Jov00332 1.15

Journal of Vision (2007) 7(8):4, 1–15 The effect of sildenafil citrate (Viagra®) on visual sensitivity Institute of Ophthalmology, University College London, Institute of Ophthalmology, University College London, Lindsay T. Sharpe Moorfields Eye Hospital, London, UK Whittington Hospital Highgate Hill and Institute of Urology, Middlesex Hospital, London, UK Institute of Ophthalmology, University College London, Caterina Ripamonti Institute of Ophthalmology, University College London, The erectile dysfunction medicine sildenafil citrate (Viagra®) inhibits phosphodiesterase type 6 (PDE6), an essential enzymeinvolved in the activation and modulation of the phototransduction cascade. Although Viagra might thus be expected toimpair visual performance, reports of deficits following its ingestion have so far been largely inconclusive or anecdotal. Here,we adopt tests sensitive to the slowing of the visual response likely to result from the inhibition of PDE6. We measuredtemporal acuity (critical fusion frequency) and modulation sensitivity in four subjects before and after the ingestion of a100-mg dose of Viagra under conditions chosen to isolate the responses of either their short-wavelength-sensitive (S-)cone photoreceptors or their long- and middle-wavelength-sensitive (L- and M-) cones. When vision was mediated byS-cones, all subjects exhibited some statistically significant losses in sensitivity, which varied from mild to moderate. The twoindividuals who showed the largest S-cone sensitivity losses also showed comparable losses when their vision wasmediated by the L- and M-cones. Some of the losses appear to increase with frequency, which is broadly consistent withViagra interfering with the ability of PDE6 to shorten the time over which the visual system integrates signals as the light levelincreases. However, others appear to represent a roughly frequency-independent attenuation of the visual signal, whichmight also be consistent with Viagra lengthening the integration time (because it has the effect of increasing the effectivenessof steady background lights), but such changes are also open to other interpretations. Even for the more affected observers,however, Viagra is unlikely to impair common visual tasks, except under conditions of reduced visibility when objects arealready near visual threshold.
Keywords: Viagra, sildenafil citrate, visual sensitivity, temporal sensitivity, temporal resolution, light adaptation,visual transduction, PDE6 Citation: Stockman, A., Sharpe, L. T., Tufail, A., Kell, P. D., Ripamonti, C., & Jeffery, G. (2007). The ef fect of sildenafil citrate(Viagra®) on visual sensitivity. Journal of Vision, 7(8):4, 1–15, http://journalofvision.org/7/8/4/, doi:10.1167/7.8.4.
closely related phosphodiesterase enzyme PDE6 (e.g.,Wallis, Casey, Howe, Leishman, & Napier, ).
Estimates suggest that Viagra has about 10% of the effect Since its approval in 1998, over 1 billion doses of on PDE6 that it has on PDE5 (Food and Drug Adminis- sildenafil citrate (Viagra) have been prescribed as a tration Joint Clinical Review, see Table 1 of treatment for erectile dysfunction (Pfizer, ). It works Laties & Zrenner, PDE6 plays an essential role in by inhibiting cyclic guanosine monophosphate (cGMP)- phototransduction, the process by which photons of light specific phosphodiesterase type 5 (PDE5), which is an are absorbed and converted into electrical signals for enzyme expressed in the smooth muscle of the corpus transmission to the visual centers of the brain. Activated cavernosa (Beavo, ; Moreland, Goldstein, & Traish, PDE6 (PDE6*) catalyzes the hydrolysis of cGMP to As an undesirable secondary effect, it inhibits a GMP. The reduction in cGMP results in the closure of ion Received September 22, 2006; published June 8, 2007 ISSN 1534-7362 * ARVO Journal of Vision (2007) 7(8):4, 1–15 Stockman et al.
channels in the plasma membrane, which blocks the inward Kelly, In cff measurements, the highest frequency flow of Na+ and Ca2+ ions leading to cell hyperpolarization that can be detected is determined as a function of (for reviews, see Arshavsky, Lamb, & Pugh, Pugh & adaptation level. These measurements are complemented Lamb, Pugh, Nikonov, & Lamb, PDE6, by temporal modulation sensitivity measurements, which however, not only activates the transduction cascade but can be used to determine sensitivity at temporal frequen- also regulates visual sensitivity. As the concentration of cies below cff and, thus, define the overall temporal PDE6* increases as the light level rises, the time over frequency response.
which the visual signals are integrated shortens and the If Viagra effectively lengthens the visual integration visual response speeds up (e.g., Govardovskii, Calvert, & time, then the way in which it alters temporal sensitivity Arshavsky, Nikonov, Lamb, & Pugh, will depend on the integration times involved. If the Tests to determine whether Viagra causes visual side integration times are long enough to selectively attenuate effects have so far been largely restricted to standard visible flicker frequencies (by integrating over more than measures of human visual performance, such as visual one cycle at some frequencies), then Viagra should acuity and color discrimination. Although such tests can impair the detection of higher rates of flicker relative to be important for clinical diagnosis, most are not parti- low rates, so that the cff is reduced and the falloff in cularly well suited for monitoring the visual effects that modulation sensitivity with increasing temporal fre- are likely to be caused by the inhibition of PDE6. As a quency steepens (before the final limiting slope). If, on result, perhaps, the outcomes of these tests have been the other hand, the integration times are very short, inconclusive, providing, at best, evidence that is largely Viagra should cause a frequency-independent divisive subjective or anecdotal (reviewed in Laties & Fraunfelder, scaling of sensitivity and, thus, a loss of cff and a vertical Laties & Zrenner, ; Marmor & Kessler, shift in the logarithmic modulation sensitivity functions, Any visual side effects are typically described in sub- without a change in shape. Frequency-independent losses jective reports as a bluish tinge or haze to vision or might also arise because the lengthening of the integra- increased sensitivity to light. These effects are rarely tion time makes steady components in the visual stimuli reported (3%) at the lowest clinical doses of 25 and 50 mg, (produced either by the background or by the flickering more often reported (11%) at the highest clinical doses of target, which must be modulated around a mean level) 100 mg, and frequently reported (50%) at doses of 200 mg more effective. This greater effectiveness arises simply or higher (Food and Drug Administration Joint Clinical because the steady (0 Hz) signals are integrated over Review, Marmor & Kessler, Morales, a longer time. Such effects are particularly likely under Gingell, Collins, Wicker, & Osterloh, ). Otherwise, S-cone isolation conditions because the intense long- Viagra is claimed to have little or no effect on visual wavelength background typically needed to desensitize performance. For example, in controlled clinical trials, the L- and M-cones also chromatically attenuates the doses of up to 200 mg of Viagra do not affect visual S-cone signal (e.g., Pugh & Mollon, We find acuity, visual fields, the Amsler grid, spatial contrast both frequency-dependent and frequency-independent sensitivity, or pupillary responses (Food and Drug changes in our data. Other explanations of these changes Administration Joint Clinical Review, ; are considered in the section.
Laties, Ellis, Koppiker, Patat, & Stuckey, ; Laties,Ellis, & Mollon, ). Transient, mild impairment ofcolor discrimination has been found with the Farnsworth–Munsell 100 test at the peak plasma levels with doses of 100 mg or more (Food and Drug Administration JointClinical Review, Laties et al., However, any effects of Viagra on chromatic discrimi- nation are inconsistent between subjects (see Laties &Fraunfelder, ; Laties & Zrenner, Marmor & The optical apparatus was a conventional Maxwellian- Kessler, ) and have not been confirmed in recent view optical system with a 2-mm entrance pupil illumi- double-blind studies (Birch, Toler, Swanson, Fish, & nated by a 900-W Xenon arc. Wavelengths were selected Laties, ; Ja¨gle et al., by the use of interference filters with full-width at half- Such standard visual tests, however, do not address the maximum bandwidths of between 7 and 11 nm (Ealing or most likely effect of Viagra, which is to disrupt light Oriel). The radiance of each beam could be controlled by adaptation by preventing the visual integration time from the insertion of fixed neutral density filters (Oriel) or by shortening enough to offset increases in light level. More the rotation of circular, variable neutral density filters appropriate tests for lengthened integration time include (Rolyn Optics). Sinusoidal modulation was produced by those that probe the temporal response, such as measures the pulse-width modulation of fast, liquid crystal light of temporal acuity or resolution (also known as critical shutters (Displaytech) at a carrier frequency of 400 Hz.
fusion frequency [cff]) and temporal modulation sensi- The position of the observer's head was maintained by a tivity (e.g., De Lange, ; Hecht & Verrijp, ; dental wax impression. The experiments were under Journal of Vision (2007) 7(8):4, 1–15 Stockman et al.
computer control. The apparatus is described in more on the two cone types because the M-cones are at a much detail elsewhere (Stockman, Plummer, & Montag, lower level of adaptation at high, 650-nm target radiancesthan are the L-cones. For the modulation sensitivitymeasurements, the 650-nm target was fixed at time-averaged radiances of 7.56 and 9.52 log quanta I sj1 I degj2 (0.43 or2.39 log10 photopic trolands).
The experimental conditions were chosen to measure the temporal properties of either the S-cones or theL- (and M-) cones.
Before making any measurements, subjects light adapted S-cone measurements to the background and target for 3 min. Subjects interacted A flickering target of 4- of visual angle in diameter and with the computer by means of buttons and received 440 nm in wavelength was presented in the center of a 9- feedback and instructions via tones and a computer- diameter background field of 620 nm. Fixation was central.
controlled voice synthesizer. Two types of temporal The 620-nm background field, which delivered 11.51 log10 measures were made: (a) temporal resolution or cff quanta I sj1 I degj2 at the cornea (4.95 log10 photopic measurements, in which observers adjusted the flicker trolands), selectively desensitized the M- and L-cones but frequency (at the maximum fixed stimulus modulation of had comparatively little direct effect on the S-cones.
92%) to find the frequency at which the flicker just For the cff measurements, the 440-nm target was modu- disappeared, and (b) modulation threshold measurements, lated at 92% contrast and varied in intensity in steps from in which observers adjusted the modulation (at a fixed approximately 6.5 to 11 log10 quanta I sj1 I degj2 (c. j1.13 frequency) to find the modulation at which the flicker just to 3.37 log10 photopic trolands). These conditions isolate disappeared. Modulation was varied by adjusting the the S-cone response up to a 440-nm target radiance of fraction of the light that is flickering, while keeping the about 10.5 log10 quanta I sj1 I degj2 (e.g., Stockman, time-average intensity of the light constant. Modulation MacLeod, & DePriest, ; Stockman, MacLeod, & thresholds enable sensitivity to be measured at frequencies Lebrun, Stockman & Plummer, The intrusion below the cff.
of the M-cones at the highest levels is clearly marked by a Each single measurement of modulation threshold or cff change in the appearance (hue and sharpness) of the target is the average of three settings. The mean data points for and by an abrupt increase in cff. For the modulation sensitivity the pre- or post-Viagra baseline measurements are the measurements, the 440-nm target was fixed at time-averaged average of at least three measurements, and the error bars radiances of 7.54, 8.82, or 9.75 log quanta I sj1 I degj2 (j0.09, 1.19, or 2.12 log10 photopic trolands).
A more objective measurement technique, such as two- alternative forced choice, was impractical in the context ofthese experiments because it is too slow to generate L-cone measurements quickly the amount of data required to explore dynamic A flickering target of 4- of visual angle in diameter changes in sensitivity following drug ingestion.
and 650 nm in wavelength was presented in the center ofa 9- diameter background field of 480 nm. Fixation wasagain central. The 480-nm background, which delivered 8.26 log quanta I sj1 I degj2 at the cornea (1.37 log10photopic trolands), served primarily to not only saturate The radiant fluxes of test and background fields were the rods but also selectively desensitize the M-cones at measured at the plane of the observer's entrance pupil lower target radiances.
with a UDT Radiometer that had been calibrated by the For the cff measurements, the 650-nm target was manufacturer against a standard traceable to the National varied in intensity from approximately 6.5 to 11.0 log Bureau of Standards and cross-calibrated by us. Neutral quanta I sj1 I degj2 (j0.63 to 3.87 log density filters, fixed and variable, were calibrated in situ 10 photopic trolands) and was modulated at 92%. These conditions isolate the for all test and field wavelengths used. Interference filters L-cone response over most of the 650-nm intensity range, were calibrated in situ with a spectroradiometer (Gamma but at high intensities, the M-cones are also likely to Scientific). Quoted radiances are time-averaged values.
contribute to flicker detection (Stiles, ; see Figure 1bof Stockman & Mollon, ). We were not concernedabout the possibility of a mixed M- and L-cone response at higher levels because there is no reason to suppose thatViagra has a selective effect on either the M- or the L-cones.
Four male observers (authors A.S., L.T.S., A.T., and However, we note that Viagra might have differential effects G.J.) participated in these experiments. All observers had Journal of Vision (2007) 7(8):4, 1–15 Stockman et al.
normal color vision according to standard tests. A way introduces extra variability into the drug group.
correction lens of +5D was used for A.T. L.T.S. and A.S.
Given that this extra variability works against rejection of are highly experienced psychophysical subjects. A.T. and the null hypothesis (that Viagra has no effect on visual G.J. were comparatively naive at the start of the experi- performance), the tests may be deemed very conservative.
ments. All four subjects were in good health with no Specifically, the data were analyzed with a two-way known cardiovascular or other risk factors. These studies ANOVA, with radiance or frequency as one factor and conform to the standards set by the Declaration of drug condition as a second factor. Drug condition was Helsinki, and the procedures have been approved by local considered as a two- or three-level factor: predrug, drug, ethics committees at Moorfields Eye Hospital and at and postdrug (if available). A p value G.05 was assumed University College London. The local ethics committee to be significant.
restricted us to making measurements on ourselves.
Subjects orally ingested therapeutic, 100-mg doses of Viagra (sildenafil citrate). Doses were typically taken in S-cone cff versus intensity functions the morning with water. No food was eaten from theprevious evening until the end of the measurements to Our initial measurements of temporal resolution were minimize interference with its absorption. Successive made under experimental conditions chosen to isolate the doses were separated by at least 1 week. Only 100-mg S-cone response, partly because of the subjective evidence doses were taken. The dose numbers given in each figure for a blue tinge to vision following Viagra ingestion (e.g., refer to separate trials, before which a single 100-mg dose Laties & Zrenner, ). S-cone-mediated cff, plotted as a was ingested. Frequently, different types of measures were function of the radiance of a 440-nm target, is shown in interleaved during a single trial.
for G.J. (top left panels), L.T.S. (bottom left), Different dosages vary slightly in their effects on visual A.S. (top right), and A.T. (bottom right). The symbols in performance, which is presumably related to variations in and the other figures (except ) refer to the Viagra plasma concentration (see Ja¨gle, Ja¨gle, Se rey, & the dose trial number given to each subject: Dose 1 Sharpe, Ja¨gle et al., ). An example of different (squares), Dose 2 (triangles), Dose 3 (circles), Dose 4 dose effectiveness can be seen in the cff data for L.T.S. in (inverted triangles), and Dose 5 (hexagons, only in . Although the effects of Viagra are consistent In each case, the dose was 100 mg. The time across doses, Dose 3 (circles) is clearly less effective than after dose ingestion is color coded according to the the other doses. In addition, the time course of the effect spectral key (the time given is the midpoint of each run, varies across subjects. For example, subjects L.T.S. and which typically lasted 12 min), which runs from violet for G.J. show measurable visual losses after taking Viagra at short times after drug ingestion to red for long. The larger shorter postingestion intervals than does A.T. Although panel for each subject shows the subject's cff or the thresholds did not always recover to their baseline modulation sensitivity functions. The smaller panel shows values during the course of our measurements, which were the losses in cff or the losses in modulation sensitivity usually limited to 3 hr after drug ingestion, their recovery relative to the mean pre- and post-Viagra control data. The was always complete by the time of the post-Viagra mean losses, averaged across drug data obtained between measurements, which were usually made 1–3 days 20 and 300 min following Viagra ingestion, are shown by following a dose.
the red lines. The same window of 20 to 300 min was used For a particular set of measurements, the pre-Viagra for the two-way ANOVA.
measurements were made on separate days before the With increasing target radiance, the baseline (pre- and Viagra measurements, whereas the post-Viagra measure- post-Viagra) S-cone cff functions for each subject (dotted ments (if carried out) were made at least 3 days after them.
open and gray circles) are typical for S-cone-mediateddetection (Marks & Bornstein, Stockman et al.,Stockman & Plummer, ). The fastest rate of Statistical tests flicker that can just be seen increases steadily withincreasing radiance over the first 2.5 log units but then To test for an effect of Viagra on each subject, we reaches a plateau at between 19 and 25 Hz. The functions adopted the conservative test of collapsing the drug data thereafter remain constant or fall slightly before rising from 20 to 300 min following drug ingestion into a single again at the highest levels. The slight fall is caused by a group and then compared this group with the control, saturation of the S-cone response that occurs at high nondrug groups. Because the influence of Viagra on vision S-cone adaptation levels on the intense orange field varies between 20 and 300 min as well as between required to isolate the S-cones (Mollon & Polden, different dose trials (see below), collapsing the data in this Stockman & Plummer, ; Stromeyer, Kronauer, & Journal of Vision (2007) 7(8):4, 1–15 Stockman et al.
Figure 1. S-cone cff control and drug data for G.J. (upper left panels), L.T.S. (lower left), A.S. (upper right), and A.T. (lower right). The pre-Viagra cff data (dotted open circles) are the average of three or more separate measurements made on days before ingestion of a 100-mgdose of Viagra, whereas the post-Viagra cff data (dotted gray circles), measured for only L.T.S. and G.J., are the average of three or moreseparate measurements made at least 3 days after drug ingestion (the error bars are T1 SE). The shapes of the colored symbols in thisfigure and in and denote the dose number, which correspond to separate trials: Dose 1 (squares), Dose 2 (triangles), Dose 3(circles), and Dose 4 (inverted triangles). The time after dose ingestion is coded by the color of the symbols (see key) and indicated in thelegend for each subject. The smaller panels highlight the losses in cff for each subject relative to the subject's mean pre- and post-Viagradata (black line). The red line indicates the mean loss averaged over time from 20 to 300 min after Viagra ingestion. The black error barsare T2 SE for the combined pre- and post-Viagra data.
Journal of Vision (2007) 7(8):4, 1–15 Stockman et al.
significant for G.J., F(2, 166) = 183.4, p G .001, L.T.S.,F(2, 159) = 154.8, p G .001, and A.T., F(1, 84) = 5.1,p = .027, but insignificant for A.S., F(1, 84) = 2.3, p = .133.
Given the large variability between observers, we decided to run a double-blind placebo control experimenton the two more affected subjects, L.T.S. and G.J., to ruleout the possibility that extraneous factors, such as thesubject's expectations, had affected the Viagra measure-ments. However, we should point out that the ultimatereliability of placebo controls is questionable with drugssuch as Viagra, which, in our subjects, frequently hadnoticeable side effects (e.g., dry mouth, headache, andindigestion). G.J., in particular, was sometimes aware ofViagra-induced visual haloes and color changes.
shows the results of the placebo control experiment. Four trials were carried out: Two of whichwere preceded by a 100-mg dose of Viagra (correspondingto Doses 6 and 7 for these subjects), and two of which werepreceded by a placebo dose. Drug and placebo trials werechosen randomly in the order listed in the figure key, andneither the experimenter nor the subject was informedwhich had been taken until after the conclusion of theentire control experiment. Measurements were made either60 or 120 min following drug ingestion.
Both subjects show substantial losses of S-cone cff during the drug trials but not during the placebo trials. Thelosses clearly mirror those found for each subject in.
We note that the absolute cff measurements in and particularly those for L.T.S., differ by a few hertz.
In general, we found that S-cone cff measurements arestable over short periods of a week or so, as shown by thestability of the pre- and post-Viagra measurements, butthat they can vary by several hertz over longer periods of Figure 2. S-cone cff data from four (1–4) trials for L.T.S. (top a month or more. The measurements in and panel) and G.J. (bottom panel), measured 60 or 120 min after the were separated by more than 2 years. Clearly, for both ingestion of either a placebo or a 100-mg dose of Viagra (see G.J. and L.T.S., the Viagra-induced losses are substan- key). The mean placebo cff values are indicated by the continuous tially larger than any long-term variability.
black lines, and the mean Viagra values, which include both the60- and the 120-min post-Viagra measurements, are indicated bythe continuous red lines.
S-cone modulation sensitivity functions shows temporal modulation sensitivities for Madsen, whereas the final rise is due to the three of the observers: L.T.S. (left panels), G.J. (center M-cones taking over detection (see Figure 4 of Stockman & panels), and A.S. (right panels), measured at low (440-nm Plummer, ). The S-cone cff functions for all four target radiance of 7.54 log quanta I sj1 I degj2, top panels), subjects show some losses in cff following ingestion of a medium (8.82 log quanta I sj1 I degj2, middle panels), and standard 100-mg dose of Viagra. For G.J. and L.T.S., the high (9.75 log quanta I sj1 I degj2, bottom panels) S-cone losses are found across all target radiances, increasing adaptation levels. The symbols and symbol colors are as slightly as the target radiance increases and reaching 11 Hz described in . In all three observers, as the S-cone for L.T.S. and 12 Hz for G.J. In contrast, for A.T. and A.S., adaptation level rises (as it does in successive panels minimal losses are found at low target radiances. For subject downward for each subject), the baseline (pre-Viagra) A.T., the losses increase with radiance, reaching approxi- sensitivities exhibit a relative improvement in sensitivity mately 10 Hz at the S-cone saturating levels, whereas for at higher frequencies. Such changes are consistent with a A.S., they reach only approximately 5 Hz.
speeding up of the S-cone visual response with adaptation Statistical analyses using a two-way ANOVA reveal and a shortening of the integration time (e.g., De Lange, that the main drug effect of Viagra on S-cone cff was Kelly, ; Matin, Stockman et al., Journal of Vision (2007) 7(8):4, 1–15 Stockman et al.
Journal of Vision (2007) 7(8):4, 1–15 Stockman et al.
The general form of the baseline functions show a good Guth, Alexander, Chumbly, Gillman, & Patterson, deal of variability, across observers, but they are consistent Luther, Schro¨dinger, Smith & Pokorny, with previous measurements (e.g., Stockman et al., ; Walls, If, however, the M- or L-cone cff functions are Wisowaty & Boynton, also compromised by Viagra, the behavioral consequences The effect of Viagra on S-cone modulation sensitivity could be of more concern.
was significant at the low level for G.J., F(1, 21) = 71.4, L-cone-mediated cff was measured in all four subjects p G .001, and L.T.S., F(1, 44) = 42.0, p G .001, but as a function of the 650-nm target radiance on a moderate- insignificant for A.S., F(1, 20) = 0.0, p = .882. Its effect intensity 480-nm background. The results are shown in at the medium level was significant for all three subjects: for G.J. (upper left panels), L.T.S. (lower left G.J., F(1, 44) = 118.4, p G .001, L.T.S., F(1, 77) = 69.5, panels), A.S. (upper right panels), and A.T. (lower right p G .001, and A.S., F(1, 33) = 122.9, p G .001; and, likewise, at the high level: G.J., F(1, 43) = 76.4, p G .001, With increasing target radiance, the baseline L-cone cff L.T.S., F(1, 78) = 52.3, p G .001, and A.S., F(1, 33) = functions for each subject (dotted open and gray circles) 97.7, p G .001. Thus, following ingestion of Viagra, the rise steadily until reaching a plateau between 38 and 52 Hz, three observers show losses of modulation sensitivity in accord with previous L- and M-cone measurements consistent with the changes in their cff settings. L.T.S.
(Hecht & Verrijp, As compared with the S-cone and G.J. lose sensitivity at all three adaptation levels, functions shown in the L-cone cff functions rise whereas A.S. loses sensitivity only at the two highest more steeply and reach a much higher plateau. These levels (cf. there is little change in his cff at differences are due mainly to postreceptoral rather than to adaptation levels below 9.00 log quanta I sj1 I degj2).
receptoral differences between the cone systems (e.g., see The S-cone sensitivity losses are not confined to the Schnapf, Nunn, Meister, & Baylor, Stockman et al., highest frequencies at each level, which correspond to Stockman & Plummer, partly because the the cff settings; they also occur at lower frequencies. The S-cone signals are mainly confined to more sluggish nature of the losses, which are highlighted by the red lines chromatic pathways.
in the smaller panels of , varies across subjects and The effect of Viagra on L-cone cff was significant for levels. In most cases, the logarithmic losses tend to G.J., F(1, 53) = 85.97, p G .001, L.T.S., F(2, 99) = 257.0, increase slightly with frequency, whereas in others, they p G .001, and A.T., F(2, 134) = 9.5, p G .001, but are roughly constant with frequency or slightly decrease.
insignificant for A.S., F(2, 127) = 1.0, p = .377. Finding a These differences may reflect the complexity of the effects significant effect for A.T. was unexpected. However, a that Viagra is likely to have on S-cone sensitivity under post hoc pairwise comparison (Scheffe´) of his data reveals these conditions, which can be either direct or indirect.
that the significant difference is only between the postdrug The Viagra-induced steepening of the modulation sensi- and the drug trials (p = .015), not between the predrug and tivity functions is consistent with the lengthening of the drug trials (p = .948).
integration time of the S-cone signal, while the frequency- Importantly, the severity of the adverse effects of Viagra independent losses across frequency are consistent with an on S-cone-mediated vision for each of the four observers is increase in the effectiveness of the steady components of mirrored in its effect on their L-cone-mediated vision. For the target and the background. In the latter case, the in- subjects L.T.S. and G.J., for whom Viagra caused a sensi- creased effectiveness of the 610-nm background on S-cone tivity loss over the entire S-cone cff, Viagra causes a com- sensitivity may be mostly indirectVby way of a postrecep- parable loss over the entire L-cone range. Like the S-cone toral, chromatically opponent nonlinear attenuation (e.g., cff data, the losses increase slightly as the target radiance Pugh, ; Pugh & Mollon, Stiles, Other increases, reaching approximately 10 Hz for L.T.S. and possibilities are considered in the section.
5 Hz for G.J. For A.T. and A.S., for whom Viagra One way to disambiguate these factors is to look at affected mainly the plateau of their S-cone cff functions L-cone modulation sensitivities, which extend to much (see Viagra had little effect on L-cone cff.
higher frequencies and are likely to be less subject toopponent attenuation, thus making any frequency-dependentsensitivity losses much more obvious.
Figure 3. S-cone modulation threshold control and drug data forL.T.S. (left panels), G.J. (central panels), and A.S. (right panels),measured at 440-nm target radiances of 7.54 (upper panels), 8.82 L-cone cff versus intensity functions (middle panels), and 9.75 (lower panels) log quanta I sj1 I degj2.
The larger panels show the S-cone modulation thresholds. The A visual loss restricted to S-cone-mediated vision might smaller panels highlight the changes in threshold for each subject not have particularly serious behavioral consequences, relative to the subject's mean pre-Viagra data (black continuous given that the S-cone signals predominantly feed into lines). The red lines indicate the mean losses averaged over sluggish chromatic channels rather than the brisk luminance time from 20 to 300 min after Viagra ingestion. The error bars channel responsible for flicker and motion perception are T1 SE in the larger panels and T2 SE in the smaller panels.
(e.g., Boynton, De Lange, Eisner & MacLeod, Other details are as described in Journal of Vision (2007) 7(8):4, 1–15 Stockman et al.
Figure 4. L-cone cff control and drug data for G.J. (upper left panels), L.T.S. (lower left), A.S. (upper right), and A.T. (lower right). The largerpanels show the L-cone cff data. The smaller panels highlight the losses in cff for each subject relative to their mean pre- and post-Viagradata (black continuous line). The error bars are T1 SE in the larger panels and T2 SE in the smaller panels. Other details are as describedin G.J. did not make the post-Viagra measurements.
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Figure 5. L-cone modulation threshold control and drug data for L.T.S. (left panels) and G.J. (right panels), measured at 650-nm targetradiances of 7.56 (upper panels) and 9.52 (lower panels) log quanta I sj1 I degj2. The larger panels show the L-cone modulationthresholds. The hexagons indicate the measurements that were made following ingestion of Dose 5 of Viagra. Dotted symbols have beenincluded where necessary to distinguish between two runs made during the same color-coded time window. The smaller panels highlightthe changes in threshold for each subject relative to the subject's mean pre-Viagra data (black continuous lines). The red lines indicate themean loss between 20 and 300 min after drug ingestion. The error bars are T1 SE in the larger panels and T2 SE in the smaller panels.
Other details are as described in Journal of Vision (2007) 7(8):4, 1–15 Stockman et al.
L-cone modulation sensitivity functions laboratory for several hours postingestion but probablyonly under conditions of reduced visibility when objects are shows temporal modulation sensitivities for already near contrast threshold (e.g., under foggy condi- L.T.S. (left panels) and G.J. (right panels), measured at low tions or under conditions of reduced illumination). In the (650-nm target radiance of 7.56 log quanta I sj1 I degj2, two remaining subjects (A.S. and A.T.), losses were top panels) and high (9.52 log quanta I sj1 I degj2, bottom restricted to more extreme conditions of S-cone isolation panels) L-cone adaptation levels. Details of the colored and strong chromatic adaptation, which are unlikely to be symbols are as described in The hexagons encountered outside the laboratory.
indicate that this was Dose 5 for both observers. Thebaseline L-cone modulation sensitivities for both L.T.S.
and G.J. (dotted circles) show a marked relative improve- ment in modulation sensitivity to higher frequenciesbetween the two levels but little change at low frequen- The ingestion of Viagra provides a unique opportunity cies, as expected (e.g., De Lange, Kelly, ; for pharmacologically modifying the human visual trans- Matin, Such improvements with adaptation accord, duction cascade and determining the consequences of the like the S-cone improvements in with a speeding inhibition of PDE6* on the transmission and regulation up of the visual response and a shortening of the of the human light response. Our findings, which show integration time with increasing light level.
both frequency-dependent and frequency-independent The effect of Viagra on L-cone modulation sensitivity Viagra-induced losses, are consistent with Viagra inter- was significant for G.J., F(1, 70) = 16.6, p G .001, and fering with the ability of PDE6* to shorten the time over L.T.S., F(1, 102) = 6.4, p = .013, at the high level, as which the visual system integrates signals as the light well as for G.J., F(1, 51) = 816.1, p G .001, and L.T.S., level increases (Stockman et al., ). The S-cone F(1, 59) = 219.9, p G .001, at the low level.
modulation sensitivity losses shown in are more In agreement with the Viagra-induced changes to their L-cone cff data, both L.T.S. and G.J. show a loss of Changes in the time constant of the visual response, L-cone modulation sensitivity after ingesting Viagra at which affect sensitivity, should also affect the delay of the both the low and the high L-cone adaptation levels. The visual response. There is one psychophysical study- sensitivity losses at the high level, which extend to 40 or available only in abstract formVin which the effects of 45 Hz, are consistent with a slight steepening of the high- Viagra upon temporal persistence have been investigated frequency slope (see the threshold losses as highlighted in (Mollon, Regan, Foo, & Morris, ). Performance on a the smaller panels), a characteristic signature of a length- perceptual grouping task that depended on visual persis- ening of the integration time of the visual response (see tence for its successful execution, modestly improved above). In Stockman, Sharpe, Tufail, Kell, and Jeffery following ingestion of 100 mg of Viagra. This increase in (these losses were modeled by assuming that the visual persistence is consistent with the detriments in change in time constant occurred at a single integrating temporal acuity and sensitivity that we report here.
stage with an exponential decay (which was assumed to Having an integration time that is ill matched to the reflect the activity of some biochemical process, such as environmental light level will, in general, degrade visual the hydrolysis of cGMP catalyzed by PDE6*). Viagra was performance, unless a special task that takes advantage of found to lengthen the integration time roughly from the added visual delay is devised.
approximately 6.9 to 12.6 ms, and, in addition, overall Human electroretinogram (ERG) recordings are another sensitivity was reduced by 0.34 log10 unit. The overall potential source of evidence about the effects of Viagra on reduction in sensitivity was attributed to the increased the delay of the visual response. Unfortunately, the effects effectiveness of the steady components of the target and of Viagra on the ERG are somewhat inconsistent, and any background acting on an adaptational nonlinearity (see, effects that have been found have typically been analyzed for details, Stockman et al., in terms of changes in implicit time and in amplitude ofthe a- and b-wave components. Although transientreductions in the rod (Vobig et al., ) and cone (Luu,Chappelow, McCulley, & Marmor, ERG ampli- tudes have been reported, they have not been confirmedby more recent studies (Ja¨gle et al., ), whichfound only small, insignificant changes. On the other Viagra caused some degradation of visual performance hand, several studies have reported small but significant in all four subjects tested. In two of the four subjects (L.T.S.
prolongations in the implicit times of the cone ERG and G.J.), the losses for cone-detected flicker were responses (Ja¨gle et al., ; Luu et al., and ubiquitous, occurring across cone types, flicker frequen- prolongations in some but not all measures of rod ERG cies, and adaptation levels. For such individuals, Viagra (Ja¨gle et al., These results are important in the may impair some behavioral tasks performed outside the context of this work for two reasons. First, they suggest Journal of Vision (2007) 7(8):4, 1–15 Stockman et al.
that the visual side effects caused by Viagra are indeed by Viagra will, if anything, generally increase flicker retinal in origin (and, in the case of the a-wave data, sensitivity, which is opposite to what we find, and mainly receptoral) rather than being attributable to some presumably may actually mitigate losses caused by the nonspecific attentional deficit, which is central in origin.
inhibition of PDE6.
Second, they suggest that the Viagra-induced lengtheningof the time constant of temporal integration implied byour results also causes, as expected, increases in the delay Higher level effects of the visual response.
We cannot exclude the possibility that some of the Viagra-induced losses may be due to high-level drugeffects, such as attentional deficits or general feelings of Other considerations malaise. However, the finding by Mollon et al. (that Viagra can improve performance in a perceptual groupingtask argues against the prevalence of a general, overall The S-cone sensitivity measured on an intense long- nonspecific loss in performance.
wavelength background field will depend upon the directeffects of the target and background lights on the S-conesand, because of chromatically opponent attenuation, upon Nonarteritic anterior ischemic optic neuropathy the indirect effects of those lights on the L- and M-cones.
Our failure to find an effect of Viagra at lower S-cone Viagra has been implicated as a possible cause of adaptation levels for A.S. and A.T. might be due to blindnessVdiagnosed as nonarteritic anterior ischemic Viagra having no effect on their L-cones, the signals optic neuropathyVin 14 cases of men who had preexist- from which, because of the intense 620-nm background, ing hypertension, diabetes-elevated cholesterol, or heart are much larger than those from the S-cones at lower disease (e.g., Cunningham & Smith, ; Pomeranz & 440-nm radiances, rather than to Viagra having no effect Bhavsar, ; Pomeranz, Smith, Hart, & Egan, on their S-cones. Consequently, both the S-cone and These cases are presently under investigation by the Food the L-cone data might be consistent in showing that in and Drug Administration. Although any link to the visual A.S. and A.T. Viagra affects only the S-cones, whereas side effects generated by Viagra, or indeed to Viagra in G.J. and L.T.S., it affects both the L- and S-cones. Why itself, is weak, a better understanding of the nature and such a difference should occur, however, is not easily extent of the visual side effects has become more pressing.
Cardiovascular changes and flicker Flicker sensitivity has been related to some systemic cardiovascular measures, but the results are complex.
This work was supported by the Wellcome Trust and Eisner and Samples (reported that the ratio of mean Fight for Sight. We thank Bruce Henning and Rhea Eskew arterial blood pressure to heart rate was inversely related for helpful advice.
to flicker sensitivity on some adapting backgrounds,whereas Gutherie and Hammond reported that Commercial relationships: none.
resting systolic blood pressure was positively related to cff Corresponding author: Andrew Stockman.
measured without a background. Other work has shown that luminance or chromatic flicker itself can increase Address: Institute of Ophthalmology, University College retinal vessel diameter and retinal blood flow (e.g., London, 11–43 Bath Street, London EC1V 9EL, England.
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