Before we go into why and how, it is best to understand how depression arises and how it is treated at the moment. Another thing important to remember is that there are two main types of depression: unipolar and bipolar depression/disorder.
Depression is one of the most common mental health conditions affecting the people of the US, with around 26% (and perhaps more) of the population suffering from it. Major depression affects around 16.1 million people in the United States. According to some estimates, depression may well become the second leading cause of disability throughout the world, trailing only ischemic heart disease. Anxiety disorders, which are often comorbid with depression, affects around 40 million adults in the US.
Unipolar depression is when a person has a consistent low mood, whereas those with bipolar disorder tend to go through “cycles” of extreme elation and extreme depression. Most (though not all) antidepressants work for unipolar depression, not necessarily bipolar depression. For those with bipolar disorder, antipsychotics are more commonly used than antidepressants, although sometimes antidepressants may be used. However, there is no evidence that antidepressants work for bipolar depression, and they may in fact increase rapid cycling.
So, what causes depression? Like many conditions, there seems to be a range of influences. Genetics, changes in hormone levels, persistent stress, grief and difficult life circumstances all seem to play a role. Depression does seem to cause changes in brain chemistry, and those who suffer from it seem to lack any balance of the neurotransmitter serotonin, which regulates anxiety, mood and happiness.
Serotonin is bound by 5-HT2 receptors (a subgroup of the 5-HT receptor, of which there are seven – 5-HT1 through to 5-HT7), and there are three 5-HT2 subgroups: 5-HT2A, 5-HT2B and 5-HT2C. Serotonin is mostly produced in the gastrointestinal tract, a location of the body where cannabis seems to have very intriguing therapeutic effects.
This means that a person who is depressed produces low levels of serotonin, has fewer receptor sites that can receive serotonin, or whose body doesn’t produce the required levels of tryptophan – the chemical precursor to serotonin. Serotonin also plays a significant role in sleep, breast milk production, appetite, memory and learning, and therefore plays an important role in homeostasis. Serotonin also seems to affect heart rate, with extremely high or low levels of serotonin being implicated in an irregular heartbeat and an increased rate of cardiovascular disease.
Norepinephrine is another neurotransmitter implicated in the development of anxiety and depression, due to its function in the flight-or-fight response and stress. Norepinephrine is produced mostly by the brain, spinal cord and abdomen, and is released directly into the bloodstream by adrenal glands. The precursor to norepinephrine is dopamine, which suggests why so many drugs have an impact on the brain’s norepinephrine system.
Norepinephrine acts on target cells by binding to and activating noradrenergic receptors, which controls flight-or-fight responses. Norepinephrine increases heart rate and blood pressure, triggers the release of glucose from energy stores, reduces blood flow to the gastrointestinal system, increases blood flow to the skeletomuscular system and inhibits voiding of the bladder. Norepinephrine systems are also targeted for many medical purposes, from enhancing the effects of anaesthetics to treating critically low blood pressure.
Depression is often also a major side-effect of many other conditions and/or treatments. Someone suffering from chronic pain or post-traumatic stress disorder (PTSD), or someone going through chemotherapy, may well feel heavily depressed as well. Unsurprisingly, feeling down in a hole all the time can lead to other problems, like trouble eating, sleeping and keeping active. This can exacerbate other illnesses, as those suffering from depression are more prone to falling sick.
Though it sounds a bit simplistic, feeling stressed, anxious and depressed all the time can either cause more serious health issues to arise, or make existing health problems worse. Depression really is a negative spiral that can lead to worse problems down the line. For this reason, it is of huge concern for many doctors and patients to find the best way in getting depression treated properly.
This means that the antidepressants used to treat depression is often used to help treat many other conditions, including: anxiety disorders; chronic and neuropathic pain; migraine; substance addiction/dependence; menstrual cramps; eating disorders (anorexia, bulimia and obesity); snoring; attention-deficit hyperactivity disorder (ADHD); PTSD; sleep disorders; and obsessive-compulsive disorder (OCD). This is because antidepressants like selective serotonin reuptake inhibitors (SSRIs) are highly specific in that they work on one particular system in the body, and in addition have a relatively high safety profile.
As for treating depression, a class of drugs known as “antidepressants” are used. Depending upon the condition, antidepressants may be used in combination with other drugs. For example, antidepressants are often used in combination with nonsteroidal anti-inflammatory drugs (NSAIDs) for chronic pain. Antidepressants are also sometimes combined with cannabis in order to beat pain, as an alternative to opioids. The types of antidepressants used are:
- Selective Serotonin Reuptake Inhibitors (SSRIs) – Precise mechanism of action isn’t known as of yet, but it is believed that SSRIs work by increasing the extracellular level of serotonin by limiting its reabsorption into the presynaptic cell. This increases the amount of serotonin available in the synaptic cleft, which is then available to bind to the postsynaptic receptor.
- Selective Norepinephrine Reuptake Inhibitors (NRIs) – As above, only working on the norepinephrine systems rather than the serotonergic systems. Second generation antidepressant.
- Serotonin-Norepinephrine Reuptake Inhibitors (SNRIs) – SNRIs induce the production of both serotonin and norepinephrine rather than inhibiting their uptake. Second generation antidepressant.
- Tricyclic Antidepressants (TCAs) – Inhibits both serotonin and norepinephrine reuptake transporters, thereby increasing the amount available in the synaptic cleft. This leads to a decreased rate of neuron firing. First generation antidepressant.
- Monoamine Oxidase Inhibitors (MAOIs) – Inhibits the activity of one or both of monoamine oxidase enzymes, monoamine oxidase A (MAO-A) and/or monoamine oxidase B (MAO-B). Used to treat atypical depression that does not respond to other antidepressants. First generation antidepressant.
- Reversible Inhibitors of Monoamine Oxidase A (RIMAs) – A subclass of the above, targeting MAO-A systems in particular. First generation antidepressant.
- Tetracyclic Antidepressants (TeCAs) – TeCAs do not inhibit the reuptake of serotonin, but they do inhibit the reuptake of norepinephrine. First generation antidepressant.
- Noradrenergic and Specific Serotonergic Antidepressants (NaSSAs) – Acts by antagonizing the alpha-2 adrenergic receptor and certain serotonin receptors such as 5-HT2A, 5-HT2C, 5-HT3, 5-HT6 and in some instances 5-HT7. This enhances adrenergic and serotonergic neurotransmission in the brain. Second generation antidepressant.
- St. John’s Wort (Hypericum perforatum) – a medicinal herb often used for mild-to-medium depression and opioid addiction. St. John’s Wort may also be used for major depression, but its efficacy is not known as the evidence is not definitive. St. John’s Wort increases serotonin production, and has negative interactions with contraceptive pills, warfarin, SSRIs, immunosuppressants, HIV medications, cholesterol medications, sedatives and chemotherapy drugs. St. John’s Wort should also be avoided by those with bipolar disorder and schizophrenia, as it may increase the chances of mania.
There is quite a bit of difference between first and second generation antidepressants with regards to their safety profiles. Although similar side-effects can occur in both, second generation antidepressants are far safer and can be used for the treatment of many different conditions. However, there are still some potential side-effects and problems, including:
- Increased chances of serotonin toxicity, especially with MAOIs, which have interactions with many different drugs, including benign over-the-counter drugs and foods with high amounts of tyramine in them (e.g. blue cheese, cured meats).
- Determining the type of depression – use of antidepressants may induce mania for those with bipolar disorder. Antidepressants are usually made for unipolar depression in mind rather than bipolar disorder. The problem here is that the bipolar disorder is often misdiagnosed as unipolar depression. Antidepressants may increase rapid cycling in those with bipolar depression due to the extreme amounts of serotonin in the synaptic cleft.
- Antidepressants may not work so well for young people, and may increase suicidal thoughts, particularly in the first month or two of beginning treatment.
- Antidepressants can take time to work – between 4 – 6 weeks.
- The patient may well need to try several antidepressants before they find one that works for them. With a working time of 4 – 6 weeks, it could be months or even a year or two before a patient finds the right antidepressant for them.
- Antidepressants may affect the efficacy of birth control pills.
- Antidepressants slightly increases the risk of spontaneous abortion. Certain antidepressants ought to be avoided (e.g. MAOIs) during pregnancy as they may increase the chances of birth defects.
- Weight gain/loss – depending upon which antidepressant is used and which system is being targeted, antidepressants may cause weight gain or loss.
- Antidepressants may cause a loss of libido.
- Discontinuation syndrome – The “withdrawal” associated with being taken off of antidepressants, which can include flu-like symptoms and mood disturbances. Similar-looking to drug withdrawal, but there is very rarely any addiction or craving for antidepressant drugs.
- Some patients complain of “emotional blunting” – the inability to feel anything due to antidepressant use.
Cannabis might be useful as a replacement or adjunct to antidepressants because:
- Cannabis works on the serotonin receptors 5-HT in a similar way to antidepressants. This means that cannabinoids may increase the levels of serotonin available in the synaptic cleft.
- Much less chance of serotonin toxicity with cannabis alone. So far, no contraindications when cannabis and second generation antidepressants are combined (please note: this is subject to further research).
- Cannabis may work for a broader range of depression types, including both unipolar and bipolar. However, figuring out which cannabinoid and terpenoid profile is most suitable for an individual with unipolar depression and one with bipolar depression is of utmost importance – just as the wrong antidepressant may induce mania, it is possible that the wrong type of cannabis may as well (again, this is subject to evidence). However, cannabis use alone does not necessarily have an effect on the risk of completed suicide, when other factors are taken into consideration.
- Due to the risks associated with using antidepressants for those under 25, cannabis may be an alternative.
- Cannabis works immediately, in comparison to antidepressants. This means a lot more can be trial-and-errored in a shorter amount of time.
- With the above in mind, it is important to remember that cannabis will work like any other medication: a certain cannabinoid and terpenoid profile will work for a certain number of people with depression (and have a neutral or negative effect for others), whereas others will respond more favorably to a different cannabinoid and terpenoid profile. This is similar to how a SSRI will work for some people, whereas others will need a SNRI or NRI.
- Again, with the above in mind, it is important to remember that dosage is also important. Just like taking too many antidepressants can have a negative effect, so too can taking too much cannabis. Similarly, taking the right amount of cannabis can prove to be beneficial. However, there is one big advantage to cannabis in all of this: you cannot overdose on marijuana alone.
- No evidence that cannabis causes spontaneous abortion or anything like that. However, expectant mothers should avoid using cannabis unless there is significant medical reason to do so.
- No evidence that cannabis reduces the efficacy of birth control pills. However, as cannabis contain cannabidiol (CBD), which is processed by the liver enzyme cytochrome P450, there may be some contraindications with benzodiazepines, barbiturates, immunosuppressants and antibiotics. There may be some negative interactions with other antidepressants, but none have been found as of yet.
- May help control eating patterns and therefore maintain weight.
- No major loss of libido for most people. For some, cannabis may enhance the libido.
- Fewer complaints of “emotional blunting”.
Now, as with any medicine, cannabis is not guaranteed to work for everyone with depression. Just like many antidepressants, it may have positive, negative or neutral effects. However, the relative safety profile of cannabis and the unique system it targets – the endocannabinoid system (ECS) – makes it a potentially perfect medication to use for many health problems, physical or mental.
Indeed, expect many conditions to be treated by a mixture of highly selective antidepressant or antidepressant-like drugs and medicines made out of unique cannabinoid-terpenoid profiles tailored specifically towards a patient. We are moving towards a world with highly specialized, small batch-produced drugs and medications for specific people. Cannabis might well help us get there!
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