending on the medication, and new side effects

become present when they are taken in conjunction with other drugs that also have psychoactive

effects on the body, such as marijuana (Schukit, 1987). Research on the interactions between

psychoactive drugs of abuse and commonly prescribed medications for mental illnesses is nearly

nonexistent, and the effects of taking such drugs together may have short-term or long-term

negative effects that are currently unknown. With the legalization of marijuana occurring in more
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states, including the state of Massachusetts, it is important that the side effects of psychoactive

drugs when also taken with commonly prescribed medications are noted. This review will

explain the current climate of marijuana research as it may interfere or impact psychiatric drug

users in the United States, and will also suggest potential solutions for the current barriers to

achieving studies that effectively suggest side effect information.

Research

Tetrahydrocannabinol, or THC, is the main psychoactive component of marijuana, and most

marijuana that is smoked recreationally contains high doses of THC as it is grown for its THC

content (Drug and Human Performance Fact Sheet, NHTSA). THC primarily interacts with 2

receptors, known as the CB1 and CB2 receptors, which are in multiple brain regions. The CB1

receptors occur primarily in the CNS and have been mainly identified in the cerebellum, basal

ganglia, and hippocampus (Mandal A, Robertson S). THC has been shown to have effects on

mood and can modulate anxiety and mood states, which may be due to the neurons in which CB1

receptors are located.

The CB1 receptor is often found on neurons that regulate neurotransmitter release, specifically

monoamine releases such as serotonin and norepinephrine. Endogenous cannabinoids or

exogenous THC can bind to these CB1 receptors to produce a myriad of effects including

increased monoamine release, decreased monoamine release, or a combination, depending on the

dosage and method of intake for marijuana (Drug and Human Performance Fact Sheet, NHTSA).

Due to the nature of the cannabinoid system and its methods of regulating neuronal release, it

may have an effect on those who take medications for mental illnesses which alter the overall

state of neurotransmitter release. These medications can include SSRIs, SNRIs, and tricyclics

(Mental Health Medications, NIMH). A search of journal articles reveals that the only
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medication studied in conjunction with marijuana is the SSRI, or selective serotonin reuptake

inhibitor. These medications target neurons that release serotonin and block the reuptake

mechanism, resulting in increased firing at the synapses of serotonin neurons and creating more

activity in them as a result.

Figure 1: An illustration describing the mechanism of a selective serotonin reuptake inhibitor. The drugs in
question bind to reuptake sites present on the presynaptic neuron, keeping serotonin in the synapse. Similar
mechanisms are present in norepinephrine reuptake inhibitors.

A review by Wilken et al analyzed research that had been done thus far in 2004, particularly

relating to the role of endocannabinoids on mood and anxiety disorders. In the Wilken review,

evidence up until that point had been contradictory on whether or not THC had anxiolytic or

anxiogenic behavioral effects on humans. Wilken observed that a blockade of CB1 receptors

could create neurochemical changes that resembled anti-depressant effects. The purpose of the

Wilken review was focused on how the endocannabinoid system could be used to create novel

therapies for those with mood and anxiety disorders. However, the review gives some insight

onto the effects of the cannabis system in mood and anxiety disorders. Specifically, the review
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outlines that the CB1 receptor antagonist rimonabant and its role in the limbic and frontal brain

structures to regulate arousal, drive, and motivation, which are dysregulated in depressed patients

and often targeted in SSRI therapies. (Wilken et al, 2004). The administration of rimonabant has

also been shown to reduce the cognitive dysfunction associated with mood and anxiety disorders,

while CB1 agonist administration produced more cognitive and motor impairments (Wilken et al,

2004). This may indicate that agonizing the endocannabinoid system with administration of

cannabis could create more problems for those with anxiety and depression, and may also

interfere with current therapies developed for those taking SSRI medications.

The role of THC on anxiety has been studied by Rubino et al, focusing on the neurochemical

changes that THC produced in the rodent brain. In Rubino's study, low doses of THC have been

found to create anxiolytic effects, with high doses providing ineffective or anxiogenic effects in

rodents, but only in interactions with the prefrontal cortex; when involving the amygdala, small

dosages of THC created anxiety in rodents (Rubino et al, 2008).

Figure 2: 1 microgram injection of THC into the basolateral amygdala resulted in decreased amounts of time
on the open arms of a maze, indicating increased anxiety levels in rodents. (Rubino et al, 2008)
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The neurochemical actions of this increased anxiety were not clear; it may have been due to

monoamine imbalances or excitatory neurotransmission, but only c-Fos activation was recorded,

so the mechanisms are unknown. This raises the possibility of THC potentially raising or

depleting monoamine release, which also has the ability to interfere with SSRI medications.

Other studies of THC have proven that it can have negative psychoactive effects, such as

disconnected thoughts, panic and panic reactions, delusions, hallucinations, and

depersonalization, all of which may exacerbate or negatively affect anxiety or depressive

disorders and increase side effects of SSRI usage (Carlini et al, 2004).

Limitations

There are limitations to the above studies outside of the fact that they do not directly use

medications to study effects. The first limitation is due to the way in which the THC is applied to

the animal models, through injection. Injection of THC may produce a different effect than the

inhalation method that is most used in humans. In the same way that ingesting marijuana and

smoking it produce different highs and different concentrations of THC in the body, an injection

into the blood is likely not going to be diffused across membranes in the same way and may

produce different effects, including a less potent "high" with fewer psychoactive effects and

fewer effects on the immune system (Drug and Human Performance Fact Sheet, NHTSA). There

is also no guarantee that these substances are crossing the blood brain barrier with the same

efficiency as other methods of diffusion, which can lead to different effects. In Rubino et al, there

were different effects seen with different levels of marijuana that were injected, and higher or

lower amounts produced or alleviated anxiety, but these effects may not translate to an inhalation

model, and there is not an easy way to test this. This leads to the animal models of rodents,
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which are similar to humans in most brain structures but do not appear to be able to inhale

marijuana in a similar way to human subjects.

In addition to the methodology regarding administration of marijuana, there are multiple strains

of marijuana with different levels of THC available, including the indica and sativa strains (Drug

and Human Performance Fact Sheet, NHTSA). The different levels of THC present in each strain

may, again, produce different highs or effects in animal or human consumption.

If the variability of the strain of marijuana is eliminated, there is still a difference in dosages seen

in the research that has been done. The Rubino study tests the difference between low and high

doses, and provides dosage information in their methodology, but do not describe why these

dosages were the ones chosen as low or high.

Finally, these studies also have the critical limitation of a narrow scope. They are only studying

the CB1 receptor, and they are only examining this receptor in how it affects serotonergic

neuronal activity. There do not appear to have been studies done to research the effects of

dopamine, norepinephrine, or other monoamine neurons, or neurons that specialize in excitation

or inhibition of activity, such as glutamate or GABA neurons. There are other receptors studied

in (Kunos et al), but they do not study these effects as compared to psychiatric medications.

Discussion

A standard should be set to remove much of the variability in marijuana research that will be

performed in the future. This standard should include a certain dosage percentage of THC. A

dose response curve can help determine the dosage that should be used for low or high rodent

studies, and secondary study can be done to determine the effects of THC dosages in comparing

human and rodent models (Rubino et al, 2008). With current technological limitations, there is
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not a cost-effective way to have rodent or animal studies done with marijuana diffusion across

the membranes of the lungs, and therefore the specific effect of smoking marijuana versus an

injection of it cannot be studied with our current animal models. In the future, as technology

allows, a follow-up study may be done to test the differences between the inhalation and

injection methods in an animal model.

Using the above standard, it is not as difficult to design a study that can be applied to the study of

marijuana and any psychiatric medication that can be safely applied to rodents. For example, an

SNRI (serotonin norepinephrine reuptake inhibitor) side effect study could involve 4 groups of

rats: group A that is injected with THC, group B that is injected with only the SNRI, group C that

has both THC and an SNRI together, and group D with a vehicle control. The effects can be

analyzed in the short term or in the long term, with small or large doses of THC as the study is

allowed. The effects studied could be different for multiple papers, one paper detailing anxiolytic

effects, another on general physical effects such as weight gain, etc. These studies can include

the same group of animals, making them cost-efficient.

Another potential reason for the lack of marijuana research thus far is due to the government,

which has prevented said research from being performed due to lack of funding. Marijuana is

still categorized as a category 1 drug, with a high rate of abuse in the same category as heroin,

and there were many accounts in the past of it being the "devil's drug" (Johnson C, NPR). This

mindset may have prematurely halted marijuana research from achieving funding, as politicians

may have a negative view of marijuana and refuse to let research be done on the premise of these

outdated beliefs. The classification of marijuana as a high-abuse drug and its controversial status

has created a climate where it is very difficult to perform marijuana research. In order to perform

research, a private investigator must have a DEA license, the study must be approved by the
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FDA, and in order to obtain the marijuana itself to perform research, the study is screened by the

National Institute on Drug Abuse, or NIDA. This vigorous screening process makes it very

difficult for researchers to obtain funding for marijuana research in even a medical situation, and

near impossible to perform a study on potential long-term side effects with other medications

that are currently on the pharmaceutical market (Johnson C, NPR).

In order to change the funding climate that marijuana research faces, there should be programs

that are aimed at educating the public on what marijuana is and what it can do. Educational

programs revolving around marijuana usage, especially if it is aimed towards those who are

currently in control of the funding for marijuana research, can help to free up funds for marijuana

research, reclassify it from a schedule 1 drug, and allow easier access to marijuana research in

academic and pharmaceutical labs across the U.S.

Conclusions

The current climate of marijuana research in the United States is uneasy. It is difficult to obtain

funding, difficult to design experiments, and difficult to find information about marijuana.

Because of these difficulties, research into the side effects of marijuana with psychiatric

medications is currently nonexistent. It is important that this research is done, and this review

analyzes current studies for future directions of research and aims to set a standard for marijuana

research in rodents. Greater education on marijuana research should aid the current research

climate, and help millions of people remain safe while still taking their psychiatric medications.
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