Monday, April 27, 2015

Marijuana

Here's another update of this post, to account for studies between 2009 and 2015.

Marijuana use is quite common in the university population I see in my clinic.

It is my opinion that sporadic recreational marijuana use is less dangerous than alcohol use, for many people.  For others, it is more problematic, and the risks may be underestimated. 

Cannabis is an acute intoxicant, which could make activities such as driving much more dangerous. Also, smoking marijuana undoubtedly causes harm to the lungs, though probably not quite to the same degree as smoking tobacco cigarettes (see references below).

There is strong evidence that marijuana use increases the risk of developing a psychotic disorder, probably by about 40%.

People who have a psychotic illness, or who have a family history of psychotic illnesses, are at higher risk for having new or continuing psychotic symptoms if they use marijuana.

Also, based on some of the evidence cited below, I would say that children and adolescents are probably much more vulnerable to negative, long-term emotional and cognitive effects from marijuana use. So I strongly recommend that adolescents and young adults abstain.

I commonly see individuals who use marijuana frequently, who have longstanding problems with motivation. This may be reflected in poor grades in school, lack of success in building a career, etc.  Whether or not this association is caused directly by marijuana use, I do think that a redirection of motivational energy away from recreational drug use is likely to help increase energy for other creative life pursuits. 

There is strong evidence that marijuana use is associated with more severe psychiatric symptoms, of almost every type; but much of this association could be due to the fact that persons with more severe symptoms are more likely to use marijuana, not the other way around. In any case, those who choose to use marijuana more regularly as a cultural pursuit may be surrounding themselves with others who have more severe symptoms.

There is some evidence that marijuana or other cannabinoids could be helpful to treat a variety of medical ailments. This evidence needs to be taken seriously.

Here is a brief survey of the very large literature on this subject:

Evidence of Risk and Harm

This 2007 review from Lancet shows convincing evidence that marijuana use increases the risk of developing a psychotic disorder, and that the risk is dose-dependent (i.e. the more marijuana one uses, the higher the risk is of developing a psychotic disorder):
http://www.ncbi.nlm.nih.gov/pubmed/17662880

It concluded that the evidence is less clear linking marijuana to other problems, such as depression and anxiety: many of the studies looking at this did not sufficiently address non-causal reasons for the association between marijuana and other problems. For example, people who are more depressed or anxious may have a higher likelihood of using marijuana to treat their symptoms. Or, people whose cultural style may lead them away from conventional treatments for depression, may be more likely to use marijuana regularly.

In this 2008 review from the British Journal of Psychiatry, the authors conclude that marijuana use is associated with worse outcome in psychotic disorders--but they say that the existing studies show only an association, not causality. Once again, confounding variables may cause this association to exist:
http://www.ncbi.nlm.nih.gov/pubmed/18978312


Many other studies looked at populations who used different amounts of marijuana over time, and compared them in terms of various symptoms and intellectual functions, etc. Unfortunately, I find this type of retrospective analysis to be weak, and highly prone to confounding variables. In order to understand marijuana's long-term effects for sure, we would need to do a long-term, prospective, randomized, controlled study. Such a study would not be ethical, so it probably will never be done.

Here are some studies looking at risk to the lungs associated with marijuana smoking:

These studies show an increased risk of lung cancer in marijuana smokers:
http://www.ncbi.nlm.nih.gov/pubmed/19057263
http://www.ncbi.nlm.nih.gov/pubmed/18238947

These studies show a likely causal association between long-term marijuana smoking and obstructive lung disease:
http://www.ncbi.nlm.nih.gov/pubmed/18238947

http://www.ncbi.nlm.nih.gov/pubmed/17666437

A significant cannabis withdrawal syndrome is described in the literature, particularly for heavy, long-term users. The syndrome involves about 2 weeks of irritability, restlessness, and insomnia, which could be quite destabilizing for someone struggling with mood symptoms, therefore leading to continued marijuana/cannabis use. Here is a 2006 review of the subject:
http://www.ncbi.nlm.nih.gov/pubmed/16612207

Animal studies could add a little bit more information into the picture, since these have been done in a prospective, controlled fashion. Here is what I've found from the animal research literature:

This study showed that chronic marijuana exposure impairs spatial memory & learning in rats:
http://www.ncbi.nlm.nih.gov/pubmed/19179850

This study showed that chronic marijuana exposure impairs social and cognitive functions in rats, but especially when the period of exposure is during the pubertal ("adolescent") phase of development:
http://www.ncbi.nlm.nih.gov/pubmed/18782382

Another study showing that marijuana exposure may be particularly harmful to the "adolescent" brain:
http://www.ncbi.nlm.nih.gov/pubmed/15582916

This study from UBC suggests that high-dose cannabinoids increase emotionality and "sensitize the stress axis":
http://www.ncbi.nlm.nih.gov/pubmed/16442741

A few recent prospective studies have demonstrated increased dysphoria, anxiety, tiredness, ideas of reference, and schizotypal symptoms as a result of marijuana intoxication. In particular, individuals with pre-existing schizotypal personality traits had a more substantial increase in schizotypal symptoms following THC exposure. This adds to an evidence base suggesting that marijuana use carries a significant risk of exacerbating a variety of psychiatric symptoms, particularly psychosis-spectrum symptoms, and particularly in those with risk factors for psychotic illness.
Here are the references, which are both from Psychological Medicine in 2009:
http://www.ncbi.nlm.nih.gov/pubmed/19017430
http://www.ncbi.nlm.nih.gov/pubmed/19335936

This interesting study involved administration of THC to healthy volunteers who did not use THC.  Some members of the cohort experienced transient psychotic phenomena, while others did not.  These differences were associated with differences in cognitive impairment and functional MRI results. This supports the common-sensical observation that some individuals may be more vulnerable than others, to having adverse neuropsychiatric effects from THC use.  
http://www.ncbi.nlm.nih.gov/pubmed/23020923


Evidence of Benefits or Therapeutic Uses

This study shows that a synthetic cannabinoid promotes neurogenesis in the hippocampus, and may have antidepressant and anxiolytic effects:
http://www.ncbi.nlm.nih.gov/pubmed/16224541

This study shows immediate relief of the symptoms of Parkinson's Disease following cannabis treatment: 

http://www.ncbi.nlm.nih.gov/pubmed/24614667

This study, from a major journal of gastroenterology, shows that cannabis dramatically improved symptoms  of Crohn's disease (a type of inflammatory bowel disease), in a prospective, placebo-controlled trial.  
http://www.ncbi.nlm.nih.gov/pubmed/23648372

 Another prospective study, showing that cannabis improves quality of life in inflammatory bowel disease:
http://www.ncbi.nlm.nih.gov/pubmed/22095142

Here's a 2012 study showing relief in muscle stiffness in multiple sclerosis patients, due to cannabis administration:
http://www.ncbi.nlm.nih.gov/pubmed/22791906

Another 2012 study from CMAJ showing relief of spasticity and pain in MS patients, following cannabis administration:
http://www.ncbi.nlm.nih.gov/pubmed/22586334


There are various references supporting the use of cannabinoids in treating pain disorders (especially neuropathic pain), spasticity, glaucoma, and nausea; some of these references are from major journals. However, I think this area is still one which requires ongoing
research to more clearly estimate benefits vs. risks, especially over long-term use.

Here is a reference to a good 2008 review of the pharmacology and potential therapeutic applications of cannabinoids such as marijuana:
http://www.ncbi.nlm.nih.gov/pubmed/18482430

Here's a good 2013 study showing that cannabis compares favorably with other standard pharmacological treatments for neuropathic pain:
http://www.ncbi.nlm.nih.gov/pubmed/23237736


This 2005 study from the prestigious journal Nature suggests that cannabinoids could reduce the progression of atherosclerosis (the main cause of heart disease):
http://www.ncbi.nlm.nih.gov/pubmed/15815632

Weaknesses in the Research Literature

The biggest weakness I see pertains to the use of retrospective studies to assess risk.   These studies tend to show an association between cannabis use and large adverse health effects.  But studies of this type are very hard to control, and there could be many biases at play.  Those who were more likely to have adverse health outcomes in the first place, may also be more likely to use cannabis, i.e. this could be a non-causal association.    The best studies to answer these questions clearly should be prospective, with large numbers, followed over years.  But it is hard to set up a study of this kind ethically, particularly if the groups are randomized.  Randomized prospective animal studies give good data, but these have ethical problems of their own, of course.

A similar trend in the literature, which perpetuates an unfairly negative bias about cannabis, is the presence of many treatment trials and research papers having to do with  "cannabis dependence."    The preponderance of such articles may give the reader an exaggerated impression of the harm done by cannabis (if any). 

Conclusions

In conclusion, I think that marijuana use is dangerous, and harmful to your health in a variety of ways, due to acute intoxication, increased risk of psychosis, possible cognitive side-effects, and lung damage. It may be particularly harmful to adolescents. As a cultural pursuit, it may distract people from other life activities, or meaningful life roles, just as any habit or addictive behaviour can. But it may have beneficial effects for a variety of medical problems.

I have to admit, to be fair, that some people have psychological benefits from marijuana use -- certainly there are many testimonial accounts of this, but evidence beyond this is not clear on this point.  The few studies touting this application tend to be of short-duration, which leads to a similar criticism as that pertaining to mainstream pharmaceuticals:  short-term benefits for symptom relief do not always translate into long-term benefits, if the use continues for years.   More research is needed to gain a better understanding of the potential risks or benefits of cannabinoids, especially over longer-term use.

I have certainly seen people for whom cannabis appears to have a better benefit:risk profile than alternative treatments, for example to treat chronic pain symptoms and associated insomnia.    It may be preferable to use cannabis instead of a benzodiazepine, opiate, pregabalin, etc., particularly if these latter agents are causing a much higher load of side effects in a given person.

For some people, cannabis could be a relatively harmless entertainment, or even a catalyst for enjoying life more richly in various settings.  In this way, it could be analogous to having a glass of wine with meals, etc.

Another angle to the analysis is to consider relative risks of cannabis compared to other accepted intoxicants, such as alcohol.  With this type of risk analysis, one could often see greater risks with alcohol compared to cannabis, on a case-by-case basis, but we don't have good group data on this.   The issue is complicated by the fact that those who are more apt to use cannabis are statistically also more apt to use alcohol and other street drugs.  It is possible that cannabis use could have "gateway" effects, leading people into a higher-probability zone of trying or using more dangerous drugs. 

A proliferation of cannabis dispensaries have appeared in Vancouver in the past year.  While I do think that legalization is a positive step, in terms of the various pros and cons for public health,  I am not happy with the idea being touted by some, that cannabis is some kind of health food, or panacea.   There is an issue of cultural freedom as well, which I support, though I think that many in this movement have an exaggerated view of the benefits of cannabis, with an underestimation of risks.


 

Tuesday, January 6, 2015

CBT as a mental workout strategy

Many studies have shown that CBT is effective for treating depression and anxiety disorders.  The studies are convincing, and the effect sizes have been large, usually comparable to medication treatments. 

CBT studies are also usually well-designed.  The therapy itself is very clear.  While some complain that a "manualized" therapy is too mechanical or detached, it is true that a very standardized therapy approach allows a much more reliable scientific study.  A less structured therapeutic style would be expected to show much more variability between one therapist and the next, or between one patient and the next.  This fact does not mean that standardized, manualized therapies are superior to less structured types, but it does mean that the standardized varieties give more meaningful research results showing without any doubt whether a psychological therapy works or not. 

I believe that CBT is a type of "fitness training" focusing on psychological symptoms and goals.  The CBT therapist is an educator and coach.  Actual CBT sessions are analogous to having a workout with a personal trainer. 

Just as with the literal situation of seeing a personal trainer, perhaps two or three times a week for 6 weeks, one could have a lot of fitness gains from the sessions alone.  

But most fitness gains--especially for skill-related activities such as learning tennis, skiing, skating, dance, or bowling--happen as a result of the hours of dedicated, earnest daily practice.  These practice hours would take place between training sessions with the coach!

Similarly, there is some improvement in symptoms due to CBT sessions alone.  But most of the gains, in my opinion, will occur as a result of focused daily practice and homework between the sessions. 

Most CBT research does not clearly indicate the number of hours of practice the patients have done, and do not have any measure of the quality of the practice done.  Just as with children doing homework activities, it matters how much time is spent, but it matters even more how good the quality is.  Was the work done in a sloppy, bored, rushed, haphazard manner, or was there evidence that the work was done with care, attention, organization, and devotion? 

Similarly, very little behavioural therapy research has looked specifically at exactly how long an exposure task needs to be in order to produce an optimal effect.

In my own look at these topics, I have reached the following conclusions: 

1) Daily homework of high quality is necessary for CBT to work best.  This is no different from getting good results in a university class, or following music lessons. 

2) Exposure tasks (which I believe are an essential part of all CBT) need to last 20 minutes in order to be most effective.  Many clinics advise 45-90 minutes at a time.  The difficulty of the exposure task has to be adjusted so that it is moderately challenging (not too easy, and not overwhelming), with some feeling of mastery when it is over.  Just as with physical workouts, at least 3-5 exposure tasks per week should be a goal. 


Wednesday, December 31, 2014

Internet Addiction

Most of us can understand the phenomenon of "internet addiction."    We can easily end up spending too much time on the internet, or on other electronic gadgets.  An interesting documentary called "Web Junkie," which is set in Shanghai, is a good introduction to the subject.  This documentary also illustrates some interesting elements of therapeutic care in China:  on the one hand, there is sort of an authoritarian, militaristic boot-camp style (epitomized by the doctor who runs the clinic).  Yet on other hand, there are some calm, gentle, patient, quiet therapists shown (such as the one female doctor). 

A recent meta-analysis by Cheng and Lee (*) showed that rates of internet addiction in different countries ranged between 2% and 10%.  Interestingly, rates were lower in countries with a higher quality of life, such as in Western Europe, and rates were much higher in countries with lower quality of life. 

Restriction of children's internet use by parents is associated with lower risks of internet addiction (**).    Low satisfaction with family relationships is a strong risk factor. (***).

Children with ADHD are at particularly high risk for internet addiction, with a strong association between addiction scale scores and ADHD severity scores. (****).  Depression, anxiety, and introversion are also risk factors.    Internet addiction is further associated with other addictive problems, including alcohol dependence and smoking. 

Another study looked at a rating scale called the IMQ-A,****** which assesses motives for using the internet.  The scale is based on the DMQ-R , which looks at a person's motives for drinking.   The highest risk for addiction is for those who are using the internet as a coping device (e.g. "to forget your worries"), while using it for social reasons or for education is less risky.


Management:
A recent review by Spada (******) suggests that the treatments thus far are quite straightforward:
 1) management of anxiety, depression, and ADHD symptoms
2) addressing family relationships if necessary
3) simply keeping track of internet use, and limiting it strictly
4) medication trials including antidepressants or stimulants if indicated.  Naltrexone 150 mg/d plus sertraline 100 mg/d was used effectively in one case. (*******).

I would add that basic lifestyle habits, including daily exercise, healthy diet, and a deliberate daily activity schedule (including social visits, work, and leisure), are essential, particularly since compulsive internet use leads to a lot of time spent alone in a sedentary posture. Postures in front of a device are also usually slumped, in a head-forward position, looking downwards.  Aside from physical health problems, this type of posture probably has negative psychological effects.  Standing and walking around regularly, with simple posture exercises, stretching in an extension position, etc. are bound to be useful.  Amy Cuddy's work on posture would be worth checking out--a good place to start would be her TED lectures. 

A few other points:
1) a bright screen should not be used near bedtime, since it will interfere with melatonin secretion, and cause sleep disruption.   An alternative for bedtime reading can be to use a device in which the font is reversed, with dim white letters on a black background. 
2) ironically, the internet can also be a valuable aid to treating psychological symptoms.  Web-based CBT can be nearly as effective as seeing a one-on-one counselor for some problems, and at the very least could be a valuable adjunct.   But the problems lie with spending too much time on-line, such that other aspects of life suffer.    Reward circuits in the brain may be fired up by numerous internet activities, in an exaggerated way, causing a distortion of judgment about the merits of continuing the activity. 

Ketamine for PTSD

Feder et al. (2014) published one of the first studies looking at possible use of ketamine to treat PTSD. * In this study, ketamine (0.5 mg/kg IV over 40 minutes) was compared with midazolam, on a randomized, double-blind basis, to treat PTSD patients.   In a crossover design, each patient was scheduled to receive a second infusion, 2 weeks later, of the drug they had not received the first time. 

I think a particular strength of this study was the use of midazolam as an active placebo.  The study would have been strengthened even further if they asked subjects afterwards to guess which medication they had received (most patients would have been familiar with benzodiazepines, and would have known that they did not lead to lasting improvements in their symptoms--presumably most of the patients would have wanted to receive the ketamine, as a novel, hopeful treatment).

The results appear similar to other studies of using ketamine to treat depression:  significant improvement in the week following the infusion.  The acute dissociative effects of the drug wear off completely within a few hours, as ketamine levels go down to zero during this time, yet the symptom improvements are maximal after 24 hours, and continue to be significant over a one-week period. 

The overall effect was to reduce PTSD and depression symptom scores at least by half, with improvements in all PTSD domains.

Side effects were not a major problem; in the 24 hours following the infusion, ketamine patients reported more blurry vision, restlessness, and nausea, compared to the midazolam patients.  Only one ketamine patient dropped out during the infusion, because he felt uncomfortable with it. 

For the patients who had received ketamine first, 7 of 22 were still responders after 2 weeks, compared to only 1 of the midazolam group. 

Once again, I think it would be useful for more studies to explore oral or sublingual ketamine dosing, since this would be much more convenient and practical for a larger number of patients.  A gradual intravenous infusion over 40 minutes leads to a fairly similar change in serum levels compared to GI absorption.  Rapid bolus dosing is an advantage of using IV, but this has not been used for administering ketamine to psychiatric patients.   There are differences in the ratio of ketamine vs. metabolites with the oral vs. IV routes, but I do not see that the differences are so great as to obstruct the benefits.   Dose finding is less precise with oral dosing, but this is a technical matter which can be simply resolved through careful titration.    In any case, science may answer this question for us, through well-designed trials.  A study design I would suggest for this would be a double-blind crossover study comparing oral ketamine + IV saline infusion   vs. IV ketamine + oral placebo, with one treatment per week for 4 weeks.  Doses could be adjusted according to response and side effects on treatments 2, 3, and 4.







Tuesday, December 30, 2014

Topiramate for Alcohol Use Disorders

Topiramate is an anticonvulsant which has shown some promise for treating a variety of psychiatric problems, including alcohol use disorders, binge eating, compulsive behaviour, and mood instability.  

One recent study, by Knapp et al, published in the February 2015 edition of The Journal of Clinical Psychopharmacology, compared topiramate with several other medications, and with placebo, for treating 85 heavy drinkers ("heavy" meaning over 35 drinks per week, for men).  * The study duration was 12 weeks.  The target dose of topiramate was 300 mg/day. 

Those in the topiramate group ended up having markedly fewer days of heavy drinking, markedly less total alcohol consumption, and reduced measures of craving, compared to placebo. In general, the topiramate group had at least twice as much improvement in these measures, compared to placebo, which was clinically very significant.  

This study was consistent with others, showing that topiramate can be an effective treatment for alcoholism.  **  

Cognitive-side effects (e.g. memory impairment)  are the main problem with topiramate.  So it is interesting to consider whether lower doses could be useful.  Martinotti et al (2014) did a small study showing topiramate 100 mg per day was useful for treating alcohol dependent patients, with a comparable effect size as the study quoted above.    ***

I am interested in topiramate for other problems which feature compulsive behaviour.  There is some promise in OCD, the studies showing mixed results.  In a genetic disorder called Prader-Willi syndrome, which is characterized by obesity, compulsive self-injury, and intellectual handicap, a trial of topiramate led to significant improvements in the compulsive self-injury.  ****   There have been several studies (e.g. *****) showing that topiramate can be of use in treating binge eating or bulimia, at doses similar to those described above.  Topiramate is also a leading preventative treatment for recurrent or chronic migraines, at a dose of 100 mg daily (******).  It is reasonable, then to think of topiramate in the many cases where there are a combination of these problems, for example a patient with recurrent migraines, who also may have binge eating symptoms, alcohol abuse symptoms, or compulsive self-injury.