PharmaChronicle Issue 03

LEARN ABOUT DRUGS IN SOCIETY! Also...

PERSONAL INTERVIEWS WITH DR. ANA ANDREAZZA & DR. HAROLD KALANT!

contents Welcome to the third issue of PharmaCHRONICLE! This time we have new writers giving us a take on pharmacology in a real world setting!

Read all about it!

5 5 9 9 The Problems with Compliance 13 13 From Infamous Club Drug to Miracle Treatment: Ketamine’s Redemption Arc

Mariel Lepra

My Journey to Understand the Role of Pharmacology and Toxicology in Society

Sefayesh Yazdani

Megan Wang and Daniel Li

INTERVIEWS

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Dr. Ana Andreazza

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Dr. Harold Kalant

Conducted by: Megan Wang, Daniel Li, and Oscar Yu

Photographer:

Yu Kylin

Megan Wang

Chris Knox

meet the t

Special Contributors:

Mariel Lepra Setayesh Yazdani

Oscar Yu Daniel Li

team

Design by:

Renee Y Liang

From Infamous Club Drug to Miracle Treatment: Ketamine’s Redemption Arc Mariel Lepra

Mention ketamine to most people and they will probably conjure up images of dead-eyed adolescents strung out on horse tranquilizers. However; open a medical journal and the story is quite different. Since the turn of the century, hundreds of articles hailing it as a miracle cure for depression have been published in reputable scientific journals. As far as drugs go, ketamine has had an interesting trajectory, reinventing itself from anesthetic, to recreational psychedelic, to respected psychiatric treatment.

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Ketamine’s Origins Ketamine’s story begins with its infamous chemical relative, phencyclidine (PCP). Synthesized in the late 1950’s, PCP (known on the street as angel dust) was used as an anesthetic in the 1950’s, but its use was limited by patients experiencing powerful, protracted hallucinations. In 1962, ketamine was derived from PCP in an attempt to create a drug which was still an effective anesthetic without producing the schizophrenomimetic symptoms of its predecessor. It was a success - ketamine was approved by the FDA as an anesthetic in 1970.1 However; it still carried a piece of its past with it: upon emergence from anesthetic doses, patients would be in a dissociative, dream-like state, albeit one less startling than PCP’s agitated hallucinations. With a safety profile preferable to that of PCP, ketamine was used as an anesthetic in humans, but with the advent of drugs like midazolam and propofol which had little to no emergence delirium, ketamine fell out of use for regular anesthetic procedures. However; ketamine remains a staple pediatric and veterinary anesthetic (and maintains its spot on the World Health Organization’s List of Essential Medicines) thanks to its favourable safety profile. The drug does not lower heart or respiration rates, qualities which become ideal in situations where a qualified anesthesiologist is not around to monitor the patient, such as in developing countries.

plorers of the mind - to achieve exactly the effect that limited its medical use, disassociation and hallucinations in high doses, which users dubbed the “k-hole”. One of the most influential proponents for ketamine’s use as a consciousness-expanding drug was American physician John C. Lily, who took the drug in isolation tanks in order to explore altered states of consciousness, which he likened to being “a peeping Tom at the keyhole of eternity”.2 Ketamine later became popular again in the raves of the 90’s, where clubbers would regularly mix the drug with MDMA (ecstasy). The media quickly picked up on the detrimental effects of ketamine, and stories of teenage fatalities (usually from polypharmacy or injuries sustained during a dissociative state) led to hysteria around the drug. Ketamine joined the ranks of heroin and cocaine in terms of notoriety in the public eye, although it remained legal as an anesthetic in human and veterinary medicine.

Redeeming Ketamine Ketamine’s shot at redemption came recently with the renewed interest in psychedelics as treatments for a variety of psychiatric disorders. So far, intravenous and sublingual ketamine have shown promise as a treatment for Major Depressive Disorder (MDD), a serious psychiatric diagnosis which lowers quality of life drastically for patients. Current treatments on the market, such as SSRIs, SNRIs, tricyclics and atypical antidepressants, may take weeks to months to treat the symptoms of depression. During this time, patients have a higher risk of suicidal ideation. Furthermore, 10-20% of people suffering from MDD meet the criteria for treatment-Resistant Depression (TRD), as they do not respond to two or more of these drugs working on different neurotransmitters3. For this subset of patients, find-

Infamy Shortly after its approval by the FDA, Ketamine resurfaced in the counterculture of the 70’s as “Special K”, used by psychonauts – self-proclaimed ex-

The molecular structure of Ketamine

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ing a novel molecular target is imperative. Several ketamine infusion trials for TRD have shown acute resolution of many symptoms of depression in patients, taking place within as little as 24 hours after intravenous infusion and lasting several days to weeks, depending on the subject and dose4.

One of the definitive clinical trials of ketamine for depression comparing symptom improvement after a single infusion of ketamine or midazolam (the active control), found that the response rate (improvement in depression severity within 24 hours) for ketamine was 64%, compared to 24% for midazolam5. The immediacy of relief and the high response rate is unprecedented in pharmaceutical treatments of depression.

pathway and consequently upregulating brain-derived neurotrophic factor (BDNF) in glutaminergic neurons7,8. It is thought that stress and inflammation cause a drop in BDNF in MDD ad therefore a decrease in neuronal density, but antidepressants currently on the market only modestly increase BDNF levels in the brain.

Ketamine in vial preparations

Why Does it Work?

While the exact molecular mechanism of ketamine’s amelioration of MDD symptoms has yet to be elucidated, preclinical studies have provided evidence for several theories. Unlike typical antidepressants, which work either on one or more of the serotonergic, noradrenergic, or dopaminergic systems of the CNS, ketamine affects glutaminergic neurons, which are more numerous in the brain. Ketamine is a potent n-methyl-D-aspartate (NDMA) receptor antagonist, binding at the same site as PCP6. Research in rats has suggested that ketamine’s antidepressant action could be a result of its ability to create new connections between neurons in the prefrontal cortex via increasing spiny dendrite density and arborization. Animal model studies have pointed to this increase in neuronal density being caused by antagonism of GluN2B subunit-containing NDMA receptors, and by ketamine activating the mTOR

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Next Steps Ketamine’s success should be taken with a grain of salt - its antidepressant effects decrease with increasing time after infusion, so patients must come in to receive another infusion once symptoms return. The necessity of a doctor and hospital setting for the treatment creates an issue with compliance after relapse; sublingual and intranasal formulations could remedy this issue. A study administering sublingual ketamine every 2-3 days or weekly to MDD patients found that 77% of patients achieved sustained

antidepressant effects9. However; this study, like many other ketamine clinical trials, was done on a small cohort of patients (n=20). Lastly, there have been no studies published on longterm safety or efficacy of ketamine treatment. Despite these potential setbacks, the once-infamous ketamine presents a deviation from the monoamine-altering status quo of antidepressants, and more importantly, hope for the millions of people worldwide suffering from clinical depression.

References 1)

Hyde, S. (2015). Ketamine for Depression. Middletown: Xlibris.

2)

Domino, E. (2010). Taming the Ketamine Tiger. Anesthesiology, 113(3), pp.678-86.

3)

Serafini, G., Howland, R., Rovedi, F., Girardi, P. and Amore, M. (2014). The Role of Ketamine in Treatment-Resistant Depression: A Systematic Review.

Current Neuropharmacology, 12(5), pp.444-461.

4)

Serafini, G., Howland, R., Rovedi, F., Girardi, P. and Amore, M. (2014). The Role of Ketamine in Treatment-Resistant Depression: A Systematic Review.

Current Neuropharmacology, 12(5), pp.444-461.

5)

Murrough, J., Iosifescu, D., Chang, L., Al Jurdi, R., Green, C., Perez, A., Iqbal, S., Pillemer, S., Foulkes, A., Shah, A., Charney, D. and Mathew, S. (2013). Antidepressant Efficacy of Ketamine in Treatment-Resistant Major Depression: A Two-Site Randomized Controlled Trial. American Journal of Psychiatry, 170(10), pp.1134-1142.

6)

Kohrs, R. and Durieux, M. (1998). Ketamine: Teaching an Old Drug New Tricks. Anesthesia and Analgesia, 87, pp.1186-93.

7)

Miller, O., Yang, L., Wang, C., Hargroder, E., Zhang, Y., Delpire, E. and Hall, B. (2014). GluN2B-containing NMDA receptors regulate depression-like behavior and are critical for the rapid antidepressant actions of ketamine. eLife, 3.

8)

Li, N., Lee, B., Liu, R., Banasr, M., Dwyer, J., Iwata, M., Li, X., Aghajanian, G. and Duman, R. (2010). mTOR-Dependent Synapse Formation Underlies the Rapid Antidepressant Effects of NMDA Antagonists. Science, 329(5994), pp.959-964.

9)

Lara, D., Bisol, L. and Munari, L. (2013). Antidepressant, mood stabilizing and procognitive effects of very low dose sublingual ketamine in refractory unipolar and bipolar depression. The International Journal of Neuropsychopharmacology, 16(09), pp.2111-2117.

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“

I call it a life-changing experience; one that has considerably changed my perception of the issue addiction in our society.

“

My Journey to Understand the Role of Pharmacology and Toxicology in Society Setayesh Yazdani

I was very eager to understand how my area of study, pharmacology and toxicology, plays an important role in society, so I decided to take PCL389. The journey started in September 2018, and I soon realized it was a different experience than that of any other pharmacology course I have taken. Now that the course has finished, I call it a life-changing experience; one that has considerably changed my perception of the issue addiction in our society. As part of the course, I was enrolled in a community placement, a harm reduction center, Just For Today (JFT). JFT is an organization

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in Scarborough, Toronto that has been offering to counsel individuals with substance use disorder (SUD) using a harm reduction model since 1981. At JFT, I participated in group discussions among those who were enrolled in counseling services. During my time at JFT, I listened to many stories about cases related to SUD – stories about relapse and family problems.

Prior to PCL389, most of my previous understanding of the issue addiction was formed through my upbringing and exposure to me-

dia. I viewed addiction as an issue that primarily originates within an individual. Shortly after starting the course and my placement, I became aware that I was holding an extremely prejudiced view of addiction and SUD. There may be many factors in the environment that could potentially contribute to this problem.

Simply said, we cannot blame an individual for experiencing SUD, as there may be numerous underlying reasons that could contribute to it. For instance, psychological and societal factors such as a lack of strong support systems, fruitful emotional bonds, and meaning-

ful relationships could all play roles. Therefore, it is of utter importance to appreciate all the factors that can contribute to SUD without prior judgement. For example, a teenager’s environment at school and their choice of peers may influence them. An adolescent who chooses to follow the behavior of a group of friends who smoke or drink is an example of how the environment affects choices that relate to addiction. It is important to understand that there might be several reasons and we do not have a definitive answer to this question.

The way we think about different issues is partly due to our personal experiences and perceptions. Similarly, I realized that I formed personal judgments and biases about individuals with SUD, and I was not even aware of them. Throughout PCL389, I was encouraged to reflect upon my experiences by asking myself why I think in a certain way. Part of my learnings from this course are a direct result of these reflection practices. For example, I started the course thinking that most people with SUD lack concern about their family members and they are resistant to positive change. I had

to ask myself: “Why do I think like this?” I realized that it was partly due to my childhood experience; observing a relative’s attitude towards his family while he struggled with SUD made me think in that way. Also, my role models at the time including my teachers at school expressed negative opinions about individuals with SUD, which made me further internalize and believe those negative comments. It was fascinating to see how my PCL389 and JFT experiences challenged my previous perceptions. At JFT, there were many instances that participants expressed their genuine concern

about the consequences of their experience with addiction on their family members. I realized that people with SUD experience the same normal feelings, emotions and concerns for their families. Stigmatizing them as apathetic individuals will not help our society nor those who suffer from SUD. I am personally now more receptive towards these individuals by removing this stigma. Such stigmas create barriers between individuals with SUD and the rest of the society. Removing them helps the society to be more sensitive towards 1

PCL389, The Role of pharmacology and Toxicology in Society is a course in the department of Pharmacology & Toxicology at University of Toronto.

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these individuals and perhaps more likely to understand their struggles with addiction. I simply learnt to open my mind to understand a person with SUD by putting my previous stigmas away. Additionally, I also realized that it is not a matter of resistance to positive change that has stopped many individuals with SUD from improving their condition; instead, it was a matter of not knowing where to seek help or not knowing how to create that change. At JFT, many participants showed their readiness to improve their condition, but many also expressed that they lack the appropriate skills

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to manage their SUD. At JFT, those members had the chance to become educated about setting goals to manage their condition. These individuals also benefited from being part of a safe environment at JFT where they can openly share their challenges without the fear of being judged. They receive help from professionals such as counselors who provide them with practical advice using the harm reduction model. They can also learn from others who experience the same issues and create a support network within the harm reduction center.

Throughout the course, I realized that many of our lectures in class and our discussions at JFT shared common themes. One common theme was the concept of relapse: the recurrence of substance use after it has been halted for a period which could be due to en-

vironmental cues. Discussions about relapse surfaced several times at JFT. Consider this general relapse case; a man goes out on a Friday night with his friends to a bar around his neighborhood. He feels an unexplained craving for alcohol and loses track of the number of his drinks and ends up intoxicated. What might have been going through his mind when he was at the bar? One of the theories that could explain his behavior is “incentive salience”; the firing of those neural connections which intensified the importance of alcohol to him. Therefore, relapse is an appli-

cable phenomenon, signifying the effects of environmental cues such as the bartender and his “Friday night buddies.” In PCL389, we also discussed that it is critical that professionals help these individuals to manage their relapse. The JFT counselors embodied the compassionate and non-judgemental attitude when dealing with relapse cases. “Harm reduction” was also another common theme. At JFT, members were not ad-

vised to try abstinence unless they wanted to, instead, they were taught methods to prevent the harms of using the substance by reducing its socioeconomic and health consequences.

This experience reminded me that our lectures in pharmacology and toxicology (P&T) go beyond our classrooms and they indeed apply to real-world cases.

I started the semester with a narrow view of P&T; viewing them as sciences mostly restricted to labs and lectures. Throughout the semester, I realized that I can apply the course

learnings to real cases at JFT and my surroundings. This experience has allowed me to adopt a more holistic view. I understand that problems like addiction are integrated into our societies and are worthy of study. I know the value of P&T research more since I have learned that part of the harm-reduction approaches in our community placements are due to advances in our understanding of addiction. After learning about the numerous theories of SUD, I realized that addiction is a multifactorial phenomenon, and more people in the society need to understand

that. I encourage my peers and classmates in the pharmacology and toxicity community and the readers of my commentary to stay open-minded when facing individuals dealing with addiction. Most importantly, share your knowledge about the harm-reduction centers that are available to them. If you are a pharmacology student reading this article, you might want to consider taking PCL389. Altogether, it was an amazing experience to take PCL389 and be a part of JFT; the learnings from these experiences will always stay with me.

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The Problems with Compliance Megan Wang and Daniel Li

PCL389 - The Role of Pharmacology and Toxicology in Society brings a fresh and unique perspective to the science behind our studies in pharmacology. It emphasizes the importance of our knowledge, and how we can use it to approach problems that arise within our community. This is especially the case when it comes to addiction; a problem that everyone recognizes, but do not have an adequate solution for. However, in this review, we will be discussing a different issue, not of drug abuse, but of drug compliance. As a course component, every student in PCL389 is required to volunteer at a community placement, and for ourselves we were placed at Margaret’s Housing and Community Support Services.

As its name suggests, Margaret’s provides shelter and support for individuals - primarily women - who suffer mental illnesses and helps them transition into independent living.

Margaret’s also hosts drop-in center, which provides food and other core services for vulnerable and homeless individuals. Many of the clients suffer illnesses such as depression and schizophrenia, while others suffer from substance use disorder.In either case, most of the clients are prescribed medications to deal with their disorders.

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The Problems with Compliance

Although many clients are especially in need of their prescribed medications, most of them do not take their medications as instructed unless they are forced to. The government assigns social workers to some of the clients to help them with rehabilitation. As required by law, most of these clients will follow the social workers’ instructions and must take their medications - if they do not, they will be subject to criminal penalty. For those who are not restricted by the law, they tend to be less compliant to their prescribed medication.

Our role at Margaret’s was to investigate the situation and reasons behind this lack of drug compliance, and develop a script that social workers can use to improve compliance within their client base.

Despite the harsh penalties surrounding non-compliance, it remains a large problem at both Margaret’s and throughout the community. One of our first tasks was to determine the reasons for medication non-compliance. To tackle this problem, we first shadowed the drop-in centers to learn about the situations of these clients. We also had the chance to talk to the staff and social workers to learn about the common health problems and some stories behind the clients. This visit allowed us to understand the population that is subject to our project. Due to the lack of resources and education, many clients place other needs above taking their medications.

Much of non-compliance is due to the clients’ unawareness of their medical condition, disbelief of medication efficacy, experience of medication adverse effects, or an inability to afford their medications.

To smoothen the conversation between social workers and the clients, we also looked into

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The Problems with Compliance

the specific medications that the clients are being prescribed. Most of these clients are being prescribed with anti-psychotic or antidepressants. Our knowledge of pharmacology was applicable in this situation, as we understood the potential side effects of these drugs. Therefore, we also take this into consideration when translating knowledge for social workers and hope that the message can be delivered to the clients. We hope that the staff can explain the scientific rationale to the clients and convince them that it is important to take the medications as prescribed, despite the adverse reactions they may be experiencing.

Through this experience, it was important to note that a combination of both pharmacology as well as soft-skills are needed to effectively communicate ideas to the public. It is especially important to approach problems from many perspectives in order to produce an appropriate solution. For example, it is obvious to a pharmacologist why benzodiazepines and alcohol should not be taken concurrently, but for a person with little drug knowledge, the reason is non-intuitive (For readers unfamiliar with pharmacology, benzodiazepines and alcohol work on the same receptor and therefore have additive effects). Therefore, this drug-drug interaction must be communicated in a simple yet effective matter. As pharmacologists, we must not only make sure that we understand our theories, but also ensure that the general public does as well.

Our time at Margaret’s has further demonstrated that pharmacology is an integration of knowledge from various disciplines. While the scientific aspect of the problem may seem

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The Problems with Compliance

obvious to health care providers, the clients may have better knowledge in the issue in social stigma and crisis. Therefore, it is important to hear about the opinions from all perspectives: including physicians, social workers, clients, and government workers. This combined knowledge will give us a complete picture of the problem and how to develop an effective strategy. As a pharmacologist, it is important to consider all aspects of the problem before attempting to find a well-rounded solution.

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In this issue, we interviewed two

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Pharmacology and Toxicology

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Dr. Ana Andreazza Dr. Ana Andreazza Dr. Harold Kalant Dr. Harold Kalant

A Discussion with

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INTRODUCTION Dr. Andreazza is an associate professor in Pharmacology and Toxicology whose research focuses on how problems in the mitochondria can affect mood disorders. She is also the instructor for PCL345 - Experimental Approaches in Drug Discovery, a seminar course that focuses on current research in pharmacology. Originally from Brazil, she received her PhD in biochemistry at the Federal University of Rio Grande do Sul. Over her career, she has received numerous awards and recognitions, and was the recipient of the Canada’s Top 40 under 40 award in 2018! We had a chance to sit down and speak with Dr. Andreazza about her research and her philosophies for success in academia.

Can you please tell us a bit about yourself?

My name is Ana Andreazza, and I am an Associate Professor at the University of Toronto. My lab focuses on understanding the role of mitochondrial function and dysfunction on mood disorders, mainly bipolar disorder. In terms of me personally, I am originally from Brazil, a wife and mother who is passionate for living the life at the fullest. I moved to Canada 10 years ago to do part of my PhD studies and then a postdoctoral fellowship with Dr. Trevor Young at the University of British Columbia. I move to Toronto in November 2010 to take a position as an Independent Scientist at the Center for Addiction and Mental Health. Moving to Canada was scary, leaving behind my family and culture, but gave me the opportunity to do what I love – to be a scientist!

What inspired you to have a career in research?

When I was 17, I heard some news about how a compound in wine, resveratrol, can potentially change how our brain works.

At the time, my father’s family made wine – but it was not good wine (please, don’t tell them!). In my naïve and enthusiastic 17 year-old mind – I thought: “I can study resveratrol and perhaps make a better wine.” Well, I decide to knock the door of Prof.

Mirian Salvador, who was studying antioxidants, and ask for a job. She graciously said yes, so I started working with her, learning about basic research, learning to pipette, and how to write a scientific paper. We continued studying resveratrol and found some interesting effects it has on brain cells (astrocytes), which made me curious about the redox modulations in the brain. I attended a symposium on bipolar disorder and asked the speaker, if there was any studies investigating the role of oxidative stress in bipolar disorder? He was not aware, so we began studying this topic, which later became part of my Masters and PhD studies.

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That’s a great question, and yes there’s a lot of differences. You need to be more creative in Brazil, because you have less resources (financially). For example, we might not have access to a certain compound to do an assay, due to a lack of availability or financial resources, so you have to redesign the experiment and think about what else can be done – this is not easy!

Being a researcher in Canada is much safer: the financial resources and structure are in place and the network of collaborations is incredible. A challenging aspect of being a researcher in Brazil is that very few faculty positions are available, and there are few scientist jobs. It’s unfortunate since we have so much creativity and phenomenal scientists there. However, I have strong hope that things will get better as the economy blooms.

Since you’ve done research in both Brazil and Canada, can you tell us a little bit about the difference in experience between the two countries?

What was your vision behind creating the course PCL345 – Experimental Approaches in Drug Discovery?

I created PCL345 to expose students to different approaches of clinical, translational, and drug d guest speakers that are experts in their field. My belief is that students will benefit from unde approaches to science. One key aspect of PCL345 is to teach students how to be creative by learn the knowledge they learned from different fields of science and to disseminate the knowledge to learning to communicate knowledge effectively is key to success in career development.

In PCL345, we put a practical spin on your pharmacology knowledge. There are three important a to show up to every class – 20% of your grade is participation! You need to show up every week b be exposed to top notch professors and get to know them. I also try to bring different professors e this course before, you can still come and learn something new. Two, it’s very difficult to stand o how to integrate knowledge. It doesn’t matter what career path you choose, you will need to be a views and put them together and create your own (unique) version. Lastly, you need to learn di in your final assignment, you will learn how to create a press release and communicate in lay l ams, but we got rid of that because that’s not the point of this course. The point of this course i to expose students to different approaches to research and guide student to learn to summarize a

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How do you think knowledge translation will play a role in the future? Knowledge translation is becoming more and more im-

development research by bringing erstanding the different views and ning to integrate (not summarize) o the lay community. In my view,

aspects to this class: One, you need because this is the only way you’ll every year so that even if you took out these days, so you need to learn able to take knowledge from many isseminate knowledge. In PCL345, language. PCL345 used to have exisn’t to purely memorize facts, but and disseminate knowledge.

portant. For example, when applying for a grant, you are expected to explain the importance of your findings and how your study can improve patient care, drug development, or disease burden. In my research program we bring patient advocates to our lab meetings so we can discuss and understand how our research can help answer questions that will impact their quality of life.

What advice do you have for undergrads who want to pursue a career in research?

Start early: find professors and ask to be involved in their lab, commit yourself to learning and dedicate your time to attending lab meetings and asking questions. You should be involved for real, not just by being present. Volunteering is a great way to start!

The earlier you start, the more you can get out of your academic experience and find out the field that you like to pursue. Define your passion and figure out your dream – think about what where you see yourself in 1, 5, or 10 years. In my view, passion is essential for pursuing a career in research. There is lot of frustration and disappointments, such as paper and grant rejections – without passion for your research question, this career becomes very challenging.

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Introduction Dr. Harold Kalant is a Professor Emeritus at the University of Toronto who specializes in addictions research -- the neurobiological and behavioral as well as the political and societal aspects. He has been invited numerous times by Health Canada, the World Health Organization, and various government committees as a consultant on cannabis and health, and by the Canadian Senate on the recent cannabis legalization, using his expertise on cannabis and dependence to advise policy makers on producing appropriate legislation. The PharmaChronicle has had a great opportunity to have a conversation with him about his career, research, as well as his perspectives on current issues.

A Conversation with

Dr. Harold Kalant Prepared by: Daniel Li, Megan Wang, Oscar Yu

1

To start off, can you please tell us a little bit about yourself?

I started out in medicine, and my original intention was to specialize in internal medicine. After a period in the Canadian army medical corps at the end of WW2, I began my specialist studies. This included a year of work in a research lab.

During my time at the lab, I met a young lady from Chile, who later became my wife. She had to return to Chile for two years to work in the Institute of Physiology there, so that meant I had to go too! I received a clinical fellowship at the main teaching hospital of the University of Chile and worked there for two years. When we came back to Canada two years later in December, I needed six more months of clinical training before I could take my FRCP exams. Unfortunately, all the clinical positions were filled at the time, so the professor urged me to return to the lab for a while, until I could resume my clinical studies in July. The director of the lab recommended that I do a Master’s degree with him, but I decided to go for the PhD in clinical biochemistry. I never went

back to the clinic! My wife and I went to England as post-docs in biochemistry at Cambridge.

When we got back, I was offered a position as Head of Biochemistry at the Defense Research Medical Labs at Downsview. The director of DRML was Dr. Ed Sellers, who two years later accepted the Chair of Pharmacology at U of T. He then offered me a position in Pharmacology. During my PhD studies I had supplemented my income by taking medical calls at the Bell Clinic, which was one of the earliest hospitals specializing in addiction treatment. That was extremely interesting. The director, Dr. Bell, was on the advisory board of the newly established Addiction Research Foundation of Ontario, that was looking for someone to set up a biological research program to complement their existing research in social sciences. Dr. Bell recommended me, and they offered me the position.

I suggested that ARF and U of T should combine the two positions, sharing the costs. This was accepted by both, and turned out to be very successful. My story really demonstrates that you can’t predict how the course of your life might go, so you must be open to changes and opportunities, and look at them without prejudice.

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2

What is your favourite part of academia?

3

Have you seen any changes in academia during your time as a student compared to now?

There has been a major change that I would like to emphasize.

When I was an undergrad, professors were considered gods, and we never questioned them. Nowadays, there’s a greater degree of freedom for students to have their own thoughts, raise their own questions, and challenge their professors’ thoughts and perspectives. This is a very good change.

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That’s hard to say...I enjoy teaching, I enjoy research, I enjoy policy questions, and I enjoy talking to the public. The problem of addiction is of great social importance, but there are lots of misconceptions about it.If you want your research to have a beneficial effect, you have to be prepared to talk to the public and to government about the nature of the problem, the goals we have to set, and how to achieve those goals.

The old system was too prone to propagating misconceptions because you were expected to believe what you were told. There is a much healthier approach today. We now recognize that everybody has something to learn from everybody else, provided objectivity and fact are respected by all.

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You mention a lot in your research that despite neuroscience advancements, addiction can’t be explained by it alone.

Can you tell us a bit about how other factors can come into play?

There are wide differences of opinion among addictions researchers.

I have my views, but they aren’t shared by everyone. A competing view, and one that’s backed by a lot of grant money, is that addiction is a chronic relapsing brain disease caused by excessive ingestion of a drug. The trouble with this view is that there are other addictions not related to drugs; there are behavioral addictions, which show all the same traits, influences, and many of the same changes in brain function. For example, a gambling addiction. There are major addictions that are social problems and show many of the same changes as drug addiction.

There’s now lots of evidence that people differ in their susceptibility, and that there are genetic factors that increase the risk of addiction.

Economic factors also come into play: many people think that the poor are more likely to become alcoholics, but that’s not true. The richer you are, the more you are able to spend on alcohol and other drugs. Over the years, statistics have shown that per capita alcohol consumption was directly

related to the mean disposable income. Another thing is social influences: different societies have different beliefs, traditions and attitudes towards drug use. All these factors influence the risk and frequency of addiction.

Addiction is a maladaptive form of learning. As you know from operant learning, if you reinforce a behavior, you increase the probability of its repetition. If you repeat that behaviour with greater frequency and intensity, you may find that you can’t do without it.

That’s the essence of addiction.

Many think physical dependence is the basis of addiction, but it’s not. If you’re being treated with opioids in the hospital, you may become physically dependent on them, but you’re not likely to become an addict looking to give them to yourself. You have to self-administer to acquire a compulsive need for it; it has to be something you do on your own motivation. Then it becomes conditionally linked to stimuli associated with drug-taking, that can elicit further drug-taking even when you would like to stop.

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With your idea about the importance of self-administration in the development of addiction, what’s your attitude to the legalization of cannabis?

I think it was premature. Cannabis is no worse than alcohol with respect to risk of addiction, and it made little sense that people could legally drink harmful amounts of alcohol, yet even having a small amount of cannabis could put them in jail. Yet there was an alternative to legalization, which was decriminalization. We don’t yet know enough about how to prevent the main problems that are likely to occur when cannabis is made too easy and too inexpensive to get, so instead of legalizing it we could simply have made it no longer a criminal offence to possess small amounts for personal use. We should study the places that did legalize it and see what their experience has been, and whether they have been able to prevent the negative outcomes. That would have helped us develop safe practices concerning its use, that permit legalization when it can be done safely.

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But I think that the government had mixed motives. They said they would legalize cannabis in accordance with the best principles of public health, to help keep it away from kids, and to kill the black market. But they don’t know how! Alcohol is illegal for people under the age of 19, but kids are still drinking. By the time they get to grade 12, around 20% of them have been drunk at least once in the past month. If they can’t keep alcohol out of the hands of kids, why did they think they could do it with cannabis? The second problem is that the claim to adhere to the best principles of public health, has no meaning unless they state clearly what those principles are. Otherwise, it’s just a buzzword. They said legalization would largely take cannabis out of the black market. But if kids can’t buy cannabis legally, they will just go to the black market as they did before. It hasn’t gotten rid of the black market in places that legalized; in Colorado, Washington, and Alaska, the black market is doing just fine. My point is that the government stepped into something with good intentions, without knowing how to achieve them. That’s not good policy. If you look at the current craze in the stock market, where everyone is expecting to make billions, that has nothing to do with ood public health policies!

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Since you believe legalization wasn’t the best idea, what do you think we as scientists (and scientists in the making) can do to propose a solution?

I wish I could answer that! I’ve tried and tried repeatedly. I was invited to testify before the Taskforce, by the committee of the senate, and by many other groups and organizations. I give them my view, they thank me and tell me I had interesting points, but nothing changes. How do we convince the government to implement our policy ideas? That’s the $64 question.

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An important problem with opioids is that if you’re addicted, you tend to switch from oral to intravenous use, because oral absorption is too slow. You want your effect now, instantly! If you look at how the oral opioids, especially OxyContin, were used by addicts during the recent “epidemic”, they were dissolved in water and injected intravenously. That increased the risk of overdose and strengthened the addiction. Also, if you get drugs from the black market, you don’t know what they contain, witness the “heroin” that was really fentanyl. That could be rapidly fatal when injected i.v. You need to be able to rapidly give an antidote if something goes wrong.

Unfortunately, you won’t be able to do that in conventional hospitals, because users don’t tend to

Currently the government has programs to make things better, like harm reduction, clean-needle programs, safe-injection sites, etc. what are your thoughts on that?

take drugs near a hospital. They just take drugs out of sight of the police. Safe-administration sites was an answer for that. The police don’t conduct raids there, the users get a clean needle and syringe, they inject under the observation of a nurse, and if the drug they’re using is overly potent they can immediately get an antidote.

That has in fact saved many lives, and the Ontario government’s decision to put a freeze on these sites is not a logical solution. It’s perhaps driven by ideology; a belief that drug use is inherently evil.

We need to get rid of the idea that addiction is evil; it’s harmful, it’s problematic, but it’s not malicious. The evil aspect is the drug pusher, but the users aren’t doing drugs for “evil” purposes.

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Since you started cannabis research a long time ago when there was a lot of stigma surrounding it, did you have any difficulty getting into this career?

Actually no, in fact I got my supply of cannabis from the RCMP! We were conducting cannabis research under the aegis of a government agency, doing it for medical purposes, to help and prevent people from getting into harmful drug use. We never had any trouble getting access to cannabis, but this wasn’t true for everybody. Some researchers had

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What qualities do you look for in students who wish to join your research group?

I don’t have a lab anymore, I’ve retired and at my age, the thought of writing grant proposals is no longer very attractive! My research is literature-based: analyzing changing patterns, data, and policy recommendations. I currently have undergrads who have similar interests. I would like someone who recognizes that facts alone are only a small part of the necessary basis for good policy. There need to be an understanding of existing policy, a clear objective for any poposed change, accurate facts, recog-

lots of difficulty getting it, because the government put restrictions on them. I think our group had good luck...perhaps the RCMP in our part of the country was more lenient. They have been helpful to some drug research in British Columbia, but in some other provinces they’re not so helpful. Now that cannabis is legal, research will be much easier to conduct.

nition of alternative options, value judgments, and cost-benefit analyses to select the best option.

Working in a lab, you usually have a well-defined single problem. In most undergraduate projects, you work on a small part of an ongoing project. You have a limited amount of time, so you only get a particular objective. You will need to read the literature on that topic, and discuss with your supervisor to come up with an experimental design. I would like students who prefer to do the same kind of thing, but with the literature. I would also prefer that they have a wide enough interest to not just like one particular topic, but to look at the big picture of the issue of which their project is a part.

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Finally, what advice do you wish to give to students who wish to pursue academia?lty getting into this career?

That’s a hard one, I think the motivation needs to be there. Motivation is not something that someone else can guarantee that you will accept. Others can tell you what research is about, and you have to see if that appeals to you or not. You should talk to people about it, and most people who do research would be happy to have a conversation with you. The more

you know about the research process, the more you’ll know whether it appeals to you or not, and if you don’t think you’ll like it, don’t do it! There are many things you can do in the broad field of pharmacology, all of them have good features and all of them have difficulties, and you need to think about which activities you will get personal satisfaction from.

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PharmaChronicle is a magazine composed of student writings.

All our articles are by students for students!

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We are always looking for new contributers for future issues! If you’re enthusiastic towards research and want to share your undergraduate work with fellow pharmacy students, please reach out!

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Contact pharmachronicle.uoft@gmail.com for more information.

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We look forward to hearing from you!

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Brought to you by the PHARMACHRONICLE team.

PHARMACHRONICLE Volume 3. January 2019