Looking in the Bargain Bin: Rhodiola Rosea and Memantine as Off-Label Options

Ever since the beginning of my career, I have had a mild aversion to name-brand pharmaceuticals. By nature, I am skeptical, and experience has proved this skepticism useful: most newly minted pharmaceuticals do not live up to the hype. Granted, there have been some helpful developments in recent decades. Trintellix, Latuda, and Vyvanse come to mind. They were not game changers but were helpful for making treatment more accessible with a reduced side effect burden. TMS and ketamine/Spravato are game changers in a sense, but for the purposes of this discussion I am considering things that can be prescribed in a typical outpatient practice.^*

Nevertheless, we often find ourselves searching for answers when we have followed the typical protocols and have not had an adequate response to treatment. I like to look in the bargain bin for treatments that are generic, have some good evidence, and are not commonly used for whatever reason. For example, pregabalin for GAD or pramipexole for MDD.

Of course, whenever we experience treatment failures we want to:

1. Reconsider the diagnosis.
2. Consider whether recreational substance use or abuse is interfering with treatment effectiveness.
3. Consider underlying medical problems or medications as a cause.
4. Consider whether life circumstances, such as being in an abusive relationship, are interfering with treatment.

Once those questions have been answered, it is time to consider off-label treatments. One resource I rely on for ideas is the Psychopharmacology Algorithms at Harvard South Shore.

Today I will look at two potential off-label treatments, their clinical science, and the evidence behind them.

Rhodiola Rosea for Generalized Anxiety Disorder

Rhodiola rosea (also known as golden root, Arctic root, or roseroot) is a flowering plant used in traditional medicine across Russia, Scandinavia, and parts of Asia for centuries. It falls into the category of adaptogens: substances thought to help the body manage stress and restore physiological balance. The adaptogen category is crowded with products that do not survive close examination. Rhodiola is a more interesting case than most.

Its active compounds, primarily rosavin and salidroside, appear to modulate serotonin, dopamine, and norepinephrine activity and to influence stress hormone pathways including cortisol (Lucius, 2024). Anti-inflammatory and neuroprotective effects have been demonstrated in preclinical work, though translating animal data to human outcomes always requires caution.

The clinical evidence for anxiety is thin but worth knowing. The most directly relevant study for GAD is a small open-label pilot trial by Bystritsky and colleagues, in which ten patients with diagnosed GAD received 340 mg of rhodiola extract daily for ten weeks. Hamilton Anxiety Rating Scale scores dropped significantly, from a mean of 23.4 at baseline to 14.1 at ten weeks. Five of the ten met the threshold for treatment response, and four achieved remission scores. No one discontinued due to side effects, though dizziness and dry mouth were reported (Bystritsky et al., 2008). Ten patients in an open-label trial is not much to go on, and placebo effects cannot be ruled out.

A larger randomized trial by Cropley and colleagues enrolled 80 mildly anxious participants and compared rhodiola extract to a no-treatment control group over 14 days. The rhodiola group showed significant reductions in self-reported anxiety, stress, anger, confusion, and depression, with mood improvements appearing as early as three days into treatment (Cropley et al., 2015). The design is more rigorous, though the participants had mild rather than clinical-level anxiety and the trial was short.

There is also a trial combining rhodiola with sertraline. A hundred patients received either sertraline alone or sertraline plus rhodiola at 300 or 600 mg daily for twelve weeks. The combination produced no adverse interactions and improved quality of life and clinical outcomes compared to sertraline alone, which is reassuring from a safety standpoint and hints at possible additive benefit (Lucius, 2024).

Rhodiola is not going to replace first-line treatment for GAD. The trials are too small and the evidence too preliminary for that. But for a patient who has had a partial response to standard treatment, who wants to minimize medication burden, or who is asking about adjunctive options, it is worth discussing. The safety profile is good, the cost is low, and the pharmacology is plausible. We need better trials, but the existing data is enough to take it seriously.

Memantine for Cognitive Impairment in Major Depression and Bipolar Disorder

Memantine is FDA-approved for moderate to severe Alzheimer's disease. It works as an NMDA receptor antagonist, blocking a subtype of glutamate receptor that, when chronically overactivated, appears to contribute to neuronal damage and cognitive decline. That mechanism has caught the attention of researchers in mood disorders.

We are at a moment when concerns about cognitive function (memory, attention, processing speed, executive function) are bringing a lot of people in for evaluation, many of them wondering whether ADHD explains what they are experiencing. Sometimes it does. But cognitive complaints are also a well-documented feature of both major depressive disorder and bipolar spectrum disorders, persisting even after mood symptoms have stabilized. Before pursuing an ADHD workup or a stimulant trial in someone with a history of depression or a bipolar spectrum presentation, I think it is worth asking whether the cognitive picture might be driven by the underlying mood disorder. If the answer is yes, or even possibly yes, memantine becomes an interesting option to consider.

There is a pharmacological basis for this. Glutamate dysregulation has been increasingly implicated in the pathophysiology of both MDD and bipolar disorder, and NMDA receptor modulation has become a legitimate therapeutic target in psychiatry. Ketamine's success in treatment-resistant depression is the most prominent example. Memantine works on the same receptor via a different mechanism, without the dissociative effects or abuse potential that make ketamine impractical for most outpatient settings.

The evidence is modest but real. A randomized controlled trial of adjuvant memantine versus placebo in euthymic patients with bipolar disorder found improvements across several cognitive domains, along with increased hippocampal neuronal viability on neuroimaging (Iosifescu et al., 2013). A systematic review and meta-analysis of memantine's effects on depressive symptoms across major mental illnesses, including MDD, bipolar disorder, and schizophrenia, found a statistically significant reduction in depressive symptom scores compared to placebo, with a small effect size (Hedges' g = -0.17, p = 0.009) across eleven trials and 899 participants (Gao et al., 2022). A separate systematic review of memantine in bipolar disorder found conflicting results and concluded that evidence does not yet support routine use (Vreeker et al., 2016). Promising, not proven -- that is probably the fairest way to put it.

Memantine is generally well tolerated. Side effects can include dizziness, headache, and constipation. It is renally cleared and needs dose adjustment in patients with significant kidney impairment. At typical doses of up to 20 mg daily, it does not carry the risks associated with stimulants, which matters when you are working with a population where stimulant prescribing warrants extra caution.

For a patient who has good mood stability but is still struggling cognitively, who feels like they cannot hold information the way they used to, who is losing track of things, who describes a kind of mental fog that standard treatment has not touched, memantine is a reasonable option to try. It is not dramatic. But sometimes undramatic is what you need.

I have tried memantine in at least one patient with a bipolar diagnosis who came in with significant concerns about memory and executive function. The trial was a success. That is a sample size of one, and I would not build a clinical guideline around it, but it is the kind of outcome that makes you want to reach for something again.

Closing Thought

Neither rhodiola rosea nor memantine is going to top the list of bargain bin finds. Pregabalin for GAD and pramipexole for MDD have stronger evidence and a longer track record in off-label use. Both are promising enough to try when you have run out of better-supported options, but neither has the trial data yet to say much more than that.