Reducing Anxiety, Panic, and OCD
Anxiety is part of life. You can't avoid some anxiety. A moderate amount of anxiety can actually help improve performance in many situations, but when anxiety becomes overly intense, as in extremely stressful situations, or in people with pathologic conditions like panic disorder, obsessive-compulsive disorder (OCD), or post-traumatic stress disorder (PTSD), it can be debilitating and even dangerous. The pharmaceutical industry has made billions of dollars selling drugs that are very effective for reducing anxiety, panic, and OCD, including the benzodiazepines (eg, Librium7, Valium7, and Xanax7) and more recently, the SSRIs. Preliminary evidence suggests that 5-HTP may also be quite effective for relieving acute anxiety states.
Serotonin and Anxiety
Serotonin may be important for regulating anxiety, but the mechanisms involved are less well-understood and more complex than they are for depression. In animal studies, for example, reducing serotonin function with certain drugs appears to reduce anxiety.24 Similarly, benzodiazepines, which reduce anxiety in humans, also reduce serotonin activity. On the other hand, rapid depletion of tryptophan, leading to a reduction in serotonin, has been reported to exacerbate both panic and aggression,25 while treatment with SSRIs, which enhance serotonergic activity, have clear anti-anxiety activity.262728 Studies using L-tryptophan or 5-HTP, which increase serotonin activity, suggest that these amino acids may also be effective anxiety-reducing agents.
Evidence for 5-HTP
In one early study, L-tryptophan was found to be effective in reducing the symptoms of OCD.29 The first study investigating the possible anti-anxiety effects of 5-HTP was published in 1985.30 This was a small, uncontrolled pilot study conducted in the Netherlands. The subjects were 10 individuals diagnosed with anxiety disorders according to standard criteria (seven of the patients had "panic disorder;" three had "generalized anxiety disorder"). 5-HTP treatment (300 mg/day) lasted 12 weeks, during which their level of anxiety was assessed weekly using the Spielberger State-Trait Anxiety Inventory (STAI) and the Hamilton Anxiety Scale (HAS).
By week 12, panic attacks had almost completely disappeared in the seven patients suffering from that disorder; overall 9/10 patients showed improvement as measured by the STAI and HAS scales. Improvement was apparent by week 4 and continued until week 8, after which it leveled off. Figure 6 shows the mean symptom scores before 5-HTP treatment (Baseline) and after 12 weeks of 5-HTP. Significant improvement was seen for depression, anxiety and phobic anxiety.
Although this study was limited by the small number of subjects and a lack of proper controls, the same investigators conducted a larger double-blind, comparative, placebo-controlled study a few years later. The results showed that 5-HTP had significant activity that was on a par with the anti-anxiety drug clomipramine (Anafranil7) on some measures, but not on others.31 In this study, 45 patients diagnosed with anxiety disorders (generalized anxiety disorder, panic disorder, agoraphobia, or OCD) were randomly assigned to receive either 5-HTP, clomipramine, or placebo. The trial lasted 8 weeks. The results (Fig. 7) showed that both 5-HTP and clomipramine were about equal and both were significantly superior to placebo in reducing anxiety beginning at week 2 on this measure of anxiety (State-Anxiety Inventory, A-STATE). On other measures, 5-HTP was generally superior to placebo but less effective than clomipramine. Since these investigators used a lower maximum dose of 5-HTP (150 mg/day) in this study than they used in their earlier study (300 mg/day), it is possible that a higher dose would have produced a more dramatic result.
As we noted above, the relationship between serotonin and anxiety appears to be quite complex. For example, anxiety can be relieved both by agents that interfere with serotonergic function (eg, benzodiazepines) as well by agents that enhance serotonergic function (eg, 5-HTP and SSRIs). In addition, treatment with 5-HTP and SSRIs has sometimes been reported to result in an aggravation of anxiety (or depression) during the first week or two of therapy before clinical improvement occurs.
Scientists have not yet pinned down the reason for these paradoxical responses. The hypothesis that has the most support at the present time suggests that reducing serotonergic activity generally lowers anxiety. In people with anxiety disorders, serotonin receptors become hypersensitive. In other words, they overreact to a burst of serotonin molecules that would normally not increase anxiety. Thus, when a person with an anxiety disorder takes 5-HTP or an SSRI, the extra serotonin produced initially overstimulates these hypersensitive receptors and may lead to an aggravation of the anxiety. With continued stimulation, though, these receptors eventually become less sensitive -- a process known as downregulation -- and anxiety levels eventually decline.24
Although the definitive studies on the role of 5-HTP for treating anxiety have yet to be done, considerable research with SSRIs indicates that these drugs can be very effective for reducing excess anxiety. There is every reason to believe that 5-HTP is just as effective while producing fewer unwanted side effects. However, users of 5-HTP (like SSRI users) should not be surprised if they feel more anxious initially before anxiety begins to decline.
Heading Off Migraine Attacks
There is little doubt that alterations in serotonin function are involved in the common painful and often debilitating syndrome known as migraine headache, or simply migraine. Although the precise mechanisms have yet to be elaborated, it is believed that migraine results when certain blood vessels in the brain dilate abnormally and that serotonergic mechanisms help control that dilation.32
The drugs that have been found to be most effective for treating active migraine attacks are those that stimulate specific subtypes of serotonin receptors (eg, 5-HT1D), which results in the constriction of these blood vessels. These drugs, known as serotonin agonists, include Imitrex7 (sumatriptan), Migranal7 (dihydroergotamine), and several other recently introduced drugs. In addition, SSRIs have been increasingly used prophylactically between migraine attacks to prevent subsequent attacks.
A few studies suggest that 5-HTP may also be useful for heading off future migraine attacks, although there is no evidence that it does any good once an attack has commenced. In one study, Spanish researchers gave either 5-HTP or methysergide (a well-known migraine treatment which also affects serotonergic function) to 124 people with migraine ("migraineurs"). Significant improvement occurred in both groups -- 71% in the 5-HTP group and 75% in the methysergide group. The 5-HTP-treated patients experienced reduced intensity and duration of their headaches, although the number of headaches was unchanged. 5-HTP also caused far fewer side effects than methysergide. These results prompted the authors to suggest that 5-HTP could be the treatment of choice for migraine prophylaxis.33
A group of Italian researchers confirmed the efficacy of 5-HTP as prophylaxis for migraine attacks in a double-blind, placebo-controlled study in 31 migraineurs.34 For the first 2 months of the study, the researchers randomly assigned the patients to receive either 5-HTP or placebo. For the second 2 months, the 5-HTP group was switched to placebo and the placebo group to 5-HTP (a "crossover" design). They used two measures of efficacy: 1) headache index (HI), which was simply the number of headaches per month; 2) headache density, which was calculated by multiplying the frequency of headaches by their severity.
Compared with the pretreatment baseline, the investigators found a highly significant reduction in headache frequency and severity. HI improved 31 to 38%, and HD improved 41 to 43%. Although the magnitude of these improvements seems modest, the authors point out that these patients had had long-lasting, very frequent, and severe headaches before treatment and that 83% had failed to respond to previous prophylactic agents. The major problem with this study was the presence of a very large placebo effect. As a result, there was no statistically significant difference between the 5-HTP and placebo conditions. Nevertheless, almost two-thirds of the patients expressed a preference for 5-HTP over the placebo.
Side effects of related to 5-HTP were described as "generally mild and transient." The authors concluded that 5-HTP was "a medication of some efficacy and remarkable safety, providing us with another alternative approach to migraine prophylaxis."
Fibromyalgia is a puzzling syndrome characterized by chronic muscle aching, multiple tender points, fatigue, morning stiffness and disturbed sleep. The cause(s) is largely unknown, although some evidence suggests that low levels of tryptophan in the blood may be a factor.3536 This view has been reinforced by the fact that tricyclic antidepressants and SSRIs have been reported to offer some relief.373839 Treatment with oral tryptophan, however, does not seem to help.40
5-HTP has been evaluated as a treatment for fibromyalgia in two major studies in Italy. In a double-blind, placebo-controlled study,41 50 patients diagnosed with fibromyalgia took either 5-HTP or placebo for 30 days. Taking 5-HTP resulted in significant improvement according to several criteria:
- A decline in the number of tender points
- Reduced pain
- Less morning stiffness
- Better sleep
- Less anxiety
- Less fatigue
For two of the measures -- fatigue and sleep patterns -- the 5-HTP-treated patients were significantly better than placebo after only 15 days, as shown in Figures 8-10.
Because the first study was limited to 30 days, the same research group conducted a second trial to see how long the improvement would continue.42 They gave 5-HTP (100 mg 3/day) to 50 people with fibromyalgia for 90 days. There was no placebo control.
As in the first study, they found a significant decrease in all clinical variables, compared with baseline. Improvement was clear after 15 days and continued for up 60 days, after which it generally leveled off. Nearly 50% of the participants experienced "good clinical improvement." Side effects were generally mild and transient.
How does 5-HTP relieve fibromyalgia? No one really knows. It is thought that low serotonin levels may be associated with greater pain sensitivity. Some evidence suggests that increasing serotonergic function using drugs like the SSRIs or 5-HTP may, therefore, raise pain thresholds. Lack of sleep is often an important factor in fibromyalgia. Thus, improving sleep patterns may also contribute to the feelings of relief.
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