Melatonin and Buspar: Breakthrough Novel Anti-depressant


I wrote an article recently about Melatonin and promised a follow up article on how to use it, if at all. I’ve been really distracted lately and I want to do that article the justice it deserves, so in the meantime I thought I’d share a little finding I made a month or so ago about an unusual combination of Buspar and Melatonin. The results are incredibly interesting.

Buspar (buspirone) is a very old anti-anxiety drug that is truly hit or miss. For a lot of people, it does very little, if anything at all, to decrease anxiety. For some people, however, it is a godsend that rivals sliced bread. I think a lot of people find it to be less than satisfactory because they previously used Benzodiazepines such as Clonazepam or Alprazolam or even Etizolam to treat their anxiety. These are GABA related drugs and have a profoundly different impact on anxiety. They are immediate, effective and unfortunately come with a nasty reputation of withdrawal and tolerance issues. For those that have used benzos in the past, the seemingly weak and slower acting Buspar fails to meet their expectations or treat their disease.

A little bit of background info on Buspar, because I find it fascinating.

Buspirone is a partial agonist at the 5ht1a receptor, and this is believed to be the main reason why Buspar is effective for treating anxiety. Another effect of Buspar is the antagonism, particularly at the presynaptic receptors of Dopamine (D2 to be more specific, but D3 and D4 are also affected, although somewhat less so). This actually causes an increase of dopamine release. When a presynaptic receptor is antagonized, the body senses that levels of that specific neurotransmitter must be low, so it releases more, post-synaptically. Buspar is also a weak A1 adrenoreceptor agonist. This is a case similar to the antagonism of D2, in that agonizing the A1 receptor leads the body to believe that there is too much adrenaline being released, so adrenalin levels are lowered.

Buspar has been used in the treatment of cocaine dependence, alcohol withdrawal and traumatic brain injuries with enough success to warrant further research. Buspar can take several weeks to have a positive effect on anxiety, and yet for some people, there is a slight acute reaction that can either alleviate or aggravate anxiety, depending on the patient.

Melatonin has been beaten to death. If you read my previous article on Melatonin, you’ve probably learned that it can be useful, but it can also be disruptive to the circadian rhythms if used improperly (at excessive doses or timed inappropriately), but is also a very powerful anti-oxidant. I would wager to guess that most people living in an industrialized nation have a pretty pronounced disruption of their circadian rhythms and melatonin release. Darkness signals the pineal glad to release Melatonin and most of us are exposed to way too much light way too late in the evening. Even during the night, a few weak sources of light, such as alarm clocks and power buttons on appliances can produce enough light to disrupt the rhythm of Melatonin release. A good practice for those wishing to optimized their Melatonin release is to restrict light after 9 oclock, and wear a sleeping mask at bedtime. It is also crucial for the sleep patterns to be normalized, retiring at the same time every night and waking up with similar consistency.

Melatonin has been studied for its use in alleviating depression for a long time. Several attempts at creating an anti-depressant that agonizes the Melatonin receptor have shown promise, although not completely successful. A notable example is Agomelatine, but even this chemical has other effects at serotonin receptors that may explain the limited anti-depressant effect, so it’s almost inconsequential to the discussion.

So what happens when we combine the two?

The results of a study were published in December of 2012, which shows the combination of Buspar and Melatonin at night can lead to alleviation of Major Depressive Disorder. Unlike SSRI’s, which have become a gold standard in the treatment of depression, The combination of these two odd-ball compounds is not dependent upon manipulation of serotonin or any other major neurotransmitter.

Instead, the researchers believe the positive benefit lies in the increase of neurogenesis that follows administration of these two compounds. By the way, if you’re wondering what the dosages were, the study used 15mg of instant release Buspar (briggs-meyer received a patent for a time-released version but never actually produced it, which would have been quite promising because Buspar has a ridiculously short half-life and a time released version may have shown some seriously beneficial differences compared to its instant-release parent drug) and 3 mg of Sustained release Melatonin.

SSRI’s along with other anti-depressants such as tricyclic anti-depressants, all seem to increase neurogenesis, particularly in the hippocampus, which is responsible for the formation of memories. What does this mean in simple terms? I think the best way to describe the phenomenon is this: Stressful events, along with an inclination to inadequately respond to stressful events can lead to the loss of neurons in the hippocampus. Positive thinking and health moods are actually produced by certain neural pathways. In other words, we have “learned” how to be happy. We have the ability to make choices about how we feel and respond to situations. In a healthy brain, that network of connections is alive and well, and when a stressful event occurs, it is easy to find a way to think about it that produces a positive response to that stressor. With depression, those networks begin to unravel, and begin to deteriorate, leaving just a few pathways left. Those neurons tend to produce negative thinking. Again, another way to think of it is that we slowly lose the ability to do anything but the one or two behaviors or attitudes that have survived this burn-off process. When the brain’s ability to make new connections is restored through the use of drugs such as Buspar and Melatonin, new choices for behaving and thinking begin to emerge and we slowly find ourselves out-thinking the depressive thoughts and behaviors that became second nature to us.

So while there are several different types of anti-depressants, and each one of those options tend to work slightly differently (in the case of tianeptine, it actually increases the storage of serotonin, so it lowers serotonin levels available in the synapse) but in the end achieve the same result, an increase of options, of new behaviors and attitudes that will allow us to cope with the stress and think about things in a way that promotes happiness and relief.

So how exactly does Buspar and Melatonin do this? Researchers are just beginning to look at this. It has been shown in this study, that neither drug on its own was capable of producing the same resulting increase in growth, so there is something uniquely magical about the combination of these two agents which deserves further examination.

The irony of this is that I had recently acquired a decent amount of buspar, and I had recently begun taking melatonin again to try and help with sleep. I decided, after reading this article, to give the combination a go,  and I’m not really sure how I feel about the results. I have tried three or four times now to take the combination, and each time I wake up in the morning with a feeling of unease. I am not sure if it is placebo, or if it is an acute reaction that will fade with time. I am certain of one thing though: I will be trying this combination again starting tonight and will stick it out for at least two weeks before making my decision as to whether or not it will be a useful tool for my own personal growth and emotional well-being.

If any of you have had the opportunity to try these two medications in tandem, I would love to hear your results, positive or negative!

The Combination of Buspar and Melatonin in Treating Major Depressive Disorder

We used in vitro neurogenesis-based human neural stem cell (hNSCs) assays and rodent in vivo behavioral assays to identify potential novel antidepressants. A combination of buspirone and melatonin displayed antidepressant activity in these assays whereas neither buspirone nor melatonin alone showed any antidepressant-like profile. After evaluating numerous combination ratios, we determined that low dose buspirone 15 mg combined with melatonin-SR 3 mg yielded optimal antidepressant efficacy in our pre-clinical platform. The low dose of buspirone suggested that antidepressant efficacy might be achieved with only minimal adverse event liability. Based on these data, we conducted an exploratory 6-week, multi-center, double-blind, randomized, placebo- and comparator-controlled study of the combination of buspirone and melatonin in subjects with acute Major Depressive Disorder (MDD). The combination treatment revealed a significant antidepressant response in subjects with MDD on several measures (Clinical Global Impression of Severity and Improvement, Inventory of Depressive Symptomatology) compared to either placebo or buspirone 15 mg monotherapy. These preliminary findings have clinical implications and suggest that a platform of pre-clinical neurogenesis matched with confirmatory behavioral assays may be useful as a drug discovery strategy.





    • I have gone back and forth on this one. I have found that Buspar wasn’t suiting me well after a period of time. I haven’t really stopped taking melatonin, and I found something called flibanserin, which is a very selective 5ht1a agonist and works better than buspar IMO. I have been using these two together for a couple months now. The only drawback to this protocol is that flibanserin can cause a pretty dramatic drop in blood pressure if one consumes ethanol in combination. But like I said, I don’t drink much anymore these days, and so I haven’t had as much an issue with this. And drinking may very well contribute to long term depression and anxiety anyways, so anything that keeps me from imbibing is probably helping me to keep my brain in check from a health standpoint regardless.

      Have you combined these two before? Have you tried anything similar? I would love more feedback and discussion from readers, so that we can all learn from other people’s experiences and not leave it to me to be a guru of sorts on these topics. I’m just another avid fan of research and lifestyle augmentation via supplementation. So I look forward to hearing more from other people about their own experiences, research or ramblings! Bring it!

  1. I was on benzos for years and finally decided to taper off a year ago. I had been prescribed buspirone in the past but never took it. I had some tabs that were a few months old and I took 15mg one night to try it out. I was pleasantly surprised. Not only did it eliminate my anxiety but I did feel a certain level of euphoria induced happiness. I tried again the next night and found the same happened. I have been on every anxiolytic and anti-depressant there is and may be on to something here. I also tried it with hydroxyzine last night and was almost dancing. I tried 15mg of buspar and 50 mgs of hydroxyzine and was dancing. Overall, I think buspar is okay it just has to be taken at the correct dosage to be effective.