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L-DOPA, a precursor of dopamine, has been the gold standard for the treatment of Parkinson’s disease. Its many benefits include improved sexual function, increased cognitive performance and motivation, better sleep, and pain relief. However, it can also cause a wide range of side effects. It can be obtained as regular medication or from natural sources. Keep on reading to learn more about L-DOPA.
What is L-DOPA (Levodopa)?
But the benefits of L-DOPA go beyond Parkinson’s disease. They include improved sexual function, mental alertness, motivation, and sleep. It is also able to relieve pain and help with weight loss, while mixed effects were reported in depression, anxiety, and oxidative stress. In addition, it can be used as a “smart drug,” given its positive effects on cognitive function in healthy individuals.
Besides common medications, L-DOPA can be obtained from multiple natural sources, such as the plant Mucuna pruriens.
However, L-DOPA may also cause side effects, including involuntary, abnormal muscle movements (dyskinesia) in patients with Parkinson’s disease.
Mechanism of Action
L-DOPA Increases Dopamine
L-DOPA is a direct precursor of dopamine – it is the compound that dopamine is made from. It gets converted to dopamine by the enzyme aromatic amino acid decarboxylase (AADC or AAAD) [R].
Importantly, unlike dopamine, L-DOPA is able to cross the blood-brain barrier. This means that taking L-DOPA increases dopamine in the brain, which is key in the fight against brain diseases, including Parkinson’s [R].
L-DOPA Increases Testosterone
L-DOPA also has an effect on the levels of testosterone. It was shown to prevent the decrease in testosterone levels in 32 Parkinson’s disease patients, and to increase the levels of the hormone in rats. This effect may be due to the dopaminergic inhibition of prolactin, which prevents decreases in the levels of luteinizing hormone and testosterone [R, R].
L-DOPA May Increase Adrenaline/Noradrenaline
However, a study in 36 young hypertensive patients showed no changes in blood plasma levels of noradrenaline after L-DOPA treatment [R].
Effects of L-DOPA
1) L-DOPA Improves Parkinson’s Disease Symptoms
L-DOPA is currently the most effective drug for the improvement of Parkinson’s disease symptoms. Parkinson’s disease is a movement disorder characterized by a range of motor symptoms that include slowness, rigidity, tremor at rest, postural instability, and shuffling gait. These symptoms are often accompanied by the appearance of cognitive and psychiatric problems [R].
A pathological hallmark of the disease is the dramatic reduction of dopamine and dopamine-responsive neurons in the brain, particularly in a crucial area that controls movement, called substantia nigra [R].
The benefits of L-DOPA are due to an increase of dopamine levels in the brain. Improved life expectancy has been shown in 176 patients treated for 12 years [R].
L-DOPA improves Parkinson’s motor symptoms such as slowness of movement, rigidity, and tremor, but not the non-motor symptoms. It is particularly useful as an early treatment before more extensive degeneration of dopamine neurons [R, R].
An increase in brain noradrenaline levels may also explain the benefits of L-DOPA treatment in Parkinson’s disease, particularly in alleviating depression, reduced vigilance, and sleep impairment that is often associated with motor symptoms [R].
To avoid the negative effects of long-term use of L-DOPA, other drugs have been developed over the years [R].
However, L-DOPA remains the prime therapy for Parkinson’s due to a combination of factors. It [R]:
- activates both D1 (DRD1) and D2 (DRD2) receptors
- possibly activates adrenergic receptors (which bind adrenaline and noradrenaline)
- has high efficiency (it takes less time to reach an effective dosage)
- reduces the release of the inhibitory neurotransmitter gamma-aminobutyric acid (GABA)
A DB-RCT in which 86 Parkinson’s disease patients took increasing doses of an L-DOPA inhalation powder showed rapid improvement of motor function after 4 weeks of treatment [R].
Furthermore, an analysis of 11 DB-RCTs showed that, compared to therapies that avoid L-DOPA in favor of other drugs, the use of L-DOPA alone was a more efficient for the treatment of motor symptoms of Parkinson’s, with reduced risk of treatment discontinuation due to adverse effects [R].
A study including 60 Parkinson’s disease patients with and without dementia found that L-DOPA improved motor and cognitive function, although verbal attention and memory deteriorated, which may be due to fluctuations in attention [R].
In a rat model of Parkinson’s disease, this drug improved cognitive deficits and synaptic activity in the hippocampus, a critical area for learning and memory [R].
2) L-DOPA May Improve Cognitive Function
Similar results were reported from a DB-RCT with 22 healthy young adults taking L-DOPA, who showed improved word recall over five learning sessions and better recognition accuracy at a 1-month follow-up, compared to placebo [R].
Improvements in working memory and in long-term memory were also reported upon L-DOPA usage in a DB-RCT with 18 healthy humans [R].
However, L-DOPA may impair memory in Parkinson’s disease patients depending on the status of their brain dopamine system and specific gene variations (polymorphisms) [R].
A (DB-RCT) study with 26 healthy young adults with normal cognitive function showed that a single-dose L-DOPA impaired stimulus-reward learning [R].
Similar findings were reported in another (DB-RCT) study with healthy participants, which demonstrated that single administration of L-DOPA decreased the ability to filter out distracting information (interference control) in 15 young subjects, but not in 13 older participants [R].
Single-dose L-DOPA also caused less efficient learning of stimulus-response associations in 40 healthy young adults (DB-RCT) [R].
3) L-DOPA Increases Testosterone Levels and Libido
Treatment with L-DOPA significantly prevented the lowering of testosterone levels in early Parkinson’s disease in a study with 32 male patients, compared with untreated subjects. This may be due to dopamine’s ability to inhibit prolactin, a hormone which lowers the levels of luteinizing hormone and testosterone [R].
Of note, Mucuna pruriens, a natural source of L-DOPA (see below) increased testosterone levels in 75 infertile men aged 25 to 40 years [R].
Research in rats showed that oral doses of L-DOPA equivalent to 160 mg/kg in humans increased testosterone levels in the blood after 7 to 14 days. This effect is probably secondary to increases in the levels of luteinizing hormone [R].
L-DOPA is well-known to increase libido in patients with Parkinson’ disease. For example, it increased sexual interest in a study with 7 male patients with this disease [R].
In a study of 8 sexually impotent male patients, treatment with L-DOPA for 12 weeks increased libido in two patients [R].
In men, but not in women, a single consumption of L-DOPA increased the magnitude of a reflex regulated by preparation for motivated action (Achilles tendon reflex) in response to sexual stimulation [R].
L-DOPA Improves Erectile Function
L-DOPA increased penile swelling (tumescence) in 12 subjects, who were 50 years old or older and had normal levels of androgen (testosterone is the main androgen in men). In addition, L-DOPA augmented maximum penile circumference in 9 subjects younger than 50 years [R].
Furthermore, a study with 8 sexually impotent patients showed that 12-week treatment with L-DOPA increased the frequency of spontaneous erection during the night. L-DOPA also increased penile erection in 6 patients [R].
4) L-DOPA Can Improve Mental Alertness
In comparison with other dopaminergic medications for Parkinson’s disease, L-DOPA induced higher levels of alertness in 48 patients, whose nigh-time sleep and daytime wakefulness were measured over 2 days [R].
Also, in a Parkinson’s disease study, L-DOPA improved alertness in all 60 patients with and without dementia [R].
Improvements in alertness were also noted in a DB-RCT of 6 subjects with periodic limb movements following two doses of L-DOPA given for 5 days each [R].
Of note, contradictory results have also been reported. A study with 10 healthy men indicated a decrease in alertness with L-DOPA [R].
5) L-DOPA Increases Motivation
In an MRI study of 28 healthy adults, L-DOPA improved motivation by increasing brain activation related to punishment processing. The study also found that novelty seeking was associated with the observed effects on motivation [R].
L-DOPA also improved motivational deficits in Parkinson’s disease. A study with 23 patients and 28 controls showed increases in motivation in the patients [R].
6) L-DOPA Reduces Weight and Body Fat Mass in Parkinson’s Disease
Although scientists debate whether the weight loss in Parkinson’s disease is due to L-DOPA treatment, the aging process, disease mechanisms, or a combination of these factors, studies suggest that L-DOPA contributes to weight reduction in these patients.
Specifically, a study with 7 patients treated over 1-3 years with L-DOPA suggested that the weight loss in Parkinson’s could be due to the breakdown of fat that results from L-DOPA-induced higher blood levels of insulin. However, this effect may also be due to the aging process [R].
In another study with 56 subjects, including 28 Parkinson’s disease patients and 28 controls, L-DOPA contributed to weight loss in Parkinson’s [R].
7) L-DOPA Can Improve Sleep
In a DB-RCT of 6 subjects with periodic limb movements, increasing doses of L-DOPA given over 2-week periods improved sleep, particularly in the first 3 hours [R].
In macaques with Parkinson’s disease, treatment with this drug resulted in partial, but significant, improvement of all sleep parameters – including sleep episodes during the daytime, sleep fragmentation and sleep efficiency at nighttime [R].
However, reports of negative findings can also be found. In 32 Parkinson’s disease patients, L-DOPA did not improve any of the sleep variables analyzed, while the time spent awake increased [R].
8) L-DOPA Reduces Pain
L-DOPA has well-known pain relieving properties. Treatment in patients with Parkinson’s disease showed that this drug reduced pain intensity in 8 of 14 patients with severe pain [R].
However, a different study with 17 Parkinson’s disease patients showed that, although some patients reported an improvement of pain with L-DOPA, objective measurements with sensory testing did not reveal pain reduction [R].
In sleep-deprived rats, which show decreased numbers of dopaminergic neurons in a crucial brain area responsible for pain control (periaqueductal gray matter), L-DOPA decreased pain sensitivity to a hot plate [R].
Research in mice showed that the pain-relieving effects of this drug occur after conversion to dopamine and are mediated by D2 receptors [R].
9) L-DOPA May Improve Vision
In a pilot trial with 33 children and adolescents with residual amblyopia (a condition often called lazy eye, in which the vision in one of the eyes is reduced even if using prescription glasses due to the brain favoring the other eye), L-DOPA/carbidopa treatment for 8 weeks improved visual acuity with no serious side effects [R].
In another (DB-RCT) study in 32 patients with optic nerve injury resulting from trauma (indirect traumatic optic neuropathy), treatment with L-DOPA for 1 month, and starting 6 days after trauma, improved visual acuity [R].
10) L-DOPA May Help Combat Addiction
A study with 136 treatment-seeking cocaine-dependent subjects, showed that 12-week treatment with L-DOPA in combination with behavioral therapy increased cocaine-negative urine samples, evidencing reduced cocaine consumption, in comparison with placebo [R].
11) L-DOPA May Help With Schizophrenia
In a meta-analysis of 30 studies involving 716 patient, L-DOPA was found beneficial in the treatment of schizophrenia when added to a regimen with antipsychotic drugs (which bind to dopamine receptors), particularly in reducing negative symptoms, such as apathy, social withdrawal, and impaired attention [R].
12) L-DOPA May Increase The Immune Response and Inflammation
Activation of the inflammatory response in the brain is one of the mechanisms proposed for L-DOPA-induced abnormal muscle movements (see below). Specifically, studies suggest that L-DOPA leads to chronic and abnormal activation of microglia and astrocytes, which disrupts the communication between neurons and synaptic activity [R].
In opposition, a study in mouse and human immune cells showed that L-DOPA released by active melanoma cells can inhibit the production of new lymphocytes (types of white blood cells) upon immune challenge [R].
13) L-DOPA May Increase or Decrease Oxidative Stress
The role of oxidative stress in aging and in diverse brain diseases is substantially documented. Therefore, researchers have been focusing on the development of antioxidant therapies that might improve cell damage.
This result is in line with other research showing that the conversion of L-DOPA to dopamine gives rise to other compounds involved in oxidative stress, including quinones, semiquinones and hydrogen peroxide [R, R].
Furthermore, the pro-oxidant effects of L-DOPA can also be explained by the induction of programmed cell death (apoptosis) [R].
In rats, administration of L-DOPA increased oxidative damage in the brain, a key step in the development of several diseases [R].
14) L-DOPA May Increase Impulsive and Risk-Taking Behavior
L-DOPA treatment in Parkinson’s disease may increase risk-taking behavior and cause impulse control disorders, which include compulsive eating, pathological gambling, hypersexuality, and compulsive buying [R].
These are observed in later stages of the disease, in which dopaminergic medication leads to abnormal dopamine peaks and hyperstimulation of specific brain mechanisms (mesolimbic system) [R].
15) L-DOPA Can Improve or Worsen Depression and Anxiety
Alpha-methyl-para-tyrosine (AMPT), a chemical that blocks catecholamine production, increases sleepiness and mildly increases negative mood and anxiety in healthy men. Treatment with L-DOPA reversed the negative effects of AMPT on alertness and mood in 41 healthy men [R].
However, a study including 38 Parkinson’s disease patients showed that, although short-term treatment (about 12 months) reduced depression at least temporarily, longer-term treatment (about 20 months) did not result in any benefit [R].
Additional studies demonstrated that L-DOPA failed to improve depression and anxiety in Parkinson’s disease. In fact, it may even worsen symptoms, via disruption of noradrenaline and serotonin systems [R, R].
The effect of L-DOPA on serotonin is well documented. Research shows that L-DOPA may disrupt the release of serotonin, and decrease its levels outside the neurons. This would affect the efficacy of antidepressants that increase extracellular serotonin levels (selective serotonin reuptake inhibitors) [R].
A similar increase in anxiety was reported in rats treated over 28 days with L-DOPA [R].
16) L-DOPA May Decrease Bone Density
L-DOPA treatment has also been associated with an increased risk of osteoporosis and bone fracture in patients with Parkinson’s disease due to the L-DOPA-induced exaggerated blood levels of the amino acid homocysteine (hyperhomocysteinemia). This was reported in a study with 95 patients aged 55 years or older and in another study with 54 patients, which showed decreased bone mineral density in the spine and hip [R, R].
The significant body of research on treatments shows that this drug it is generally safe and well-tolerated, but relevant side effects have been reported, including:
- Agitation [R]
- Anxiety [R]
- Hallucinations [R, R]
- Dizziness [R]
- Confusion [R]
- Nausea [R]
- Vomiting [R]
- Coughing [R]
- Hypotension (low blood pressure) [R]
- Gut bleeding [R]
- Arrhythmias [R]
- Insomnia [R]
- Vivid dreams [R]
- Somnolence (sleepiness, drowsiness) [R]
- Hair loss [R]
- Excessive libido [R]
Long-term treatment with L-DOPA frequently causes abnormal muscle movements in Parkinson’s disease patients. Dyskinesia is normally caused by depletion of dopaminergic neurons that occurs in Parkinson’s and with age. This has been attributed to both a direct effect in the basal ganglia and excessive release of L-DOPA-derived dopamine in the striatum, a critical brain area in the control of movement [R].
At the molecular level, L-DOPA leads to dyskinesia through activation of dopamine D1 receptors, which results in the production of dynorphin-B, an opioid peptide [R].
A possible role of serotonin receptors has also been proposed after findings in both rat and macaque models of Parkinson’s [R].
Increased aggression (hostility, impulsiveness) was reported in 1 out of 10 schizophrenic patients [R].
Limitations and Caveats
As detailed in the above sections, L-DOPA may elicit opposite effects depending on a number of factors, such as dosage, inter-subjects differences, and the presence of a disease. These aspects need to be considered if planning to take the drug.
L-DOPA usage is not recommended with a substantial number of drugs, such as:
- Solian (amisulpride, an antipsychotic) [R]
- Bromopride (a dopamine receptor blocker used to treat vomiting and nausea) [R]
- Clorgyline (a monoamine oxidase inhibitor) [R]
- Marplan (isocarboxazid, an antidepressant) [R]
- Zyvox (linezolid, used to treat bacterial infections) [R]
- Amira (moclobemide, an antidepressant) [R]
- Eutonyl (pargyline, an antihypertensive) [R]
- Nardil (phenelzine, an antidepressant) [R]
- Dogmatil (sulpiride, an antipsychotic) [R]
- Parnate (tranylcypromine, an antidepressant) [R]
- Domperidone (a dopamine D2 receptor blocker) – it increased the levels of L-DOPA in the blood of 18 patients with Parkinson’s disease [R]
Nicotine reduced the blood levels of L-DOPA in 6 of 8 healthy subjects. In addition, the study suggested that nicotine may affect L-DOPA cellular transport [R].
L-DOPA and Hormones
Apart from testosterone, L-DOPA can also affect a number of other hormones.
Of note, the effects are noted in women with polycystic ovarian disease, who have elevated androgen levels, and in obese patients. Both of these groups showed a reduced release of growth hormone in response to L-DOPA [R, R].
However, L-DOPA decreased the concentration of cortisol in a study with 12 Parkinson’s disease patients, possibly due to reduced levels of serotonin – a regulator of cortisol release [R].
However, this effect was not shown in a study with 10 healthy subjects [R].
Natural Sources (and Other Forms of Supplementation)
L-DOPA can be obtained from diverse natural sources, particularly Mucuna pruriens, commonly known as velvet beans or cowitch, and other members of the Mucuna family (Holtonii, Andreana, Aterrima, and Gigantean). Seeds of Mucuna pruriens contain an average of 4-7%, with levels as high as 9% [R, R].
- White bark acacia (Acacia leucophloea)
- Tamarind (Tamarindus indica)
- Dunchi fiber (Sesbania bispinosa)
- Sword bean (Entada scandens)
- Mountain ebony (Bauhinia variegata)
- Sword jackbean (Canavalia gladiata)
- Moth bean (Vigna aconitifolia)
- Cowpea (Vigna unguiculata)
- Zombi pea (Vigna vexillata)
- Algarrobo (Prosopis chilensis)
- Purple orchid tree (Piliostigma malabarica)
- Maloo creeper (Phanera vahlii)
- Jerusalem thorn (Parkinsonia aculeata)
- Senna (Cassia floribunda)
- Woolly senna (Cassia hirsuta)
- Cocobolo (Dalbergia retusa).
L-DOPA can also be obtained from pills as a regular drug, under trade names such as Duopa, Rytary, Parcopa, Sinemet, Stalevo, Madopar, Pharmacopa, Prolopa, and Atamet.
L-DOPA is taken with carbidopa, which prevents the conversion of L-DOPA into dopamine outside the brain. This allows more L-DOPA to reach the brain. As carbidopa does not cross the blood-brain barrier, L-DOPA is converted into dopamine in the brain, increasing dopamine levels [R].
Individual doses will be different for each patient, and 3 to 4 months of treatment may be needed to establish a stable regimen[R].
Adjustment is frequently necessary when the effectiveness decreases as a result of long-term use in Parkinson’s disease. This can lead to abnormal, involuntary movements and rapid worsening of symptoms. Combining L-DOPA with other medications is an alternative strategy [R, R].
To stabilize the levels of dopamine, L-DOPA can be taken with drugs that inhibit dopamine breakdowns, such as monoamine oxidase-B (MAO-B) inhibitors and catechol-O-methyltransferase (COMT) inhibitors [R, R].
Using dopamine agonists may also prolong the effects of L-DOPA while avoiding the occurrence of side effects [R].
Fragmentation of L-DOPA oral dosing, with L-DOPA administered up to 6 or 7 times a day at 3-hour intervals, can be an effective strategy, though with potential for delayed response [R].
In late-stage Parkinson’s, substitution of regular with controlled-release and liquid formulations may help improve the therapeutic effect [R].
A (DB-RCT) study in 50 healthy adults over two study weeks showed that the rs1800497 genetic variant of the DRD2/ANKK1 gene influences the effect of L-DOPA on motor learning. People with this variant have less dopamine binding sites in the brain, and L-dopa helps them learn better, while it is less effective in people without this variant [R].
An additional (DB-RCT) study in 205 healthy male subjects showed that a variant of the DRD4 gene, which codes for the dopamine receptor D4, accounts for differential susceptibility to gambling behavior after single-dose administration of L-DOPA. Specifically, subjects who carry at least one copy of a 7-repeat variant show increased gambling propensity after receiving L-DOPA [R].
Several user reports regarding L-DOPA supplementation can be found online. The reported effects are diverse and include:
- Enhanced mood
- Improved motivation
- Improved focus/attention
- More confidence
- Fluidity of movement
- Higher sex drive
- Body and mind rush
Rare reports of adverse effects include:
- Worsening of depressive symptoms with associated suicidal thoughts
- Enhanced aggressiveness
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