Cobbers on the Brain

Whether we like it or not, the film industry has always had a significant influence on the representation, as well as our understanding of mental illness. With the popularity of Hollywood comes both, positive and many negative consequences.

Movies, such as Split are said to have done more harm than good in trying to show and destigmatize personality disorders. Split, while tackling dissociative identity disorder (DID), has been officially categorized under “schizophrenia movies” by Google. Another example that is categorized under the same genre and adding to the confusion is the movie Shutter Island, in which some might argue it is DID that is being represented, or even Delusional Disorder rather than Schizophrenia. It seems as though movies that show DID are commonly mistaken for showing schizophrenia. As one might imagine, mislabeling and miscathegorizing movies is quite problematic for various reasons, the most important one being that they are two completely different mental disorders. How? – you might say, so let’s look at them now.

What may be the cause of schizophrenia?

As indicated in the table, one of the major differences is that DID is mostly associated with traumatic life experiences, while schizophrenia is mainly associated with genetic factors. Given the significant focus of research on the biological background of this disorder, we are able to suggest some explanations as well as offer pharmacological treatment.

The above visual is showing a cell signaling pathway, the Wnt/B-catenin pathway, which plays an important role in early development. Dopamine is a key regulator of this signaling cascade, and in the event of increased levels it can lead to abnormally high levels of GSK3 and B-catenin, resulting in the overall inhibition of the pathway. This inhibition results in low levels of TCF/LEF, which are transcription factors at the end point of the Wnt signaling cascade, and are involved in growth. Schizophrenic patients presented with higher than normal levels of dopamine, and researchers thus have concluded that the disruption of this signaling pathway may result in the development of schizophrenia.

So, what now?

While there is no cure for schizophrenia at this time, doctors are able to offer various treatment options.

1. Psychosocial Interventions

• • Therapy
    • Individual and/or family therapy are amongst the options, as well as something called an electroconvulsive therapy.
  • Skills training
    • Behavioral skills training (BST) is a method frequently used by many applied behavior analysts in order to teach skills one might be lacking due to mental illness(es).

2. Pharmacological treatment

• • Antipsychotics
    • First and second-generation antipsychotics are targeting dopamine in the signaling pathway.
  • Lithium
    • This medication is targeting Akt and GSK3 (both of which that were mentioned above) to regulate the overall Wnt signaling pathway.

Links and/or images:

https://pubmed.ncbi.nlm.nih.gov/23379509/

https://www.mayoclinic.org/diseases-conditions/schizophrenia/diagnosis-treatment/drc-20354449

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5216848/

An Overview of Addiction

Drug addiction, also known as substance use disorder, is the inability to control impulses regarding drug-seeking and drug-using behavior. Addiction can result from knowingly overindulging in a substance, from being administered drugs in a clinical setting that are inherently addictive, and everywhere in between. Regardless of the cause of these behaviors, the brain is affected in a very similar way. Some drugs are addictive by their very nature, such as nicotine or opiates, and some are not addictive but the repeated administration can result in a dependency, leading to the same addictive outcome.

What are Gateway Drugs?

Gateway drugs are drugs that encourage the user to experiment with stronger, more dangerous drugs; not by the way of “I smoke cigarettes so now I want to try heroin” but by the way that these drugs are so addictive that they make the brain more susceptible to becoming addicted to new substances. This is best explained by the gateway-drug effect, which explains that the repeated use of particular psychoactive drugs increases the chance of using and becoming addicted to other substances, usually stronger and more dangerous, by altering neural connectivity throughout the brain (particularly the nucleus accumbens (NAc) and ventral tegmental area (VTA)). Some of these drugs include tobacco, alcohol, and marijuana, but the list is difficult to completely define.

Animal Models of Multi-Drug Addiction

While the gateway-drug effect has been shown in humans, it has been the most easily studied in animal models. Studies show that repeated THC injections in mice increase the self-administration of morphine, heroin, and nicotine. Nicotine addiction in mice was found to increase cocaine consumption and drug-seeking behavior compared to non-addicted mice. Alcohol was found to increase drug-seeking behaviors for cocaine and decreased the average time needed to become addicted to the substance. In all of these experiments, profound changes were seen in the reward regions of the brain in very similar ways, regardless of drug class.

Neurophysiology of Drug Addiction

Figure 1 – Reward, Plasticity, and Behaviors associated with Chronic Drug Use

Drugs become addictive largely by their effects on dopamine signaling in the NAc and VTA, which play overarching roles in reward, motivation, and addictive behaviors due to the large deposits of dopaminergic neurons in these areas. In the context of gateway drugs, even a single administration of a substance can increase dopamine release in the NAc and VTA, which can have immediate, long-term effects on both the affected neuron and synapse (Figure 1). Figure 1 shows that repeated drug exposure increases DA activity and encourages AMPA receptor migration to the post-synaptic domain and decreases NMDA receptor density, which ultimately increases long-term potentiation (LTP). By having a very high amount of AMPA receptors on the postsynaptic cell, it is much more sensitive to excitation, which strengthens the connections between the two neurons.

Conclusions

Ultimately, this explains that repeated drug use strengthens the connections between neurons in the NAc and VTA which makes it very difficult to stop the use of an addictive drug. Gateway drugs do exactly this. By becoming addicted to this small collection of substances, the brain can be altered for years, even permanently, encouraging the use of stronger, dangerous drugs. This is not to say that smoking marijuana or having a cocktail now and then will lead to drug addiction, but it is important to understand the risks of chronic use.

Sources

1. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3898681/
2. https://www.mayoclinic.org/diseases-conditions/drug-addiction/symptoms-causes/syc-20365112
3. https://www.sciencedirect.com/science/article/pii/S0092867415009629
4. https://bluefirewilderness.com/blog/gateway-drugs-nipping-drug-use-in-the-bud/

Pre-knowledge before using naltrexone 

Naltrexone is an opioid antagonist that is not addictive and does not cause withdrawal symptoms with the use of stopping it. Naltrexone blocks the euphoric and sedative effects of opioid receptors and reduces opioid craving. Before starting Naltrexone, an individual needs to wait 7 days after their last use of short-acting opioids and 10-14 days for long-acting opioids and alcohol. Accidental or intentional ingestion of naltrexone in opioid dependent people will result in an acute block of opioid receptors and precipitate a severe opioid withdrawal reaction. Symptoms of withdrawal can appear after only five minutes following ingestion and may last up to 48 hours. 

How was naltrexone created?

Naloxone, the long-acting naltrexone is a MOR antagonist. It was first synthesized in 1963 by Endo Laboratories. Though the drug remained essentially dormant for several years, it attracted interest in 1972 when Congress passed the Drug Abuse Office and Treatment Act for the purpose of developing non-addictive treatments for heroin addiction. At that time, methadone, a long acting MOR agonist, was the only medication available for opioid addiction. It seemed to stop cravings yet not produce as significant of a “high” or cognitive inhibition of heroin. However, in some cases individuals did report having experienced some of these cravings.

How does naltrexone work? 

https://www.researchgate.net/figure/Mechanism-of-action-of-naltrexone-The-reversible-interaction-of-an-opioid-agonist-with_fig1_259961081

Repeated exposure to drugs of abuse can lead to an increase in delta FosB levels that persist for a long time after the cessation of drug treatment. To give a little background, research has found that the transcription factor of delta FosB is a mechanism that drugs of abuse produce changes within the brain the contribute to the addiction phenotype. FosB transcription factors accumulate within the nucleus accumbens and dorsal striatum. These brain regions are heavily impacted by repeated drug abuse.  https://pubmed.ncbi.nlm.nih.gov/11572966/

Naltrexone attenuates ethanol consumption via antagonizing the down regulation of CaM kinase IV and the phosphorylation of CREB in the striatum region induced by forced ethanol exposure. Naloxone increases the firing of VTA dopamine neurons by inhibiting VTA GABAergic interneurons. It has been shown that μ opioid receptor agonists indirectly increase dopamine release in NAc and caudate putamen and that the induction of delts FosB by psychostimulants is mediated by D1 dopamine receptor pathway. Furthermore, naltrexone attenuates striatum dopamine levels, which are increased by systemic administration of ethanol. Therefore, naltrexone-induced attenuation of dopamine levels may contribute to its attenuation of FosB/delta FosB IR upregulation observed in current study. In summary, the present study demonstrates that chronic voluntary consumption of large quantities of ethanol induces FosB/delta FosB expression selectively in the subregions of the striatum and the prefrontal cortex, which is reversed by naltrexone treatment. https://www.pnas.org/content/85/14/5274.short. https://www.sciencedirect.com/science/article/pii/S0014299904002249

https://www.researchgate.net/figure/Representative-in-vitro-drug-release-profile-of-the-lead-formulation-of-extended-release_fig6_8157185

Figure 1. Representative in vitro drug release profile of the lead formulation of extended-release naltrexone.

A near linear in vitro release profile shows the extended release of naltrexone over one month trial that indicated the success rate after so many days once an individual has started taking naltrexone.

Clinical Review

More research needs to be conducted regarding the use of naltrexone as an antagonist in addiction recovery. The nature, severity, and duration of naltrexone induced acute opioid withdrawal varies greatly between people and the clinical course of events is unpredictable. With the trend for more addicts to be treated with naltrexone in the community, and the possibility that current addicts may see naltrexone as a misguided means to break the cycle of drug dependence, the potential exists for increasing numbers of similar presentations. Physicians involved in the emergency care of these patients must be aware of the dramatic clinical course of the ingestion of naltrexone in opioid misusers and be prepared to manage the complications. 

Preconceptions of Addiction

What comes to your mind when you hear the word “addiction?” Maybe you think coffee—how you have to have it every morning to be able to function. Maybe you think of a loved one that has battled alcoholism for years. Or maybe you imagine a creepy old man lurking in a dark alley, wearing a trench coat and offering you a small bag of white powder. Personally, I tend to think of the latter example. The stereotypes associated with addictions, and the way media portrays this illness, tend to lend themselves to these types of images. However, addictions don’t relate only to drugs, and they don’t only affect people with drug history. In fact, I would be willing to bet that every single person on the planet has at least one addiction, though it isn’t necessarily dangerous. Addictions could include social media, food, or television. An addiction can be thought of something you want to stop doing, thinking, or taking, but find it nearly impossible to do so, despite the consequences. Is there something in your life that you think could be an addiction? Keep your “addiction” in mind as you read through the rest of this post. . . Relating an abstract idea to yourself helps you to understand it (or so I have been told).

Addicted to Science

The main brain pathway that has been studied in addiction is the reward pathway, primarily the areas of the ventral tegmentum (VTA) and the nucleus accumbens (NAc). An image of where these areas are located within the brain is shown below.[1]

There are two molecular components of the reward pathway that interact in drug addiction.

cAMP Response Element Binding Protein

cAMP response element binding proteins (CREB) are activated in the NAc during drug addiction. CREB is important in addiction because it contributes to the impaired reward pathway highlighted above. When CREB is activated, it produces a peptide (dynorphin) that suppresses dopamine transmission from the VTA (where dopamine is produced) to the NAc which is the reward center of the brain (reinforces an activity or feeling). I know that summary was really scientific and had a lot of acronyms, so I will do my best to break this down a little more. There is a protein in the brain that is activated in the brain’s reward center when an individual is addicted to something—CREB. This protein produces another protein that stops a neurotransmitter called dopamine from traveling from its production site to its destination. Think of the function of the CREB as placing a “road closed” sign in the brain. The road closed sign (dynorphin) stops the car (dopamine) from getting to its destination (NAc), which causes the driver (you) to be upset (no activation of reward center). This is a really simplistic way of describing the function of CREB, but I think it illustrates the central idea in a more relatable way.

Delta FosB

So, we just discussed the role of CREB in the brain where addiction is concerned, but CREB has a special relationship with another protein called Delta-FosB. This protein is the predominant Fos family protein that is expressed after repetitive drug exposure. The Delta-FosB protein’s function is essentially opposite to that of CREB—FosB increases sensitivity to the addictive stimulus and promotes a natural reward response. I don’t have a driving-related analogy for FosB, but you are welcome to add your own.  FosB and CREB have a really important interaction in the brain’s reward pathway. Dynorphin, as I previously discussed, suppresses dopamine transmission from the VTA to the NAc. However, when FosB is present, dynorphin is suppressed. To talk about it in terms of car analogies, FosB temporarily removes the “road closed” sign imposed by CREB.

The Two Frenemies and Their Role in Addiction

In this final section, I will try to sum up what I talked about in the previous sections then relate it to some characteristics of addiction, as well as the development of addiction, itself. CREB, as we previously discussed, puts a roadblock in the brain that prevents dopamine from activating the NAc which is responsible for giving the “high” feeling. Based on this information, drug tolerance (needing more of the drug to receive the same effect) is induced by the activation of CREB. FosB is responsible for temporarily removing this roadblock, thus allowing dopamine to travel to the NAc and trigger a “high.” I hope this illustrates how these two proteins are related to characteristics of addiction, but how do they relate to the development of addiction? Great question. Another characteristic of FosB is that it induces synaptic plasticity. Synaptic plasticity is the strengthening and/or growing connections in a neural pathway. This means that, when FosB is present due to repeated drug use, it is strengthening the pre-existing connections and creating new connections in the reward pathway which results in greater and faster activation of that pathway. Addiction occurs because you have taught your brain how to respond to the presence of a specific stimulus via positive reinforcement.

[1] https://www.researchgate.net/figure/1-The-dopaminergic-mesocorticolimbic-circuit-the-VTA-ventral-striatum-including-the_fig2_270788950

Overview

If you are anything like me, you don’t see the point in gambling. You see that you are risking a lot with minimal chance of winning big. Around 6-9% of young adults experience problems related to gambling. Gambling becomes an addiction once a person starts to compulsively gamble, even when it takes a toll on your life. Compulsive gambling is a serious condition that can destroy lives.

Symptoms

A person might be a compulsive gambler if they are preoccupied with how to get more gambling money, needing to gamble with increasing amounts to get the same thrill, try to cut back and are unsuccessful, or they gamble to escape problems in their life. Unlike most casual gamblers who stop when losing or set a loss limit, people with a compulsive gambling problem are compelled to keep playing to recover their money; a pattern that becomes increasingly destructive over time (Mayo Foundation et al., 2016).

Biological similarities between substance abuse and compulsive gambling

Pathological gamblers generally have lower levels of norepinephrine than normal gamblers. Furthermore, norepinephrine is secreted under stress, arousal, or thrill, so pathological gamblers gamble to make up for their under dosage. It was also found during MRI and fMRIs that, “Monetary reward in a gambling-like experiment produces brain activation very similar to that observed in a cocaine addict receiving an infusion of cocaine (Jazaeri et al., 2012).

Comparing substance abuse and compulsive gambling

Compulsive gambling is described as “persistent and recurrent maladaptive gambling behavior,” similar to the description for substance dependence and abuse (Jazaeri et al., 2012). One of the key components to categorize substance abuse is withdrawal. One of the criteria for compulsive gambling is a need to gamble with increasing amounts of money to achieve the desired excitement. This is an example of “tolerance” in gambling. Furthermore, substance abuse includes a persistent desire or unsuccessful efforts to cut down or control substance use. Similar in compulsive gambling, a person may desire to cut down on the amount they gamble, but may find themselves unsuccessful (Jazaeri et al., 2012).

Treatments

There are a few ways to treat compulsive gambling including, therapy, medications, and self-help groups. Therapy can include behavioral or cognitive therapy. Behavior therapy uses systematic exposure to the behavior you want to unlearn and teaches you skills to reduce your urge to gamble. Cognitive behavioral therapy focuses on identifying unhealthy, irrational and negative beliefs and replacing them with healthy, positive ones. For medications, antidepressants and mood stabilizers may help problems that often go along with compulsive gambling such as depression, OCD or ADHD. Narcotic antagonists, which are useful in treating substance abuse, may help treat compulsive gambling (Mayo Foundation et al., 2016).

Conclusion

Although I may not understand the desire some people may have to gamble, it is clear that this is a serious disorder that some people cannot control. It is important to recognize if someone you know might be a compulsive gambler so you can reach out to them and help. If you currently are like me and do not gamble, you should probably keep it that way.

Works cited

Jazaeri, S. A., & Habil, M. H. (2012). Reviewing two types of addiction − pathological gambling and substance use. Indian Journal of Psychological Medicine, 34(1), 5–11. https://doi.org/10.4103/0253-7176.96147

Mayo Foundation for Medical Education and Research. (2016, October 22). Compulsive gambling. Mayo Clinic. Retrieved from https://www.mayoclinic.org/diseases-conditions/compulsive-gambling/symptoms-causes/syc-20355178.

Figure 1; provided by me

Our current culture seems to be very adamant about legalizing the recreational use of marijuana. As someone who works in the healthcare field and often sees people who are suffering from marijuana induced psychosis, I often find myself wondering if that is wise. Lets put our personal opinions aside and look at the effects that marijuana has on the brain. As a caveat I would like to mention that the effects which I speak about will almost entirely be negative. To be fair however, here are some of the speculated benefits of marijuana; it is used to treat chronic pain, used in different aspects of cancer treatment, and it is used to help treat symptoms of epilepsy (MediLexicon International).

Currently, legalization on a state level would allow 21 year old’s to have, purchase, and use marijuana recreationally. But that is not to say individuals who are younger than 21 will not use. 23% of adolescents in grades 8-12 report using marijuana in the past month as is, what happens when marijuana becomes even more available (Jacobus, J., & Tapert, S. F)? If 23% of high schoolers used marijuana when it was illegal in almost every state (the article I am referencing is from 2015),  what will the percentages be when states legalize it for those over 21? Will the punishments for violating the age requirement be similar to alcohol, punishments that seem to be no more than a slap on the wrist? If that is the case then we need to look at the affects that marijuana has on the adolescent brain. There are certainly side effects of marijuana in adults as well, here are some of them; increased risk of psychosis (including schizophrenia), increased likelihood to experience suicidal thoughts and depression, increased rates of testicular cancer, and increased risk of respiratory diseases (MediLexicon International). However, for the sake of this blog I am going to focus primarily on adolescent marijuana use.

Those that use marijuana during their adolescent years show impaired attention and memory later in life even after quitting. Individuals who use marijuana during their adolescent years lose on average 6-8 IQ points by their mid-adult years (National Institute on Drug Abuse). Figure 2 below shows a nice overview of some of the negative aspects of adolescent marijuana use. Although some adults are prescribed marijuana to help with anxiety and depression, it has been shown that marijuana use in adolescence can actually worsen depression and anxiety. There is a common argument that “marijuana is not addictive, so unlike other things I can quit whenever I want.” Now to an extent this is kind of correct, but not entirely. Research varies but it has been found that 9-30 percent of indidiuvals who use marijuana develop something known as a substance use disorder (National Institute on Drug Abuse). A substance use disorder essentially means that the individual cannot stop using the substance in question even when it is causing them health and social problems. Okay, so how does this dependency reflect in children. The answer is in a bad way, those that use before age 18 are four to seven times more likely than adults to develop a marijuana use disorder. Those that try quitting after becoming dependent report the following symptoms; grouchiness, sleeplessness, decreased appetite, anxiety, and cravings. Although marijuana is not as addictive as something like alcohol or opiates, it certainly has addictive characteristics (National Institute on Drug Abuse).

Figure 2, shows a summary of the negative psychological affects on adolescent users

What evidence is there to support the bold statement that “marijuana is a gateway drug?” Well, its complicated and certainly in a way that makes it feel intentional. Many of the studies and research done on marijuana has political and ideological agendas that influence the research itself (Powell, A.). It is hard to find evidence that is not biased, therefore take this next statement with some pessimism. Almost all of the studies conducted on the “gateway drug theory” are done using animal models. It has been found that animals exposed to THC at younger ages have enhanced reactions to addictive substances later on in life. They are also more likely to show addictive behaviors to those addictive substances, this is shown by their increased behavior of self-administering drugs (National Institute on Drug Abuse).

It has been speculated, and partially verified that THC changes the brains reward system in a way that alters connections and reduces vital structures of the brain. These structures include regions associated with memory, learning, and impulse control (National Institute on Drug Abuse). Additional changes linked to THC use include; gray matter alterations, damaged white matter integrity, and abnormal neural functioning (Jacobus, J., & Tapert, S. F.). Some of these changes in brain structure/functioning are shown in the two figures below. Speaking on each of these altered brain structures would propel me well into the completely rambling section of blogging, so I will not.

Figure 3 ; shows abnormally high levels of a protein that is directly linked to stress

Figure 4; shows the hippocampus and amygdala before and after cannabis use, after use there is a clear size difference

Something important to note about cannabis use relates to dosage, the saying “all things in moderation,” is certainly applicable here. There is certainly a valid concern for individuals using cannabis before their brains are fully formed. However for adults, dosage is important because like all things dosage, and therefore quantity, can determine if something is recreational or detrimental to the user. All of the negatives and positives that I have listed are dependent on different quantities of marijuana use. For adults this varies wildly by person, perhaps controlled usage can do more good than bad. However, for adolescence there seems to be no real benefit, only negatives. The reality of our situation is that adolescent individuals will continue using marijuana even if it is not legalized. If we legalize the drug perhaps we can limit the lacing and contamination of the drug itself via a regulated provider. Many of the individuals I meet in the hospital used marijuana that was laced with something more potent. There are many in our society that believe that marijuana has no negatives to it, that it is simply harmless. If we legalize marijuana, there is a concern that this idea of a “harmless” plant will continue and even grow exponentially until marijuana is thought to be completely safe by society as a whole. The reality though is that nothing is cut and dry, we need to have honest conversations without falling into the trap of completely believing one side over the other. Our brains are on the line here, literally…

Jacobus, J., & Tapert, S. F. (2014). Effects of cannabis on the adolescent brain. Current pharmaceutical design. Retrieved October 11, 2021, from https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3930618/.  

MediLexicon International. (n.d.). What are the health benefits and risks of cannabis? Medical News Today. Retrieved October 11, 2021, from https://www.medicalnewstoday.com/articles/320984#What-are-the-medical-benefits-of-marijuana?  

National Institute on Drug Abuse. (2021, April 13). What are marijuana’s long-term effects on the brain? National Institute on Drug Abuse. Retrieved October 11, 2021, from https://www.drugabuse.gov/publications/research-reports/marijuana/what-are-marijuanas-long-term-effects-brain.  

Powell, A. (2020, February 24). Professor explores marijuana’s safe use and addiction. Harvard Gazette. Retrieved October 11, 2021, from https://news.harvard.edu/gazette/story/2020/02/professor-explores-marijuanas-safe-use-and-addiction/.